Complex stability constants (Ks/M1), enthalpy (H°/(kJmol1)), and entropy changes (TS°/(kJmol1)) for intermolecular complexation of bile salts with natural β-CD and its mono-modified derivatives in aqueous solution
\r\n\tAll book chapters are produced by forward-thinking specialists in the area of renewable energy and smart grids, with detailed analysis and/or case studies. This book is intended to serve as a reference for graduate students, academics, professionals, and system operators.
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He is currently a Chair Professor of Electrical Power Engineering with Aston University, Birmingham, UK, and also a Marie Curie Fellow with Massachusetts Institute of Technology, Cambridge, MA, USA. His research interests include fault analysis and condition monitoring of electric machines and power electronics for renewable energy.",institutionString:"Aston University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Aston University",institutionURL:null,country:{name:"United Kingdom"}}}],coeditorOne:{id:"321201",title:"Dr.",name:"Shubo",middleName:null,surname:"Hu",slug:"shubo-hu",fullName:"Shubo Hu",profilePictureURL:"https://mts.intechopen.com/storage/users/321201/images/system/321201.jpg",biography:"Dr. Shubo Hu received a B.S. degree and a Ph.D. degree in Electrical Engineering from Dalian University of Technology, Dalian, China, in 2012 and 2019, respectively. Currently, she is an academic in the Faculty of Electronic Information and Electrical Engineering, Dalian University of Technology, China. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"39515",title:"Thermodynamics of Resulting Complexes Between Cyclodextrins and Bile Salts",doi:"10.5772/51406",slug:"thermodynamics-of-resulting-complexes-between-cyclodextrins-and-bile-salts",body:'Cyclodextrins (CDs), a class of macrocyclic oligosaccharides consisting of six, seven, or eight glucose units linked by α-1,4-glucose bonds, have been widely used as receptors in molecular recognition in the field of supramolecular chemistry because they are able to form inclusion complexes with hydrophobic guests in aqueous solution owing to their hydrophilic outer surface and their lipophilic cavity [1–3]. Therefore, much effort has been devoted to the design and synthesis of a wide variety of cyclodextrin (CD) derivatives to explore their binding behaviors for model substrates [4]. In order to further explore their inclusion complexation mechanism, most of these studies have been focused on the binding modes and complexation thermodynamics based on CDs and their derivatives in recent years [5]. Among the numerous guests researched, bile salts attracted much more attention because they are one kind of important surfactant-like biological amphipathic compounds possessing a steroid skeleton, which have distinctive detergent properties and play an important role in the metabolism and excretion of cholesterol in mammals [6]. For example: the thermodynamics and structure of inclusion compounds of glyco- and tauro-conjugated bile salts with CDs and their derivatives have been studied by Holm et al.during the last years [7–11]; the interactions of different kinds of bile salts with β-CD dimers linked through their secondary faces have been investigated by Reinhoudt and Vargas-Berenguel et al. [12–14]. It has been demonstrated that the formation of inclusion complexes between CDs and guest molecules is cooperatively governed by several weak forces, such as van der Waals interactions, hydrophobic interactions, hydrogen bonding, electrostatic interactions, and every weak force does its contribution to the complexation. In this chapter, the related investigations concerned on the binding modes, binding abilities, molecular selectivities and their thermodynamic origins of CDs and their derivatives with four typical bile salts (Cholate (CA), Deoxycholate (DCA), Glycocholate (GCA), and Taurocholate (TCA)) (Figure 1) have been summarized, which will be discussed from the aspect of the types of host molecules: (1) natural CD series; (2) modified CD series; (3) bridged CD series. This summary is helpful to improve understanding ofthe correlation between the structural features and molecular-recognition mechanism from thermodynamic viewpoints, and further guide its biological, medicinal and pharmaceutical applications in the future.
Molecular structures of four typical bile salts
Since two protons located closely in space (the corresponding internuclear distance is smaller than 3–4 Å) can produce NOE (Nuclear Overhauser Effect) cross-peaks between the relevant protons in NOESY (Nuclear Overhauser Effect Spectroscopy) or ROESY (Rotating Frame Overhauser Effect Spectroscopy) spectra, 2D NMR spectroscopy has become an important method for the investigation of the interaction between different kinds of CDs and guest molecules. It is well-known thatonly H3, H5, and H6 of CDs can give cross-peaks foranalyzing host–guest interactions, as H2 and H4 are notfacing to the inner cavity and H1 is affected by D2O. For example, the ROESY study on the resulting complex of natural β-CD 1(Figure 2) with CA has been reported by Tato et al. [15,16]. The results successfully indicated that in the 1:1 complex between 1 and CA the steroid body entered forward into the inner cavity of 1 by the side of the secondary hydroxyl groups, with the side chain folded toward the steroid body, i.e., rings D and C are totally and partially included, respectively. Therefore, the binding modes of bile salts with different kinds of CDs have been widely deduced by 2D NMR spectroscopy during the last years.
Structure of natural β-CD
The microcalorimetric titrations can be used to simultaneously determine the enthalpy and equilibrium constant from a single titration curve. Titrations were performedbelow the critical micelle concentration of bile salts.In each run, a solution of the host (guest) molecules in syringe was sequentially injected into thecalorimeter sample cell containing a solution of guests (hosts). Each addition of hosts (guests) into the sample cell gave rise to a heat ofreaction, caused by the formation of inclusion complexesbetween hosts and guests. The heats of reactiondecrease after each injection because less and lessmolecules in cell are available to form inclusion complexes.A control experiment was performed to determine the heatof dilution by injecting a host (guest) solution into a pure solution containing no guest (host) molecules. The dilution enthalpywas subtracted from the apparent enthalpy obtained in eachtitration run, and the net reaction enthalpy was analyzed byusing the “one set of binding sites” model. This model will work for anynumber of sites N if all sites have the same Ks and H°. Inthis case, the total heat Qwas fitted via a nonlinear least-squaresminimization method to the total host concentrationin cell (Mt) using the following equation:
where N is the number of binding sites of host, Xt is the totalconcentration of guests in cell and Vo is the cell volume. The value of Q above can be calculated (for any designated valuesof N, K, and H) at the end of the ith injection and designatedQ(i). Then the correct expression for the heat released, Q(i),from the ith injection is
where dViis the volume of titrant added to the solution. Alongwith obtaining of Ks and H° in this fitting program, the Nvalue in eq 1 can also be obtained, which represents thenumbers of guests bound to one host molecule.
The ORIGIN software (Microcal), used for the calculationof the binding constant (Ks) and standard molar reaction enthalpy(H°) from the titration curve, gave the relevant standardderivation on the basis of the scatter of data points in asingle titration experiment. The binding stoichiometry was alsogiven as a parameter when fitting the binding isotherm. Knowledge of the binding constant (Ks) andmolar reaction enthalpy (H°) enabled the calculation of thestandard free energy of binding (G°) and entropy change(S°) according to
where R is the gas constant and T is the absolute temperature.
The microcalorimetric experiments of natural β-CD 1with bile salts (CA, DCA, GCA, and TCA) showed typical titration curves of 1:1 complex formation [17]. The stoichiometric ratios observed from curve-fitting results of the binding isotherm fell within the range of 0.9–1.1. This clearly indicated that the majority of the inclusion complexes had a 1:1 stoichiometry of bile salts and 1.
Thermodynamically, the binding behaviors of bile salts by 1were entirely driven by favorable enthalpy changes accompanied by small unfavorable entropy changes, which are attributed to the predominant contribution of the van der Waals interactions arising from the size/shape fit and geometrical complement between host and guest and to the accompanying decreases in translational and structural freedoms upon complexation.
As can be seen from Table 1, the enthalpy change for the complexation of 1 with DCA is more favorable than that with CA, which directly contributes to the increased complex stability. It is reasonable that DCA possesses a more hydrophobic structure due to the absence of C-7 hydroxyl group as compared with CA, as a result, it is easier to bind into the cavity of 1, which leads to more favorable hydrophobic and van der Waals interactions and gives larger enthalpy and entropy changes. However, the enhanced favorable entropy gain by the desolvation effect may be canceled by the unfavorable entropy change caused by the structural freezing of the resulting complexes of 1 and DCA. Therefore, the stronger interaction between 1 and DCA only shows the larger negative enthalpy change, directly contributing the relatively larger complex stability constant. Meanwhile, 1 shows a lower binding ability upon complexation with GCA and TCA. Compared with 1 and CA, the complexation of 1 with GCA and TCA exhibit similar enthalpy changes but much more unfavorable entropy changes. The more polar side chains of GCA and TCA may be the reason for it.
The ROESY study on the resulting complex of 2(Figure 3) with CA has been reported by Tato et al. [15]. The results exhibited different interactions of the side chain of CA with H5 and H6 of 2 from natural β-CD 1. The facts indicated that the side chain was unfolded, with the negative carboxylate group moving toward the positive protonated amino group, and the side-chain elongation produced a deeper penetration of the steroid body in the inner cavity of 2.
The ROESY experiments of modified β-CD 3 in the presence of CA or DCA have been performed in D2O by Liu et al. [17]. The results indicate that the D-ring of CA is accommodated shallowly in the cavity and CA enters 3 from the second side of CD with the side chain and D-ring. At the same time, the side chain with the negative carboxylate group of CA moves toward the positive protonated amino group of 3. For the resulting complex of DCA–3, the ROESY spectrum exhibits entirely different NOE cross-peaks and the D-ring of DCA is included within the cavity of CD from the primary side of CD. Meanwhile, the ethide protons of chiral tether interact with H6 of CD.
2D ROESY NMR experiment of 5 and CA has also been performed by Liu et al. in D2O to investigate the binding mode between bile salt and CD [18]. The results show that steroid body enters the CD cavity from the second side with its tail and D-ring parts.
In host 8, the adenine group is deeply inserted into the β-CD cavity with an orientation parallel to the C7 axis of β-CD while the thymine and uracil groups are shallowly inserted in the β-CD cavity with an orientation perpendicular to the C7 axis of β-CD [19]. As a result, upon complexation with DCA guest, the deeply included adenine group in host 8 should be expelled from the cavity upon complexation with DCA guest, however, the shallowly included thymine and uracil groups in hosts 9 and 10 are hardly influenced by the inclusion of DCA guest.
The binding modes of L/D-Trp-β-CD (11 and 12) with bile salts have been examined by Liu et al. by 2D ROESY NMR experiments [20]. For L-Trp-β-CD (11), the results show that in the absence of guest, L-Trp residue is only shallowly included or perching on the rim of the CD cavity. However, in the presence of DCA,the D-ring of DCA is close to the wide end of CD cavity, and the D-ring of DCA and the side chain is co-included in the same cavity from the primary side of 11. For D-Trp-β-CD (12), the 2D NMR results indicate that the D-Trp residue attached to β-CD is more deeply self-included than the corresponding L-Trp residue in the absence of guest. However, in the presence of DCA, the carboxylate side chain and D-ring of DCA penetrate into the CD cavity from the secondary side shallowly.
The binding modes of L/D-Tyr-β-CD (13 and 14) with bile salts have further been examined by Liu et al. by 2D ROESY NMR experiments [21]. The results show that the L-tyrosine moiety was self-included in the β-CD cavity from the narrow opening. The DCA guest entered the β-CD cavity from the wide opening with the tail and the D ring and coexisted with the L-tyrosine substituent in the β-CD cavity to form a cooperative inclusion manner. For D-tyrosine-modified β-CD (14), the D-tyrosine substituent was deeply self-included in the β-CD cavity and might be located in the center of the β-CD cavity. Upon complexation with DCA, the D-tyrosine substituent of 14 wouldpartially move out of the β-CD cavity. Compared with DCA + 13 complex, DCA penetrated into the β-CD cavity of 14 more deeply (Figure 4).
Structures of mono-modifiedβ-CD derivatives
The possible binding modes of 11–14 (11 (c); 12 (d); 13 (a); 14 (b)) with DCA
The microcalorimetric experiments of aminated β-CDswith bile salts clearly indicate that the majority of the inclusion complexes had a 1:1 stoichiometry [17]. Thermodynamically, the binding constants of 4 upon inclusion complexation with DCA, GCA, and TCA are less than that with natural β-CD 1. It is reasonable that modified β-CD 4decreased the microenvironment hydrophobicity of natural β-CD cavity due to the hydrophilic carboxylic group in the sidearm, and at the same time there is electrostatic repulsion between the anionic carboxylate at the sidearm of 4 and anionic carboxylate or sulfonate of bile salts. Unexpectedly, the resulting complex stability of aminated β-CD 4 with CA is higher than that of native β-CD 1,which is mainly attributed to the more favorable enthalpy change. The possible reason may be the enhanced cooperative van der Waals, hydrogen-bonding, and electrostatic interactions exceeding the decreased hydrophobicity of the interior of β-CD 4.
Positively charged monoamino-modified β-CD 2 and modified β-CD 3 possessing an additional binding site in the chiral arm evidently enhance the molecular bindingability and selectivity towards CA and DCA compared tothose for native β-CD 1, which is mainly attributed to the more favorable enthalpy change accompanied with unfavorable entropy change [17]. The more favorable enthalpy change most likely originates from effective electrostatic interactions and theadditional binding site of hydroxyl group. In addition, the unfavorable entropy change is likely to originatefrom the conformation fixation of host and guest and the rigidcomplex formation upon complexation. β-CD derivatives 2 and 3 give a lower binding ability upon complexation with GCA and TCA as compared to the complexation with CA and DCA, which is similar to that for the complexation of β-CD1 and derivative 4. For the same reason, the more polar side chains at C23 for GCA and TCA remarkably affect their binding thermodynamics.
A study of 13C chemical shifts as a function of concentration at different pH values has been performed by Tato et al., which shows a different behavior of complexation for CA and DCA with 5 resulting in 1:1 and 1:2 inclusion complexes [22]. However, the complexation phenomena do not depend on the pH of the solution. 13C NMR chemical shifts of the host and guest molecules change on passing from the free to the complexed state. The side chains in 5 at position C-6 have a significant effect on the complexation process with the bile salts. The ROESY experiments confirm the overlap of the CA molecule with 5 resulting a 1:1 inclusion complex, while in the case of DCA molecule, the first molecule of 5 encapsulates the bile salt to a larger extent than the second molecule of 5, resulting a 1:2 inclusion complex. Hence the most important factors for the formation of a stable inclusion complex are the relative size of 5 and the bile salt molecules, the nonpolar cavity of 5, the hydrophobicity of the bile salts, and the presence of an electrostatic environment outside the toroidal cavity.
The nucleobase-modified β-CDs 8–10 exhibit distinguishable binding abilities toward bile salts compared with parent β-CD 1 [19]. Host 10 shows increased binding of TCA/GCA. Host 9 exhibits increased binding of GCA while hosts 8–10 show less binding of the other bile salts. The inclusion complexation of hosts 8–10 is driven by favorable enthalpy changes, accompanied with unfavorable entropy changes. The driven forces are hydrogen-bonding and van der Waals interactions, simultaneously producing marked geometric configuration change. Host 8 displays weaker binding ability for every bile salt than hosts 9 and 10 owing to expelling adenine group from β-CD cavity to accommodate bile guests in hosts 8, which is unfavorable to the host–guest complexation.
The microcalorimetric titrations of L/D-Trp-modified β-CD (11 and 12) with a series of bile acids, i.e., CA, DCA, GCA, and TCA, showed typical titration curves, which can be nicely analyzed by assuming the 1:1 complex stoichiometry [20]. Modified β-CDs11 and 12 exhibited appreciably smaller binding abilities for GCA and TCA guests than those of native β-CD 1 since GCA and TCA, possessing a strongly hydrophilic and hydrated sulfonate tail, are not expected to deeply penetrate into the CD cavity by removing the originally included L/D-Trp group out of the hydrophobic cavity. In contrast, DCA and CA, possessing a less hydrophilic/hydrated carboxylate tail, showed comparable or even stronger binding and higher selectivities for host’s chirality than TCA and GCA.
The ITC experiments of hosts 13 and 14 with bile salts (CA, DCA, GCA, and TCA) also showed the typical titration curves of the 1:1 complex formation [21]. The stoichiometric ratio “N” observed from the curve-fitting results was within the range 0.9 to 1.1, which clearly indicated that the majority of the inclusion complexes had a 1:1 binding mode. Thermodynamically, the binding of all CDs with the bile salts was entirely driven by the favorable enthalpy changes accompanied by the unfavorable entropy changes. 14 gave the higher bind ability toward CA and DCA than 1 and 12 due to the introduction of D-tyrosine substituent and the conformational difference between 12 and 14. In addition, the bind constant of 14 for DCA was slightly bigger than that for CA. Possessing a more hydrophobic structure due to the absence of the C-7 hydroxyl group as compared with CA, DCA was easier to bind to the β-CD cavity than CA, which consequently led to the more favorable hydrophobic interactions between hosts and guests. Host 14 exhibited the obviously smaller binding abilities for GCA and TCA guests than 1 and 12. Thermodynamically, the decreased binding affinities of host 14 toward GCA and TCA arose from the entropy change rather than the enthalpy change due to the weakened hydrophobic interactions and the relatively poor size-fit between host and guest. Compared with 1 and 11, 13 showed clearly decreased binding abilities toward all four of the bile salts, especially for GCA and TCA. Thermodynamically, the inclusion complexation of 13 with four bile salts exhibited the favorable enthalpy changes and unfavorable entropy changes. The favorable enthalpy gain of 13 was slightly higher than those of 1 and 11, but the entropy loss of 13 was much more than those of 1 and 11 toward corresponding guests.
The interactions of CA, DCA, GCA, and TCA with 15 and 16have been studied by Ollila et al.by means of isothermal titration calorimetry [23]. The results show that both CA and DCA bound to 15 and 16 with a 1:1 stoichiometry. The binding constant was significantly higher for DCA to 15 and 16 compared to CA. This difference in binding affinity is likely explained by the more hydrophobic nature of DCA due to the absence of the C-7 hydroxyl group, which is present in CA. The binding affinity was somewhat lower for CA binding to 15 compared to 16, while DCA showed a markedly lower affinity for 15 compared to 16. GCA and TCA have lower affinities to 15 and 16 compared to CA and DCA. TCA bound with lower affinity to 15 compared to GCA. Both GCA and TCA gave the same 1:1 stoichiometry for binding to 15 and 16 as did CA and DCA.
For 17, all the hydroxyls are methylated, and the loss of hydrogen bonds for the resulting complexes is inevitable [24]. Therefore, host 17 only shows weak complex stability constants to bile salts, which are much lower than those of 1 and 16. In addition, the release of higher energy water molecules in the cavity of β-CD upon complexation with guests makes the inclusion complexation more favorable, which cannot be obtained in the cases of 17 because almost no water molecule resides in the cavity of 17. Besides that, 17 should need some conformational adjustment to accommodate bile guests, which is entropy-unfavorable for the inclusion complexation.
1H ROESY experiment has been performed by Liu et al. to confirm the binding model of host 19 with CA [25]. The results indicate that CA molecule is included into the hydrophobic cavity from the secondary side of β-CD, with the side chain folded towards the steroid skeleton, and the anthracene group is excluded outside the cavity of β-CD. CA molecule and the tether of β-CD can be co-included into the cavity through the induced-fit interaction between host and guest.
2D ROESY NMR experiments accompanied with molecular modeling studies have been performed by Liu et al. to investigate the binding modes of DCA with 21 and 22 [26]. The results show that the side chain and D-ring of bile salts were encapsulated in the β-CD cavity from the wide opening (Figure 5).
2D ROESY NMR experiment of complex of 23 with CA has also been performed to investigate the binding geometry between permethylated β-CDs and bile salts [24]. The results show that CA is deeply included into the cavity of host 23 with its ring A in the region of the narrow side and ring D in the region of the broad side. However, upon complexation with CA guest, the appended naphthalene group in 23 is not entirely expelled out of the cavity of permethylated β-CD but is removed from the central cavity to the region of the narrow torus rim. The cooperative inclusion manner of both guest molecule and substituent sidearm into the cavity is mainly benefited from the extended framework of permethylated β-CD.
The stoichiometric ratios gotten from curve-fitting results of the binding isotherm fellwithin the range of 0.9–1.1, indicating that the resulting complexes of bile salts and CDs (18–20) are 1:1 [25]. As compared with parent β-CD 1, modified β-CDs 18–20 with different chain length not only enhanced molecular binding ability but also significant molecular selectivity upon inclusion complexation with homologous steroids, except for resulting complex of 20 with TCA. The stability constants for the inclusion complexation of hosts and the each steroid molecule decreased in the following order: DCA > CA > GCA > TCA. The hydroxyl group at the C7 carbon atom of CA, GCA and TCA guests prevented deeper inclusion of the steroids in the β-CD cavity than that of DCA guest. On the other hand, the tether length of the host and induced-fit interactions also played crucial roles in the selective molecular binding process of modified β-CD 18–20 with guests. Host 19 possessing suitable tether length could encapsulate more tightly the steroid guests than the other, through the size/shape-matching and the induced-fit interactions between the host and guest.
Thermodynamically, the inclusion complexation of 18–20 with steroid guests is entirely driven by favorable enthalpy contribution with negative or minor positive entropy change [25]. The strong interaction between host and guest leads to the more favorable negative enthalpy change, which is counteracted by the relative more unfavorable negative entropy change. The introduction of anthracene group with different chain length, and additional binding site to CD rim can significantly enhance the binding ability of parent CD toward steroid guests.
The possible binding mode of 22 with DCA
The binding behaviors of two β-CD derivatives bearing 8-hydroxyquinolino and triazolylquinolino groups (21 and 22) with bile salts have been studied in aqueous buffer solution by means of microcalorimetrical titration [26]. The results showed that the host–guest binding behaviors were mainly driven by the favorable enthalpy changes, accompanied by the unfavorable entropy changes, and the hydrogen-bonding interactions and van der Waals interactions were the main driven forces governing the host–guest binding.
The binding stoichiometry of the permethylated β-CD derivatives 23 and 24 with bile salts has been determined by the Job’s plot method, which showed that hosts and guests formed 1:1 complexes [24]. Thermodynamically, hosts 23 and 24 show much higher binding ability to bile salts than permethylated β-CD 17 when the naphthalene (or quinoline) sidearm is appended on it. The pronounced enhancement of complex stabilities for hosts 23 and 24 can be attributed to the cooperative complex interactions of both the cavity of permethylated β-CD and the chromophore sidearms. Furthermore, it should be mentioned that host 24 always forms more stable complexes with bile guests than host 23, which indicates that the N atom on the quinoline ring plays a crucial role during the course of recognition of bile guests.
Hosts | Guests | pH | Ks | H | TS | Methods | Refs. |
1 | CA | 7.2 (PBS) | 4068 | –22.98 | –2.38 | ITC | 17 |
DCA | 7.2 (PBS) | 4844 | –25.79 | –4.76 | ITC | 17 | |
GCA | 7.2 (PBS) | 2394 | –22.99 | –3.7 | ITC | 17 | |
TCA | 7.2 (PBS) | 2293 | –23.77 | –4.59 | ITC | 17 | |
2 | CA | 7.2 (PBS) | 11160 | –25.53 | –2.43 | ITC | 17 |
DCA | 7.2 (PBS) | 7705 | –32.16 | –9.98 | ITC | 17 | |
GCA | 7.2 (PBS) | 2075 | –25.90 | –6.97 | ITC | 17 | |
TCA | 7.2 (PBS) | 2309 | –26.89 | –7.69 | ITC | 17 | |
3 | CA | 7.2 (PBS) | 16920 | –28.11 | –3.98 | ITC | 17 |
DCA | 7.2 (PBS) | 9382 | –35.78 | –13.11 | ITC | 17 | |
GCA | 7.2 (PBS) | 3904 | –24.74 | –4.24 | ITC | 17 | |
TCA | 7.2 (PBS) | 2796 | –20.37 | –0.7 | ITC | 17 | |
4 | CA | 7.2 (PBS) | 4832 | –24.90 | –3.87 | ITC | 17 |
DCA | 7.2 (PBS) | 4034 | –38.91 | –18.33 | ITC | 17 | |
GCA | 7.2 (PBS) | 2221 | –19.75 | –0.65 | ITC | 17 | |
TCA | 7.2 (PBS) | 1322 | –32.75 | –14.93 | ITC | 17 | |
5 | CA | 7.2 (PBS) | 11060 | –36.44 | –13.36 | ITC | 18 |
DCA | 7.2 (PBS) | 11350 | –41.15 | –18.01 | ITC | 18 | |
GCA | 7.2 (PBS) | 3050 | –25.48 | –5.59 | ITC | 18 | |
TCA | 7.2 (PBS) | 3061 | –18.43 | 1.47 | ITC | 18 | |
6 | CA | 7.2 (PBS) | 25315 | –34.26 | –9.13 | ITC | 18 |
DCA | 7.2 (PBS) | 30300 | –38.13 | –12.55 | ITC | 18 | |
GCA | 7.2 (PBS) | 3098 | –25.82 | –5.89 | ITC | 18 | |
TCA | 7.2 (PBS) | 4659 | –14.86 | 6.08 | ITC | 18 | |
7 | CA | 7.2 (PBS) | 25850 | –23.53 | 1.65 | ITC | 18 |
DCA | 7.2 (PBS) | 24785 | –27.59 | –2.51 | ITC | 18 | |
GCA | 7.2 (PBS) | 4722 | –21.22 | –0.25 | ITC | 18 | |
TCA | 7.2 (PBS) | 3022 | –24.29 | –4.43 | ITC | 18 | |
8 | CA | 7.2 (PBS) | 1726 | –31.0 | –13.3 | ITC | 19 |
DCA | 7.2 (PBS) | 2839 | –34.8 | –14.9 | ITC | 19 | |
GCA | 7.2 (PBS) | 1032 | –25.7 | –8.5 | ITC | 19 | |
TCA | 7.2 (PBS) | 1003 | –26.6 | –9.5 | ITC | 19 | |
9 | CA | 7.2 (PBS) | 2567 | –29.3 | –9.9 | ITC | 19 |
DCA | 7.2 (PBS) | 3137 | –34.0 | –14.0 | ITC | 19 | |
GCA | 7.2 (PBS) | 2898 | –31.2 | –11.4 | ITC | 19 | |
TCA | 7.2 (PBS) | 2284 | –30.0 | –10.8 | ITC | 19 | |
10 | CA | 7.2 (PBS) | 2605 | –28.6 | –9.1 | ITC | 19 |
DCA | 7.2 (PBS) | 3813 | –33.7 | –13.3 | ITC | 19 | |
GCA | 7.2 (PBS) | 3140 | –29.6 | –9.7 | ITC | 19 | |
TCA | 7.2 (PBS) | 2402 | –28.8 | –9.5 | ITC | 19 | |
11 | CA | 7.2 (PBS) | 2020 | –23.2 | –4.3 | ITC | 20 |
DCA | 7.2 (PBS) | 2310 | –32.1 | –12.9 | ITC | 20 | |
GCA | 7.2 (PBS) | 1110 | –23.4 | –6.0 | ITC | 20 | |
TCA | 7.2 (PBS) | 1060 | –23.1 | –5.8 | ITC | 20 | |
12 | CA | 7.2 (PBS) | 6680 | –37.9 | –14.5 | ITC | 20 |
DCA | 7.2 (PBS) | 6770 | –46.0 | –24.1 | ITC | 20 | |
GCA | 7.2 (PBS) | 1760 | –24.9 | –6.4 | ITC | 20 | |
TCA | 7.2 (PBS) | 1470 | –24.3 | –6.2 | ITC | 20 | |
13 | CA | 7.2 (PBS) | 871 | –26.7 | –9.9 | ITC | 21 |
DCA | 7.2 (PBS) | 1087 | –33.1 | –15.8 | ITC | 21 | |
GCA | 7.2 (PBS) | 428 | –28.3 | –13.3 | ITC | 21 | |
TCA | 7.2 (PBS) | 391 | –25.7 | –10.9 | ITC | 21 | |
14 | CA | 7.2 (PBS) | 8689 | –41.7 | –19.2 | ITC | 21 |
DCA | 7.2 (PBS) | 9962 | –50.5 | –27.9 | ITC | 21 | |
GCA | 7.2 (PBS) | 1105 | –30.5 | –13.1 | ITC | 21 | |
TCA | 7.2 (PBS) | 809 | –26.7 | –10.1 | ITC | 21 | |
15 | CA | 7.4 (Tris–NaCl) | 2510 | –7.9 | 38.6 | ITC | 23 |
DCA | 7.4 (Tris–NaCl) | 4429 | –10.65 | 34.0 | ITC | 23 | |
GCA | 7.4 (Tris–NaCl) | 1764 | –8.2 | 34.5 | ITC | 23 | |
TCA | 7.4 (Tris–NaCl) | 1399 | –8.75 | 31.0 | ITC | 23 | |
16 | CA | 7.4 (Tris–NaCl) | 2693 | –5.7 | 46.6 | ITC | 23 |
DCA | 7.4 (Tris–NaCl) | 6276 | –6.8 | 49.9 | ITC | 23 | |
GCA | 7.4 (Tris–NaCl) | 1958 | –7.9 | 36.6 | ITC | 23 | |
TCA | 7.4 (Tris–NaCl) | 2148 | –7.2 | 39.6 | ITC | 23 | |
17 | CA | 7.2 (PBS) | 61 | ITC | 24 | ||
DCA | 7.2 (PBS) | 774 | ITC | 24 | |||
GCA | 7.2 (PBS) | 228 | ITC | 24 | |||
TCA | 7.2 (PBS) | 162 | ITC | 24 | |||
18 | CA | 7.2 (PBS) | 11760 | –42.70 | –19.47 | ITC | 25 |
DCA | 7.2 (PBS) | 15030 | –42.72 | –18.87 | ITC | 25 | |
GCA | 7.2 (PBS) | 3870 | –25.23 | –4.75 | ITC | 25 | |
TCA | 7.2 (PBS) | 2647 | –20.99 | –1.47 | ITC | 25 | |
19 | CA | 7.2 (PBS) | 18965 | –32.37 | –7.95 | ITC | 25 |
DCA | 7.2 (PBS) | 22485 | –36.48 | –11.46 | ITC | 25 | |
GCA | 7.2 (PBS) | 4888 | –21.61 | –0.56 | ITC | 25 | |
TCA | 7.2 (PBS) | 3755 | –19.15 | 0.7 | ITC | 25 | |
20 | CA | 7.2 (PBS) | 11850 | –33.23 | –9.98 | ITC | 25 |
DCA | 7.2 (PBS) | 13365 | –39.57 | –16.20 | ITC | 25 | |
GCA | 7.2 (PBS) | 4254 | –20.07 | 0.65 | ITC | 25 | |
TCA | 7.2 (PBS) | 1833 | –26.58 | –7.96 | ITC | 25 | |
21 | CA | 7.2 (PBS) | 2216 | –25.04 | –5.94 | ITC | 26 |
DCA | 7.2 (PBS) | 2007 | –51.92 | –33.07 | ITC | 26 | |
GCA | 7.2 (PBS) | 2434 | –31.07 | –11.74 | ITC | 26 | |
TCA | 7.2 (PBS) | 3478 | –23.98 | –3.76 | ITC | 26 | |
22 | CA | 7.2 (PBS) | 2443 | –35.60 | –16.25 | ITC | 26 |
DCA | 7.2 (PBS) | 3177 | –33.89 | –13.90 | ITC | 26 | |
GCA | 7.2 (PBS) | 2811 | –34.94 | –15.24 | ITC | 26 | |
TCA | 7.2 (PBS) | 2809 | –30.37 | –10.68 | ITC | 26 | |
23 | CA | 7.2 (Tris–HCl) | 910 | Fluorescence | 24 | ||
DCA | 7.2 (Tris–HCl) | 4320 | Fluorescence | 24 | |||
GCA | 7.2 (Tris–HCl) | 4340 | Fluorescence | 24 | |||
TCA | 7.2 (Tris–HCl) | 3820 | Fluorescence | 24 | |||
24 | CA | 7.2 (Tris–HCl) | 3290 | Fluorescence | 24 | ||
DCA | 7.2 (Tris–HCl) | 7460 | Fluorescence | 24 | |||
GCA | 7.2 (Tris–HCl) | 10690 | Fluorescence | 24 | |||
TCA | 7.2 (Tris–HCl) | 8710 | Fluorescence | 24 | |||
25 | CA | 7.4 (Tris–NaCl) | 7400 | –22.3 | –0.2 | ITC | 27 |
DCA | 7.4 (Tris–NaCl) | 6700 | –32.1 | –10.2 | ITC | 27 | |
26 | CA | 7.4 (Tris–NaCl) | 1280 | –28.3 | –10.5 | ITC | 27 |
DCA | 7.4 (Tris–NaCl) | 2570 | –33.3 | –13.8 | ITC | 27 | |
27 | CA | 7.0 (PBS) | 1650 | Fluorescence | 38 | ||
DCA | 7.0 (PBS) | 2660 | Fluorescence | 38 | |||
28 | CA | 7.0 (PBS) | 588 | Fluorescence | 38 | ||
DCA | 7.0 (PBS) | 1520 | Fluorescence | 38 | |||
29 | CA | 7.0 (PBS) | 60.4 | Fluorescence | 38 | ||
DCA | 7.0 (PBS) | 1030 | Fluorescence | 38 | |||
30 | CA | aqueous solution | – | Fluorescence | 36 | ||
DCA | aqueous solution | – | Fluorescence | 36 | |||
GCA | aqueous solution | – | Fluorescence | 36 | |||
31 | CA | aqueous solution | – | Fluorescence | 36 | ||
DCA | aqueous solution | – | Fluorescence | 36 | |||
GCA | aqueous solution | – | Fluorescence | 36 | |||
32 | CA | aqueous solution | – | Fluorescence | 36 | ||
DCA | aqueous solution | – | Fluorescence | 36 | |||
GCA | aqueous solution | – | Fluorescence | 36 | |||
PBS: Phosphate Buffer Solution; ITC: Isothermal Titration Calorimetry; Tris: Tris(hydroxymethyl)aminomethane; –: The guest-induced variations in the excimer emission are too small for these values to be determined. |
Complex stability constants (Ks/M1), enthalpy (H°/(kJmol1)), and entropy changes (TS°/(kJmol1)) for intermolecular complexation of bile salts with natural β-CD and its mono-modified derivatives in aqueous solution
All the permethylated β-CD derivatives (17, 23 and 24) present the weakest binding ability to CA guest because the cavity of permethylated β-CD possesses a broader hydrophobic region in comparison with 1, and then permethylated β-CD is more suitable to include bile guests with longer tails (GCA and TCA) than 1 [24]. Moreover, there are similar structures between CA and DCA except for the difference of one hydroxyl in ring B. It is attractive that DCA can be included more tightly by 17, 23 and 24 than CA. One reasonable explanation is that the absence of one hydroxyl in ring B makes the whole framework of DCA more hydrophobic than CA, and thereby DCA is more suitable to be immersed into the cavity of permethylated β-CDs.
ROESY experiments for the complexes of CDs (25, 26, 33, and 35) and DCA have been performed to illustrate the binding modes between the CDs and bile salts [27]. The results show that the bridge linker does not interact with DCA and the bile salt molecule is not cooperatively bound by the two cavities of one dimer molecule. DCA is not included in the cavity of the dimer from the primary side (narrow open), but penetrates slightly into the cavity from the secondary side (wide open) using the side chain and D-ring moiety. For 33 (Figure 6), the A-ring moiety of DCA is simultaneously shallowly included in one of the cavities of another CD to form a liner structure. For monomer 25, the D-ring moiety of DCA penetrates deep into the cavity of 25 from the secondary side. However, for monomer 26, DCA is included in the cavity of 26 from the secondary side by its A-ring moiety, differing from other CDs (by D-ring moiety).
To further obtain the information about the binding modes of bile salts with diseleno- and bipyridine-bridged β-CDs, 2D ROESY spectra for typical host–guest pairs have also been determined by Liu et al. [28]. For dimer 35 and CA, the results indicate that the carboxylate side chain and D-ring of CAmay penetrate into the CD cavity from the secondary side shallowly and two CAmolecules are bound separately into two cavities of 35 from the secondary side, which is consistent with the 1:2 binding stoichiometry (Figure 7a). For dimer 39 and DCA, the results are quite different and show a 1:1 cooperative binding mode. The A-ring of DCApenetrates deeply into one CD cavity of 39, attributing to the less steric hindrance and higher hydrophobicity of the substituent group on the C-7 position of DCA (Figure 7b). Under the same experiment using DCAas guest, host 38 adopts a different binding mode from 39. The carboxylate side chain of two DCAmolecules deeply penetrates into the CD cavity of 38 from the secondary side separately.
To obtain the information about the binding modes between bile salts and oligoethylenediamino-bridged β-CD dimers (42–44), 2D ROESY spectra for typical host–guest pairs have been determined by Liu et al. [29]. The results of ROESY experiments indicated that the D ring and side-chain of bile salt guest enter one β-CD cavity from the wide opening, and the linker group is partially self-included in the other β-CD cavity (Figure 8).
From ROESY experiments, Zhao et al. found that the D-ring of CA is wholly included in the CD cavity of 45 from the wide opening, while the side-chain is located near the narrow opening of CD cavity and folded toward the steroid body and the phenyl moiety is not driven out of the CD cavity even after the guest inclusion [30]. Similar binding mode is also observed in other cases of 45/bile salts complexes.
The binding modes between the aromatic diamino-bridged β-CDs 46–48 and bile salts have also been investigated by Zhao et al. via 2D ROESY experiments and the results show that the D-ring of CA is wholly included in the CD cavity with the wide opening, while the side chain is located near the narrow opening of the CD cavity and is folded toward the steroid body [31]. The phenyl moiety is not driven out of the CD cavity even after the guest inclusion.
Structures of bridged β-CDs
To obtain the information about the binding modes between bile salts and sulfonyldianiline-bridged β-CD 49, 2D ROESY spectra for typical host–guest pairs have further been determined by Zhao et al. [32]. The correlation signals, along with the 1:1 binding stoichiometry, jointly indicate a host-linker-guest binding mode between 49 and CA. That is, upon complexation with 49, the carboxylate tail and the D ring of CA penetrate into one CD cavity of 49 from the wide opening deeply, while the phenyl moiety of the CD linker is partially self-included in the other β-CD cavity. Similar binding modes are also observed in other cases of 49/bile salt complexes.
The binding modes of binaphthyl-, biquinoline- and dithio-bridged β-CDs (50–55) and bile salts have been investigated by 2D ROESY experiments in aqueous solution [33]. The results show that CA enters the CD cavity of 53 from the second side of CD with the side chain and D-ring. The side chain with the negative carboxylate group of CA moves toward the positive protonated amino group of 53. The other binaphthyl-, biquinoline- and dithio-bridged β-CDs/bile salts complexes show a similar binding mode as the complex 53/CA, with only a slight degree of difference in the depth of guest insertion.
The possible binding modes of 35 with CA (a) and 39 with DCA (b)
The possible binding mode of 42–44 with CA
To elucidate the difference in binding behavior between the CD dimer and monomer, two CD dimers (33 and 35) and their monomer analogs (25 and 26) have been used for titration microcalorimetry with CA and DCA [27]. It is interesting that the results of the thermodynamic measurements show a 1:1 binding stoichiometry for hosts 25, 26 and 33, but 1:2 stoichiometry for host 35. In addition, although the stability constants for the complexation between dimer 33 and the bile salts are much larger than those for monomer 26, the long-linked dimer 35 unusually displays a lower cavity binding ability than its corresponding monomer 25 upon complexation with both guests CA and DCA. The enhancement of the binding ability of dimer 33 compared to monomer 26 could be ascribed not only to the cooperative binding but also partly to the peculiar self-inclusion conformation of 26 that leads to more unfavorable entropy changes, especially for the 26–CA pair. For 35, the two guest molecules are separately and independently included in the two cavities of 35 because the longer linker, especially the ethylenediamino moiety of dimer 35, makes it possess a relatively large conformational freedom. As the considerable entropy loss cancels the advantage of enthalpy gain, dimer 35 displays relatively weak binding abilities. Both hosts 35 and 25 show similar binding ability for DCA and CA. The reason is that either binding with host 35 or host 25, the two guest bile salts are included into the cavity of CDs by its D-ring and side-chain moiety, which reduces the influence of the substituent in C7. However, while binding with hosts 33 and 26, the A-ring moiety participates in the binding process, so the more hydrophobic C7 substituent of DCA makes it bind more strongly with the host CDs, giving the higher binding constants than with CA, especially for host 26.
Either for diseleno-bridged β-CDs (34–37) or for bipyridine-bridged β-CDs (38–41), the host–guest stoichiometry changes in the same order, that is, from 1:2 to 1:1 with the increase of spacer length [28]. For diseleno-bridged β-CDs, only 36 and 37 adopt the 1:1 binding mode. However, for bipyridine-bridged β-CDs, only host 38 adopts the 1:2 binding mode; the others all show the 1:1 cooperative binding mode. The thermodynamic results reveal that, with the longest spacer, 37 gives the largest stability constants in all diseleno-bridged β-CDs, while the largest stability constants of bipyridine-bridged β-CDs toward each guest molecule is obtained by the dimers 39 and 40 with the moderate spacer lengths, which suggests that only the CD dimers possessing the proper spacer length can give the perfect cooperative binding toward guests.
For the dimers adopting 1:1 cooperative binding mode, the enthalpy changes are not only the main contribution to the binding process but also the determining factor for the binding abilities [28]. Comparing the diseleno-bridged β-CDswith bipyridine-bridged β-CDs, all of the bipyridine-bridged β-CDsdisplay much stronger binding abilities toward bile salts than corresponding diseleno-bridged β-CDs, which indicate that the presence of rigid spacer favors formation of a relatively fixed binding mode and results in the close contact between two CD cavities and guest molecule, leading to the stronger binding abilities. On the other hand, due to the presence of the bipyridine fragment, the hydrogen bond between the hydroxyl group of the bile salt and the nitrogen atom of bipyridine might also be taken as a plausible explanation for the strong binding abilities of bipyridine-bridged β-CDsas compared with diseleno-bridged β-CDs. Upon complexation with CAand DCA, all dimer hosts adopting a 1:1 binding mode show higher binding abilities than native β-CD 1 due to more favorable enthalpy changes, which perfectly confirms the advantage of cooperative binding of guests by two CD cavities.
1:1 binding stoichiometry is observed for all the complexes between bile salts and oligoethylenediamino-bridged β-CDs (42–44) [29]. The inclusion complexation of bile salts with 42–44 is driven by favorable enthalpy changes, accompanied by slight to moderate entropy loss. Interestingly, the enthalpy changes for the inclusion complexation of 42–44 increased, while the entropic changes decreased, with the elongation of the linker group, giving a binding constant 42>43>44. The stronger binding of bile salts by the short-linked β-CD dimer is not thermodynamically accomplished by an increase of the originally favorable enthalpy gain, but by a reduction of the unfavorable entropy loss. The short-linked β-CD dimer, with a better size and hydrophobicity match to bile salts, may experience more extensive desolvation upon complexation, and thus exhibits the less unfavorable entropy loss. With the elongation of linker group, the protonated amino group in the linker is located distant from the anionic carboxylate (or sulfonate) tail of bile salt, which consequently weakens the electrostatic interactions between the linker group and bile salt. Moreover, the increase of the number of -NH- fragments in the linker group decrease the hydrophobicity of β-CD dimer to some extent, which is also unfavorable to the hydrophobic interactions between host and guest.
The stability constants of the complexes formed by β-CD dimers 42–44 with bile salts are larger than those of the complexes formed by native β-CD 1 [29]. These enhanced binding abilities of β-CD dimers may be mainly attributed to the cooperative host-linker-guest binding mode between host and guest. The electrostatic interactions between the protonated amino groups in the linker and the anionic carboxylate (or sulfonate) tail of bile salt may strengthen the inclusion complexations of these β-CD dimers with bile salts. Moreover, the hydrogen bond interactions of the hydroxyl groups of β-CD and the -NH- fragments of the oligo(ethylenediamino) linker with the carboxylate (or sulfonate) tail of bile salt also contribute to the enhanced binding abilities of β-CD dimers 42–44.
Compared with CA, GCA and TCA, DCA possesses a more hydrophobic structure due to the absence of C-7 hydroxyl group, which consequently leads to stronger hydrophobic interactions between host and guest. Therefore, DCA gives the highest binding abilities among the bile salts examined upon complexation with most CDs [29]. Possess more polar side-chains, GCA and TCA show weak binding abilities upon inclusion complexation complexation with β-CD dimers due to the relatively poor hydrophobic interactions between host and guest.
The stoichiometry for the inclusion complexation of 45 with bile salts were determined by the continuous variation method and the results showed a 1:1 inclusion complexation between 45 and bile salts [30]. The stability constants for the inclusion complexation of 45 with bile salts are much higher than those values for the native β-CD 1. These enhanced binding abilities of 45 may be mainly attributed to the cooperative host-linker-guest binding mode between host and guest because the linker group provides some additional binding interactions towards the accommodate guest. Host 45 displays higher binding ability for CA than for DCA due to the hydrogen bond interactions between the 7-hydroxy group of CA and the 2- and 3-hydroxy group of CD. Host 45 shows the weaker binding abilities upon inclusion complexation with GCA and TCA than that of CA and DCA because GCA and TCA are unfavorable to insert into the cavity from the second side of CD cavity with their D ring attributing to the more hydrophilic tail attached to the end of the D ring.
The stoichiometries for inclusion complexation of aromatic diamino-bridged β-CDs 46–48 with bile salts were further determined by the continuous variation method and the results show that all the hosts and guests form 1:1 complexes [31]. β-CD dimers 46–48 also show enhanced binding ability toward bile salts as compared with β-CD 1. The enhanced binding abilities of aromatic diamino-bridged β-CDs may be mainly attributed to the cooperative host-linker-guest binding mode between host and guest. In addition to the association of the CD cavity with a guest molecule, the linker group provides some additional binding interactions towards the accommodated guest.
Unlike the β-CD 1, the bridged β-CDs 46–48 show larger binding constants for CA than for DCA [31]. Among them, the host 47 gave the highest stability constant for inclusion complexation with CA. One possible reason for the stronger affinity for CA may involve hydrogen-bond interactions between the 7-hydroxy group of CA and the 2- and 3-hydroxy groups of CD, which subsequently strengthen the host–guest association. Moreover, all the hosts show lower binding ability for complexation with GCA and TCA as compared with complexation with CA and DCA. The highest binding constants towards GCA and TCA are with host 47. The universally decreased binding ability toward GCA and TCA must be related to structure differences between CA and DCA. Attributing to the more hydrophilic tail, which is attached to the end of the D ring, GCA and TCA are unfavorable for insertion into the cavity from the second side of the β-CD cavity with their D ring.
The binding constants for the complexation of each bile salt by hosts 46–48 increases in the following order: 47\n\t\t\t\t\t\t>48\n\t\t\t\t\t\t>46 [31]. That is, host 47 with a tether of moderate length and rigidity among the β-CD dimers studied is the most suitable for inclusion complexation with bile salts. This may be attributable to the strict size fit between these bile salts and the moderate length-tethered β-CD dimer 47, which consequently exhibits strong van der Waals and hydrophobic interactions between host and guest.
The stoichiometry for the inclusion complexation of sulfonyldianiline-bridged β-CD 49 with bile salts has also been determined by the “continuous variation” method and the results indicate that all the bile salts can form 1:1 complexes with 49 [32]. Thermodynamically, the binding constants of 49 with bile salts are larger than those of native β-CD 1. The enhanced binding abilities of 49may be also mainly attributed to the cooperative host-linker-guest binding mode between host and guest. In addition to the association of the CD cavity with a guest molecule, the linker group provides some additional binding interactions towards the accommodate guest. Distinctly, the binding constant is significantly higher for DCA compared to CA by native β-CD 1. However, different from native β-CD 1, sulfonyldianiline-bridged β-CD 49 reverses this binding selectivity, showing larger binding constants for CA than DCA. One possible reason for the stronger affinity for CA may involve H-bond interactions between CA and CD, which subsequently strengthen the host-guest association. Moreover, all the hosts show a weaker binding ability upon complexation with GCA and TCA than with CA and DCA. The universal decreased binding ability toward GCA and TCA must relate to the structure differences from CA and DCA. Attributing to the more hydrophilic tail, which is attached to the end of the D ring, GCA and TCA are unfavorable to insert into the cavity from the second side of β-CD cavity with their D ring. It is worthy to note that the binding ability of 49 is significantly larger for TCA than for GCA, which leads to a relatively strong molecular selectivity.
The stoichiometric ratios from the binding patterns for the titrations of steroids with binaphthyl-, biquinoline- and dithio-bridged β-CDs 50–55 fell within the range of 1.8-2.1, which clearly indicates that the majority of the inclusion complexes have a 1:2 stoichiometry of steroids and bridged β-CDs [33]. Thermodynamically, bridged β-CD 52, possessing a relatively short and rigid tether without amino groups, still gives an enhanced binding ability upon complexation with steroids, except TCA, when compared its one single unit of cavity with that of native β-CD 1. The enthalpy changes for the inclusion complexation of bridged β-CD 52 with DCA and CA are more negative than that of native β-CD 1, resulting in the relatively stronger binding. On the other hand, the enthalpy change for the complexation of 52 with DCA is higher than that with CA, which directly contributes to the increased complex stability. It is reasonable that, possessing the more hydrophobic structure due to the absence of C-7 hydroxyl group as compared with CA, DCA is easier to bind into the β-CD cavity than CA, which should lead to the more favorable van der Waals interactions.
All the complexation of aminated bridged β-CDs (50, 51, and 53–55) toward DCA and CA give more negative enthalpy changes as compared with that of neutral bridged β-CD 52, validating the contribution of the attractive electrostatic interactions between positively charged protonated amino group of β-CD tethers and negatively charged carboxylate group of DCA and CA [33]. Accompanied with the more exothermic reaction enthalpies, the inclusion complexation of DCA and CA by aminated bridged β-CDs (50, 51, and 53–55) exhibits more unfavorable entropy changes compared to that for neutral bridged bis(β-CD) 52, which possibly originates from the conformation fixation of host and guest and the rigid complex formation upon complexation.
Mostly, bridgedβ-CDs 50, 51, and 53–55 give the lower binding ability upon complexation with GCA and TCA as compared with the complexation with CA and DCA, which is similar as the complexation of β-CD 1 and bridged β-CD 52 [33]. The universal decreased binding ability toward GCA and TCA must relate to the structure differences from CA and DCA. The more polar side chains at C23 for GCA and TCA remarkably affect their binding thermodynamics.
2D ROESY NMR and circular dichroism spectroscopy experiments for the complexes of bile salts with bridged and metallobridged CDs with naphthalenecarboxyl linkers have been performed by Liu et al. to investigate the binding modes between host and guests [34]. The result of 57/DCA complex showed that the guest DCA was included in the β-CD cavity with the D-ring and the carboxylic tail located near the narrow opening but the B-ring located near the wide opening and the naphthyl group was excluded from the β-CD cavity upon inclusion complexation. Moreover, the result of 2D ROESY NMR showed that the ethylenediamino moiety of the linker group was also partially self-included in the β-CD cavity from the narrow opening. Similar results were also found in other ROESY experiments of hosts 57 and 59 with bile salts.
2D NMR experiments in D2O and molecular modeling studies for the complexes of bridged and metallobridged β-CDs with biquinoline linkers and bile salts have been performed by Liu et al. to deduce the binding modes between the bile salts and β-CD dimers [35,36]. The results show that a cooperative “host-tether-guest” binding mode is operative in the association of β-CD dimers with a guest molecule; upon complexation with β-CD dimers, the guest steroid is embedded into one hydrophobic β-CD cavity from the primary side, while the tether group is partly self-included in the other cavity. In the metallobridged β-CDs, the tether group is entirely excluded from the β-CD cavities as a result of metal coordination. This arrangement allows two side groups of the guest molecule to be embedded into the hydrophobic β-CD cavities from the primary side of the β-CD to form a sandwich host–guest inclusion complex.
1H ROESY experiments have been performed in D2O to investigate the binding modes between bridged and metallobridged β-CDs with oxamidobisbenzoyl linkers and bile salts [37]. The results show a “host-linker-guest” binding mode between 66 and CA. That is, upon inclusion complexation with β-CD dimer, the carboxylate tail and the D-ring of CA enter into one CD cavity of 66 from the wide opening, while the linker group of 66 is partially self-included in the other CD cavity (Figure 9a). A similar binding mode is also observed for the inclusion complexation of 66 with DCA.
The possible binding modes of 66(a) and 67 (b) with CA, and the possible binding modes of 69–72 with bile salts
With a shallowly self-included conformation, β-CD dimers 65, 67, and 68 show a binding mode different from that of 66. For example, for 67/CA complex, the carboxylate tail and D-ring of CA enter the CD cavity from the wide opening, and the carboxylate tail is located close to the linker group. On the other hand, the linker group is mostly moved out from the CD cavity after complexation with CA (Figure 9b). 65/CA, 65/DCA, 67/DCA, 68/CA, and 68/DCA complexes show a similar binding mode to the 67/CA complex.
In the cases of the metallobridged β-CDs 69–72, the strong electrostatic attraction from the coordinated CuII ions in the linker group may also favor the penetration of the carboxylate tail of bile salt into the CD cavity through the wide opening. Moreover, the 1:2 or 2:4 binding stoichiometry indicates that each CD cavity of a metallobridged β-CD is occupied by a bile salt (Figure 9c).
The interactions between hosts (27–29, 57–59) and bile salts have been studied by Liu and Ueno et al. by the method of fluorescence [34,38]. The results show that all the hosts (27–29, 57–59) can form 1:1 complexes with bile salts CA and DCA. Thermodynamically, bridged β-CDs possess much stronger binding abilities compared with mono-modified β-CDs. These enhanced binding abilities should be attributed to cooperative binding of the β-CD cavity and the linker group towards the guest molecule, leading to greatly strengthened van der Waals and hydrophobic interactions between host and guest when compared with mono-modified β-CDs. Furthermore, after metal coordination, the metallobridged bis(β-CD)s 58 and 59 significantly enhance the original binding ability of native β-CD 1, mono-naphthyl-modified β-CDs 27–29 and even parent bridged β-CD 57. This enhancement may be subjected to a multiple recognition mechanism of metallobridged β-CDs towards model substrates. On one hand, the coordination of a metal ion to the linker group shortens the effective distance of two β-CD cavities to some extent and thus improves the size-fit degree between host and guest. On the other hand, the electrostatic attraction between the anionic carboxyl group of guest bile salt and the coordinated metal ion of metallobridged β-CD may also favour the host–guest binding to some extent.
The interactions between host 51 and bile salts have been investigated by Liu et al. by the method of fluorescence [35]. The results show that all the bile salts can form 1:1 complexes with 51. Thermodynamically, the binding constants obtained for CA and DCA are much larger than those reported for mono-modified β-CDs by Ueno et al. under practically the same experimental conditions [38]. This enhancement is probably due to the cooperative binding of the steroids by 51. The complex stability decreases in the order: DCA > CA > GCA > TCA. The highest affinity for DCA is likely to arise from its more hydrophobic steroid skeleton. Host 51 shows comparable affinities toward CA and GCA, whereas TCA, possessing a highly polar anionic tail gives the lowest binding constant.
The stoichiometry for the inclusion complexation of hosts 60–64 with bile salts has also been determined by Job’s method [36]. The results show that the stoichiometry of the inclusion complex formed by the 63/CA system is likely to be 2:2, with intramolecular complexation. Stoichiometries of 1:1 (for bridged β-CD) or 2:2 (for metallobridged β-CD) were obtained in other similar cases of host–guest inclusion complexation. Thermodynamically, the stability constants of the complexes of bridged β-CDs 51, 60 and 61 with bile salts are larger than those of the complexes formed by mono-modified β-CDs 27–29 by a factor of about 1.1 to around 200 benefitting from cooperative binding. In addition to inclusion complexation of the guest molecule within one hydrophobic CD cavity, the tether group located near the accommodated guest provides some additional interactions with the guest. In control experiments, the changes in the fluorescence spectra of 30–32 upon addition of guest steroids were too small to allow calculation of the stability constants, which may be attributed to strong self-inclusion of the substituted group preventing penetration of the guest into the CD cavity. Except 60, the mono- and bridged-β-CDs display higher binding affinities for DCA than for CA. This stronger affinity for DCA is likely to arise from the more hydrophobic steroid skeleton of this compound compared with that of CA. The abilities of both the short-tethered compound 60 and the long-tethered host 61 to bind CA and DCA are unexpectedly limited compared to the binding abilities of mono-modified CDs 27–29 due to the self-inclusion of the tether group for the short-tethered β-CD dimer 60 and the steric hinderance from the relatively large 5-amino-3-azapentyl-2-quinoline-4-carboxyamide fragment on the exterior of the CD cavity for the long-tethered β-CD dimer 61, respectively.
The metal-ligated oligomeric β-CDs 62–64 have significantly enhanced (around 50–4100 higher) binding affinities for the tested guest molecules compared with those of the mono-modified β-CDs [36]. These results can be explained by considering a mechanism involving an uncommon multiple recognition behavior of metallobridged β-CDs. A metallobridged β-CD affords four hydrophobic binding sites (four CD cavities) and one (or three) metal coordination center(s), which jointly contribute to the cooperative binding of the oligomeric host with the guest molecule upon inclusion complexation. In addition, ligation of a CuII ion shortens the effective length of the tether to some extent and thus improves the size fit of the host with the guest. The cumulative result of these factors is that the metal-ligated β-CD oligomers have binding abilities around 6–200 times higher than those of their parent bridged β-CDs.
The stoichiometry for the inclusion complexation of hosts 65–72 with bile salts has been determined by Job’s method [37]. The results indicate that each of the Job’s plots for the inclusion complexation of 65–68 with bile salts shows a maximum at a β-CD dimer molar fraction of 0.5, confirming the 1:1 binding stoichiometry between host and guest. For the inclusion complexation of metallobridged β-CDs 69–72 with bile salts, however, each of the Job’s plots shows a maximum at a bridged β-CD unit molar fraction of 0.33, which indicates 1:2 stoichiometry between each bridged β-CD unit and guest. The metallobridged β-CDs 69 and 70 may only bind two bile salts to form a stoichiometric 1:2 inclusion complex. However, the metallobridged β-CDs 71 and 72 may adopt intramolecular 2:4 stoichiometry upon inclusion complexation with bile salts. Thermodynamically, the binding constants for the inclusion complexation of CA and DCA with bridged β-CDs 65–68 are higher than the KS values reported for the inclusion complexation of these bile salts with native or mono-modified β-CDs [33,38]. These enhanced binding abilities highlight the inherent advantage of the cooperative “host-linker-guest” binding mode of bridged β-CDs 65–68. In addition to the association of the CD cavity with a guest molecule, the linker group provides some additional binding interactions towards the accommodated guest.
The bile salts CA and DCA are better bound by bridged β-CD 65, which possesses the shortest linker group, than by the long-linked bridged β-CDs [37]. This may be attributable to the strict size-fit between these bile salts and the short-linked bridged β-CD 65, which consequently gives strong van der Waals and hydrophobic interactions between host and guest.
Significantly, metallobridged β-CDs 69–72 show greatly enhanced binding abilities with regard to the bridged β-CDs 65–68 [37]. These significant enhancements in the binding abilities may be attributable to a more complicated multiple recognition mechanism involving the cooperative binding of several CD cavities, conformation adjustment by the metal coordination, and additional binding interactions between the metal-coordinated linker group and the accommodated guest molecules.
Except for 66, all of the hosts examined display higher binding abilities for CA than for DCA [37]. One possible reason for the stronger affinities for CA may involve hydrogen bond interactions between the 7-hydroxy group of CA and the 2- and 3-hydroxy groups of CD.
The microcalorimetric experiments of β-CD 1 and modified β-CDs 2, 5, 6, 7 with bile acids showed typical titration curves of 1:1 complex formation [18]. However, metallobridged β-CD 56 displays a 1:2 host–guest binding stoichiometry. Thermodynamically, as compared with native β-CD 1, most oligo(ethylenediamino)-β-CDs 2, 56, and their CuII complexes 7 and 56 show enhanced molecular binding abilities and guest selectivities towards bile acids. The inclusion complexation of bile acids with native β-CD 1 and their derivatives (2, 5, 6, 7, and 56) is absolutely driven by favorable enthalpy changes accompanying with moderate unfavorable or slightly favorable entropy changes. The favorable enthalpy change is attributed to the dominant contribution of the hydrophobic interactions. Meanwhile, the unfavorable entropy given by most of the complexes is due to the decrease of rotational and structural freedom upon complex construction.
As compared with native β-CD 1, 5 shows increased binding abilities toward negatively charged bile acids guest molecules, which should be mainly due to the additional electrostatic interactions between the amino tether moiety of hosts and anionic carboxylate or sulfonate tail of guests [18]. Moreover, β-CD dimer 56 shows a larger binding constant upon inclusion complexation with CA and DCA than 5. This may be attributed to that the coordination of copper ion onto the amino tether of CD affords a more positive charged environment as compared with its precursor 5. Compared with 5, host 6 also shows stronger binding abilities toward guest molecules. However, the introduction of copper actually decreases the original binding ability of 6 towards DCA and gives comparable stability constant upon complexation with CA. All the hosts, including native β-CD 1 and modified β-CDs 2, 5, 6, 7, and 56, show the weaker binding abilities upon inclusion complexation with GCA and TCA than those of CA and DCA. It is also found that complexes stabilities enhance with the extended length of spacer for the same guest except for 2/CA to 5/CA. It is reasonable to believe that the increased stability is due to the enlarged hydrogen binding interactions.
Hosts | Guests | pH | Ks | H | TS | Methods | Refs. |
33 | CA | 7.4 (Tris–NaCl) | 6860 | –30.5 | –8.6 | ITC | 27 |
DCA | 7.4 (Tris–NaCl) | 9700 | –37.0 | –14.3 | ITC | 27 | |
35 | CA | 7.4 (Tris–NaCl) | 2700 | –27.1 | –7.5 | ITC | 27 |
DCA | 7.4 (Tris–NaCl) | 3300 | –35.7 | –15.7 | ITC | 27 | |
36 | CA | 7.4 (Tris–NaCl) | 4100 | –24.9 | –4.3 | ITC | 28 |
DCA | 7.4 (Tris–NaCl) | 5400 | –35.0 | –13.7 | ITC | 28 | |
37 | CA | 7.4 (Tris–NaCl) | 5030 | –29.1 | –8.0 | ITC | 28 |
DCA | 7.4 (Tris–NaCl) | 6100 | –40.2 | –18.6 | ITC | 28 | |
39 | CA | 7.4 (Tris–NaCl) | 12700 | –32.4 | –9.0 | ITC | 28 |
DCA | 7.4 (Tris–NaCl) | 12400 | –45.4 | –22.0 | ITC | 28 | |
40 | CA | 7.4 (Tris–NaCl) | 12400 | –25.5 | –2.2 | ITC | 28 |
DCA | 7.4 (Tris–NaCl) | 13100 | –31.9 | –8.3 | ITC | 28 | |
41 | CA | 7.4 (Tris–NaCl) | 6800 | –25.4 | –3.5 | ITC | 28 |
DCA | 7.4 (Tris–NaCl) | 7500 | –35.2 | –13.1 | ITC | 28 | |
42 | CA | 7.2 (PBS) | 21065 | –32.8 | –8.1 | ITC | 29 |
DCA | 7.2 (PBS) | 22780 | –42.7 | –17.9 | ITC | 29 | |
GCA | 7.2 (PBS) | 9707 | –23.0 | –0.3 | ITC | 29 | |
TCA | 7.2 (PBS) | 6848 | –22.4 | –0.5 | ITC | 29 | |
43 | CA | 7.2 (PBS) | 5868 | –39.3 | –17.7 | ITC | 29 |
DCA | 7.2 (PBS) | 7017 | –47.4 | –25.5 | ITC | 29 | |
GCA | 7.2 (PBS) | 4031 | –25.8 | –5.2 | ITC | 29 | |
TCA | 7.2 (PBS) | 2947 | –26.9 | –7.1 | ITC | 29 | |
44 | CA | 7.2 (PBS) | 5606 | –41.0 | –19.6 | ITC | 29 |
DCA | 7.2 (PBS) | 5511 | –52.1 | –30.7 | ITC | 29 | |
GCA | 7.2 (PBS) | 2847 | –26.5 | –6.9 | ITC | 29 | |
TCA | 7.2 (PBS) | 1877 | –29.0 | –10.3 | ITC | 29 | |
45 | CA | 7.2 (PBS) | 27050 | Fluorescence | 30 | ||
DCA | 7.2 (PBS) | 22930 | Fluorescence | 30 | |||
GCA | 7.2 (PBS) | 7200 | Fluorescence | 30 | |||
TCA | 7.2 (PBS) | 17610 | Fluorescence | 30 | |||
46 | CA | 7.2 (PBS) | 15310 | Fluorescence | 31 | ||
DCA | 7.2 (PBS) | 8790 | Fluorescence | 31 | |||
GCA | 7.2 (PBS) | 3040 | Fluorescence | 31 | |||
TCA | 7.2 (PBS) | 4100 | Fluorescence | 31 | |||
47 | CA | 7.2 (PBS) | 39900 | Fluorescence | 31 | ||
DCA | 7.2 (PBS) | 31880 | Fluorescence | 31 | |||
GCA | 7.2 (PBS) | 10400 | Fluorescence | 31 | |||
TCA | 7.2 (PBS) | 5360 | Fluorescence | 31 | |||
48 | CA | 7.2 (PBS) | 25930 | Fluorescence | 31 | ||
DCA | 7.2 (PBS) | 14330 | Fluorescence | 31 | |||
GCA | 7.2 (PBS) | 7950 | Fluorescence | 31 | |||
TCA | 7.2 (PBS) | 4590 | Fluorescence | 31 | |||
49 | CA | 7.2 (PBS) | 26200 | Fluorescence | 32 | ||
DCA | 7.2 (PBS) | 10140 | Fluorescence | 32 | |||
GCA | 7.2 (PBS) | 3150 | Fluorescence | 32 | |||
TCA | 7.2 (PBS) | 7730 | Fluorescence | 32 | |||
50 | CA | 7.2 (PBS) | 7351 | –33.0 | –10.9 | ITC | 33 |
DCA | 7.2 (PBS) | 5504 | –42.7 | –21.4 | ITC | 33 | |
GCA | 7.2 (PBS) | 5936 | –15.1 | 6.4 | ITC | 33 | |
TCA | 7.2 (PBS) | 3058 | –24.5 | –4.6 | ITC | 33 | |
51 | CA | 7.2 (PBS) | 5559 | –49.3 | –27.9 | ITC | 33 |
CA | 7.2 (PBS) | 11300 | Fluorescence | 35 | |||
DCA | 7.2 (PBS) | 8372 | –48.1 | –25.7 | ITC | 33 | |
DCA | 7.2 (PBS) | 21730 | Fluorescence | 35 | |||
GCA | 7.2 (PBS) | 2979 | –18.1 | 4.2 | ITC | 33 | |
GCA | 7.2 (PBS) | 11040 | Fluorescence | 35 | |||
TCA | 7.2 (PBS) | 4441 | –19.7 | 1.1 | ITC | 33 | |
TCA | 7.2 (PBS) | 6040 | Fluorescence | 35 | |||
52 | CA | 7.2 (PBS) | 5039 | –28.2 | –7.1 | ITC | 33 |
DCA | 7.2 (PBS) | 7900 | –31.6 | –9.4 | ITC | 33 | |
GCA | 7.2 (PBS) | 4262 | –21.5 | –0.8 | ITC | 33 | |
TCA | 7.2 (PBS) | 1975 | –22.0 | –3.2 | ITC | 33 | |
53 | CA | 7.2 (PBS) | 10700 | –30.6 | –7.6 | ITC | 33 |
DCA | 7.2 (PBS) | 8912 | –38.1 | –15.6 | ITC | 33 | |
GCA | 7.2 (PBS) | 5689 | –22.7 | –1.3 | ITC | 33 | |
TCA | 7.2 (PBS) | 2762 | –37.3 | –17.6 | ITC | 33 | |
54 | CA | 7.2 (PBS) | 9899 | –37.5 | –14.7 | ITC | 33 |
DCA | 7.2 (PBS) | 11150 | –39.9 | –16.8 | ITC | 33 | |
GCA | 7.2 (PBS) | 4061 | –23.5 | –2.9 | ITC | 33 | |
TCA | 7.2 (PBS) | 2502 | –20.2 | 0.8 | ITC | 33 | |
55 | CA | 7.2 (PBS) | 6196 | –39.3 | –17.6 | ITC | 33 |
DCA | 7.2 (PBS) | 10325 | –39.4 | –16.5 | ITC | 33 | |
GCA | 7.2 (PBS) | 2891 | –23.3 | –3.5 | ITC | 33 | |
TCA | 7.2 (PBS) | 2189 | –20.0 | –0.9 | ITC | 33 | |
56 | CA | 7.2 (PBS) | 13330 | –29.77 | –6.23 | ITC | 18 |
DCA | 7.2 (PBS) | 12065 | –34.02 | –10.72 | ITC | 18 | |
GCA | 7.2 (PBS) | 2925 | –23.36 | –3.58 | ITC | 18 | |
TCA | 7.2 (PBS) | 2478 | –21.46 | –2.09 | ITC | 18 | |
57 | CA | 7.4 (Tris–HCl) | 10540 | Fluorescence | 34 | ||
DCA | 7.4 (Tris–HCl) | 12400 | Fluorescence | 34 | |||
58 | CA | 7.4 (Tris–HCl) | 15500 | Fluorescence | 34 | ||
DCA | 7.4 (Tris–HCl) | 15700 | Fluorescence | 34 | |||
59 | CA | 7.4 (Tris–HCl) | 31400 | Fluorescence | 34 | ||
DCA | 7.4 (Tris–HCl) | 95900 | Fluorescence | 34 | |||
60 | CA | aqueous solution | 5380 | Fluorescence | 36 | ||
DCA | aqueous solution | 2790 | Fluorescence | 36 | |||
GCA | aqueous solution | – | Fluorescence | 36 | |||
61 | CA | aqueous solution | 3380 | Fluorescence | 36 | ||
DCA | aqueous solution | 3710 | Fluorescence | 36 | |||
GCA | aqueous solution | – | Fluorescence | 36 | |||
62 | CA | aqueous solution | 30500 | Fluorescence | 36 | ||
DCA | aqueous solution | 529000 | Fluorescence | 36 | |||
GCA | aqueous solution | 1745000 | Fluorescence | 36 | |||
63 | CA | aqueous solution | 196000 | Fluorescence | 36 | ||
DCA | aqueous solution | 283700 | Fluorescence | 36 | |||
GCA | aqueous solution | 13000 | Fluorescence | 36 | |||
64 | CA | aqueous solution | 246000 | Fluorescence | 36 | ||
DCA | aqueous solution | 54000 | Fluorescence | 36 | |||
GCA | aqueous solution | 891000 | Fluorescence | 36 | |||
65 | CA | 7.2 (Tris–HCl) | 18500 | Fluorescence | 37 | ||
DCA | 7.2 (Tris–HCl) | 12200 | Fluorescence | 37 | |||
66 | CA | 7.2 (Tris–HCl) | 8130 | Fluorescence | 37 | ||
DCA | 7.2 (Tris–HCl) | – | Fluorescence | 37 | |||
67 | CA | 7.2 (Tris–HCl) | 11900 | Fluorescence | 37 | ||
DCA | 7.2 (Tris–HCl) | 11500 | Fluorescence | 37 | |||
68 | CA | 7.2 (Tris–HCl) | 8820 | Fluorescence | 37 | ||
DCA | 7.2 (Tris–HCl) | 1870 | Fluorescence | 37 | |||
69 | CAa | 7.2 (Tris–HCl) | 5.73 × 107 | Fluorescence | 37 | ||
DCAa | 7.2 (Tris–HCl) | 2.03 × 107 | Fluorescence | 37 | |||
70 | CAa | 7.2 (Tris–HCl) | 9.93 × 107 | Fluorescence | 37 | ||
DCAa | 7.2 (Tris–HCl) | 3.47 × 107 | Fluorescence | 37 | |||
71 | CAa | 7.2 (Tris–HCl) | 3.96 × 107 | Fluorescence | 37 | ||
DCAa | 7.2 (Tris–HCl) | 3.78 × 107 | Fluorescence | 37 | |||
72 | CAa | 7.2 (Tris–HCl) | 2.95 × 107 | Fluorescence | 37 | ||
DCAa | 7.2 (Tris–HCl) | 6.2 × 106 | Fluorescence | 37 | |||
PBS: Phosphate Buffer Solution; ITC: Isothermal Titration Calorimetry; Tris: Tris(hydroxymethyl)aminomethane; –: The guest-induced variations in the fluorescence intensities are too small for these values to be determined. a: Unit of Ks is in M–2. |
Complex stability constants (Ks/M1), enthalpy (H°/(kJmol1)), and entropy changes (TS°/(kJmol1)) for intermolecular complexation of bile salts with bridged β-CDs in aqueous solution
In conclusion, the binding modes, binding abilities, and molecular selectivities of four typical bile salts (CA, DCA, GCA, and TCA) upon complexation with CDs and their derivatives are summarized in this chapter from thermodynamic viewpoints. Generally, native and mono-modified CDs display relatively limited binding ability towards guest molecules, probably because of weak interactions between hosts and guests, which would result in a relative small negative enthalpy change, and then, a relative weak binding. However, bridged and metallobridged CDs have greatly enhanced the binding abilities in relation to the parent CDs, owing to a multiple recognition mechanism, which would lead to a relative large negative enthalpy change, and then a strong binding.This summary of the binding modes and thermodynamic data for the complexation of bile salts with CDs and their derivatives is quite important to improve the understanding of molecular recognition mechanism in supramolecular systems and further guide the design and synthesis of new supramolecular systems based on different kinds of CDs in the future.
This work was supported by the 973 Program (2011CB932502) and NSFC (20932004), which are gratefully acknowledged.
The era of microfluidics started in 1980s with the development of silicon etching procedures which were made for microelectronics industry. This paved way for manufacturing of first of its kind devices called Micro Electro Mechanical Systems (MEMS). In these devices mechanical microelements were integrated together on a silicon wafer. In the 1990s, researchers explored applications of these devices in the field of biology, chemistry and biomedical. They used these devices for controlling liquid’s movement in micro channels which paved way for microfluidics. Laboratories on chip were developed for incorporating all the major procedures of biology, chemistry or biomedical on single platform. But, this use to come with huge cost and infrastructure for microelectronics industry. In 2000s a new era of microfluidics was started with the development of molding micro channels in polymers. This lead to decrease in cost as well as manufacturing time that caused the boom in the area of microfluidics and motivated researchers of all fields to work using them [1]. In the era of fast pacing science, microfluidic are devices to enhance pace of research and decrease the experimental cost. They run on principle of various types of taxis, majorly chemotaxis. Taxis is the movement of particles according to some external guiding agent. This agent can be heat, oxygen, pressure, electric field or chemical, etc. Various types of taxis, their applications and microfluidics are discussed in this chapter. Microfluidic is the technology where movement of the particles is on the basis of microenvironment consisting of viscosity, surface tension and pressure. In microfluidics, micro channels are molded or etched over the silicon, glass or various polymer materials such as PolyDimethylSiloxane. These types of devices are vastly being used in all the fields of research, diagnostics and therapeutics. In microfluidics, the micro channels are formed to attain the desired result which can consist of: mixing, sorting, pumping or controlling the biochemical microenvironment. They have the advantage of decreasing the response time and experimental consumables and overall cost. They have the potential to perform large scale experimentation in small scale. Important factors to be considered for fabrication of microfluidic devices are temperature resistance, superior optical transparency of the material, high hardness, excellent electrical isolation, thermal stability, chemical inertness to many fluids, biocompatibility, and surface wettability. The performance of microfluidic device depends majorly upon etched or molded micro channel’s surface properties. Therefore surface modification is an important factor to improve overall performance of microfluidic devices. Surface roughness, surface heterogeneity and solution impurity are the key parameter which affects the wettability of microfluidic device.
Molecules are always in motion irrespective of their state. Molecules in solid state have least freedom while in gaseous state have maximum freedom. Freedom of movement of molecules in liquid phase lies between molecules in solid and gaseous phases. Heat and temperature are factors that affect the movement of molecules. Enhance temperature increases the translational movement of molecules. Movement of molecules can be random or directed towards certain stimuli. Random movement is termed as “kinesis” while directed movement towards certain stimuli is termed is “taxis”. For taxis, there is sensory component to detect the attractant and motor component to enable the movement towards the stimuli [2]. Taxis are classified on the basis of the stimulus into various categories.
Aerotaxis is the movement of molecules where oxygen acts as stimulant [3]. It has been observed in bacteria and other microorganisms. Active movement of cells is observed along the gradient of oxygen. Aerotaxis plays role in cell survival as optimal concentration of oxygen is required for cell metabolism and growth [4].
Anemotaxis is the movement towards wind. It is observed in drosophila and some terrestrial mammals such as rats which tend to follow the wind. Drosophilla has been observed to move against the air current [5]. Rats were also observed to follow anemotaxis as air current carries information regarding location and odor content [6].
Barotaxis is the movement towards stimulus that is pressure. Movement due to hydraulic resistance (resistance to flow as a result of liquid) is also termed as barotaxis. This type of movement is observed in the neutrophils, a type of immune cell. Neutrophils follows path of least hydraulic resistance.
Chemotaxis can be defined as the movement of cells towards the higher chemical concentration gradient [7]. It is directional locomotion of cells and was first described in the bracken fern spermatozoa in 1884 by Pfeffer. Later in 1888, this phenomenon was described by Leber in mammalian leukocytes in response to an injury. Chemotaxis is an important process required for the growth and development of multicellular organism, immune response and cancer metastasis [8].
Durotaxis is the movement of cells towards more rigid gradient which is a result of variation in the structural property of the extracellular matrix. This type of motion implies movement towards more stiffness [9]. This type of motion has been observed in various cell types such as human fibroblast cells, mesenchymal cells and cancer cells. Substrate rigidity is the stimulus that initiates the movement in durotaxis [10].
Electrotaxis is also termed as galvanotaxis and implies movement guided through electric field or current [11]. Living cells have the tendency to sense and follow direct current electric field. This type of movement is observed in both in vitro and in vivo conditions although the mechanism behind sensing of electric field by cells remains unclear [11]. Its applications are observed in wound healing and development. Disruption of an epithelial layer in wound leads to generation of an endogenous electric field which guides migration of cells towards the wound for regeneration [12].
Gravitaxis is characterized by directional movement in response to gravity [13]. This type of movement is observed in the motile microorganisms such as euglena where gravity acts as stimulus to select their niche in environment. It can be both positive and negative. Positive gravitaxis implies movement towards water while negative gravitaxis implies movements towards the surface [14]. This type of motion is observed in Drosophila melanogaster and around 18 genes have been identified that mediate this gravitational motion in them [15]. To elucidate the mechanism of this type of motion, asymmetric self-propelled particles were studied for this motion. It was observed that shape anisotropy alone is sufficient to induce such type of motion [16].
Moisture acts as stimulus in hydrotaxis. Movement of cells, animals or plants towards more moisture is termed as positive hydrotaxis and towards less moisture is termed as negative hydrotaxis. Hydrotaxis is observed in the C. elegans as they move towards their preferred water content for mating, geographical distribution and reproduction [17]. It is also observed in the cyanobacterium in desert crusts. Cyanobacteria colonies are observed 1.5–2.0 mm deep into the desert crust but when crust surface is saturated with water, cyanobacterium moves towards the surface having higher moisture content [18].
Magnetotaxis is the movement due to magnetic field. This type of movement is a character of diverse group of gram-negative bacteria that perform their orientation and coordination movements according to earth’s magnetic field [19]. They are majorly aquatic and swim along the geomagnetic field lines. These types of bacteria are also termed as magnetotactic bacteria [20]. Supramolecular adaptive nanomoters have been developed that exhibit magnetotactic behavior and their guided motion is observed in the tissue model [21].
Phototaxis is the movement towards or away from the light source. This type of movement is characteristic of phototrophic organisms and is also observed in plants. Prokaryotes use type-I sensory rhodopsin photoreceptors for phototaxis and it allows them movement towards steep light gradient. Cyanobacteria can also perform phototaxis but they also can perform it in two-dimension only through gliding on the surface. Eukaryotes have the ability to navigate through light vector in three-dimension in open water [22].
Rheotaxis is the movement in response to water or air current. This type of motion is observed in aquatic animals where their movement occurs in response to water current [23]. When movement is towards oncoming water current, it is termed as positive rheotaxis while movement opposite of oncoming water current is termed negative rheotaxis [24]. This type of motion is observed in zebrafish, Crustaceans and American lobsters [25].
Thermotaxis is the movement towards or away from temperature gradient. In this motion, organism move towards temperature source. Slime molds and nematodes are known to move along shallow temperature gradient [26, 27]. Mammalian sperm is also observed to perform theromtaxis to reach towards the oviduct in the female body [28].
Microfluidics is the technology based upon behavior of fluids in the microenvironment. Fluids tend to behave very differently in micrometric scale as compared to macro scale. These characteristics of fluids are now been used for various studies based upon taxis. In macroscopic system, pressure, volume and temperature are the key players whereas viscosity, surface tension, high shear rate and geometric effects (high surface to volume ratios, constriction, and bifurcation) are the key drivers of the microfluidic system [29]. Microfluidics is the integration of fluids physically restricted to sub-millimeter dimensions with micro/nanostructures and devices [30]. Microfluidics is an emerging interdisciplinary field consisting of engineering, physics, chemistry, microtechnology, biotechnology and material sciences [31]. The reason for its emergence is miniaturization of operational unit in the microfluidic devices. Miniaturization is preferred as all operations can be packed in small form that can be automated and is portable [32]. Low amount of materials and chemicals are required for development and samples required is also less. Automation enables widespread use of the system without any special training requirements. Easy disposals, low cost, reduction of cross-contamination and fast response time are other benefits of the microfluidic system [33].
The global size of microfluidic devices was USD 13.5 billion in 2019 and is supposed to have a compound annual growth rate of 11.3%. The large market size is due to its multi-application and ease of usability. Basic layout of microfluidic devices consist of incorporated fluid channels in at least one direction. These channels provide high surface to volume ratio which is useful in applications such as biochemical analysis, antimicrobial susceptibility test and heat exchange modules. This field started with applications in chromatography and electrophoresis [34]. With time it has evolve and currently it has vast applications due to development of new fabrication materials and technologies [31]. Its applications include environmental sensing, biomedical applications, drug discovery, drug delivery, micro scale energy systems, artificial organs, micro scale chemical testing and production, micro propulsion, combinatorial synthesis and assays. These applications have been classified under broad categories for discussion in this chapter.
Microfluidics can be used in biomedical field as analytical arrays, gradients, separators, microdiluters, gel structures, droplets, painting cells and devices [35]. In arrays, a set of multiple microchannels is used to study the relationship between different cells with proteins or chemicals within a combinatorial system. This type of system can be used for detection of specific proteins in large number of samples, antibiotic resistance testing, etc. Microfluidics can be used for generation of very steep gradients that cannot be created using other macro techniques [35]. These gradients are useful in the study of macromolecules and cells in response to their varying environment. Biochemical gradients are useful in dictating physiological processes such as proliferation, differentiation and migration. These gradients play an important role in tissue generation as well. They are used for organ on chip techniques also. Phil et al. used drug gradients for activity measurement over CHO cells [36]. Migration and behavior of neutrophils according to protein gradient has also been studied [37]. Chung et al. used growth factor gradient to study the differentiation of human neural stem cells [38].
Microfluidics can be used as diluters where solution is passed through series of controlled dilutions to be used in a specific assay. Ainla et al. have shown use of pulse width flow modulation based designing of microdiluter [39]. They used this microfluidic diluter for analyzing the effect of Ca(2+) concentration over phospholipid bilayer spread onto a SiO2 surface. Microdiluters can also be used as immunoassays for detection of multiple antigens at a same time [40]. Microfluidics can be used in conjunction with gels or microchannels can be made in gels using soft lithography technique. Various types of gels in which microfluidic can be fabricated are agarose, agar and calcium alginate. These types of systems can be used to study complex microenvironment of cells. Takeuchi et al. used microchannels fabricated in agarose to grow Escherichia coli in presence of various molecules that can alter their phenotype [41]. Cabodi et al. used alginate based microchannels for study of mass transfer in channels [42]. Complex Microfluidic systems are now being highly researched and commercialized to develop point of care/lab-on-chip (LOC) devices and organ on chip. These devices have high potential as they can provide the customer with the easy of usability, less sample requirement, time and cost efficiency.
Point of care devices are diagnostic measures that are directly used by patients and without requirement of medical staff. A simple paper based microfluidic that can be used as point of care device are known as lateral flow test (LFT). Porous material such as glass fiber, nitrocellulose and cellulose paper can be used for fabrication of LFT. The components on microfluidic LFT device are sample collection pad, a dried conjugate pad followed by a reaction area and an absorbent wicking pad. This is incorporated within a plastic housing and plastic barriers throughout to maintain one dimensional flow. The best example of LFT is dipstick pregnancy test kit. This test works on the principle of an immunoassay. Sample which is urine is applied to the sample pad and rehydrates the goldnanoparticles conjugated detection antibodies [43]. These rehydrates antibodies bind to the target antigen present in the sample. Together they flow to the capture region which consists of control and test line. At the test line, non-labeled antibodies specific for the detection antigen are immobilized. When rehydrated labeled antibodies conjugated with the sample antigen reaches test line, it binds to the non-labeled antibodies specific for that same antigen. This interaction gives visual color change thereby making test line visible in case of positive results. This process is depicted through Figure 1a and b. The wicking pad in the device performs function of attracting the sample through LFT. After reaction membrane is completely wetted, the capture region functions through capillary action.
(a) Non-wetting phenomenon, (b) wetting phenomenon, (c) larger contact angle (non wetting), (d) wetting, (e) angle close to zero complete (wetting).
Paper microfluidics has also been used to provide point of care diagnostics for non-communicable diseases such as cardiovascular disease and cancer. In this work, synthetic urinary biomarker is used which is detected through paper microfluidics [44]. These types of devices are also being used for saliva based detection of oral diseases. In the research work by Amy et al. point of care diagnostic device for oral diseased was developed using monolithic disposable cartridge. It was designed in a compact analytical device. This device combined sample pre-treatment procedure of filtering, enrichment and mixing of sample with electrophoretic immunoassays. It can efficiently and quickly measure analyte concentration in the minimally treated and very low volume (20 μl) of saliva sample [45]. Microfluidic devices are also used for digital polymerase chain reaction (PCR) which is a very powerful gene expression analytical tool. Christina et al. showed use of microfluidic based digital PCR for prenatal detection of fetal aneuploidy. Fetal Aneuploidy is the presence of an abnormal number of chromosomes (structures that contain genetic information) in the fetus [46].
Organ on chip is the new class of laboratory models that have advantages of both in vivo and in vitro models. These chips are microfluidic devices in which tissue of interest is cultured in the favorable microenvironment simulating the actual physiological conditions efficiently. These types of devices can also be used in the field of personalized medicine. For personalized medicine, cells from specific donor patients and healthy patients can be studied under the same environment. Various examples of such devices are lung on a chip [47], atherosclerosis on a chip that made study of physiological functions of an organ and its response to various stimuli feasible [48]. Other examples are bacteria inhabited gut on a chip [49] and blood brain barrier on a chip [50]. This field of organ on chip is emerging rapidly and showcasing various organs’ culture and their physiological microenvironment simulation on these microfluidic chips.
The development in the field of integrated microfluidics was successfully laid by its incorporation with the optical elements such as plasmonic surfaces [51] and waveguides [52]. In 2000s, the development of liquid-crystal switchable gratings, microfluidically tunable photonic crystal fibers and bubble switch laid the foundation of using microfluidics as an essential part of the photonic devices. During mid-2000s a new field of “optofluidics” was evolved from the existing technologies in the field of photonics and microfluidics. Using microchannels and photonic elements, optofluidics has the strength of having precise control over light and fluidics at small scale [53]. Microfluidic systems are being used for development of photocatalytic microreactor. A planar microfluidic reactor was developed by Lei et al. It consisted of the small planar chamber where two TiO2 coated slides were used as top cover and bottom substrate. Microstructured UV-cured NOA81 layer was used as the sealant and flow input/output. This reactor has advantages of microfluidics such as easy control of flow, rapid fabrication and large surface/volume ratio. It is the key to more efficient photocatalytic water treatment [54]. TiO2 based microreactor has been developed by Matic et al. for photocatalytic applications. This system was fabricated on metal-titanium foil. Titania nanotubes were mechanically engraved in the substrate foil. Using anodization & hydrothermal treatment TiO2 anatase film was immobilized over the inner layer of these tubules. An additional TiO2 anatase layer was added on top of the film to provide larger photocatalytic area. This microreactor depicted enhanced durability and efficiency [55]. Meng et al. also developed microfluidic based photocatalytic microreactor. They used nanofibrous TiO2 through electrospun to develop this photocatalytic microreactor. It depicted enhance efficiency as compared to TiO2 film based microreactor [56].
Recently, applications of microfluidics have been developed in the form of microfluidic fuel cells. In these cells, all the systems such as fluid delivery, removal, etc. is confined to the microfluidic channel only. These cells do not require a physical barrier for separation of fuel and oxidant species and therefore they operate in co-laminar flow mode. Whereas, in conventional fuel cell a physical barrier such as proton exchange membrane is required. They can be used to power microsystems, generate on-chip power and in consume electronics as well [31]. Microfluidic fuel cells have attracted huge researchers as they are portable power sources with short startup time and environment friendly nature. Microfluidic fuel cell using laminar air flow had been developed by Eric et al. (Figure 2a). It was made through a Y-shaped microchannel consisting of two catalyst covered electrodes on opposite walls. Through these channels, fuel and oxidant merge and flow laminarly parallel between these two electrodes without turbulent mixing. They showed that this type of system can be effectively used to generate microscopic power source for room temperature [57]. There is patented microfluidic fuel cell system for portable energy applications. In this system, microfluidic container, substrate for catalytic composition, a liquid/gas separator, a fuel cell consisting of anode and cathode and electrical connections were all assembled to form this portable energy system [58]. The design of the system and fuel cell components is depicted through Figure 2b and c, respectively [58]. Luke et al. also developed these microfluidic cells based on microbial fuel that can be used to provide power supply to integrated biosensors. This system was developed in polydimethylsiloxane. Here, two carbon cloth electrodes and proton exchange membrane was used. Shewanella oneidensis MR-1 was used in anode chamber as electrogenic bacterial strain and ferricyanide was used in cathode chamber (Figure 2d). Maximum current of 2.59 μA was generated using this miniature microbial fuel cell [59]. Svetlana et al. developed a microfluidic cell for energy conversion. They developed hydrogen and oxygen based microfluidic cell using polydimethylsiloxane (PDMS) device. In this device Pt/quartz electrodes in the form of thin film were embedded into the device. The PDMS microchannel network containing liquid electrolyte was used for immersion of electrode array into it. This also performs the function of thin glass permeable membrane for feeding reactants to the electrodes. This fuel cell operated at room temperature with the maximum power density of 700 μW/cm2. The overall lifetime of this cell was comparatively higher to the exiting higher surface electrodes based fuel cells [60].
(a) The reaction of antibiotic dish with bacteria, (b) glass microchannel without bacterial coating, (c) reaction of antibiotic with bacteria in microchannel, and (d) the spreading of chemical reaction in microchannel with different antibodies.
Recent growth in the field of microfluidics has been observed in the field of environmental assessment. Microfluidics is advantageous as multiple processes such as pre-treatment, pre-concentration, separation and detection are incorporated at the same platform. It is used for trace analysis of materials as less risk of contamination is there due to preclusion of sample transportation process. Microfluidics play role in the development of subsurface energy based technologies in the future. Mark et al. developed a microfluidic system based upon high temperature and pressure. Within geo-material micromodels such as rock, cement, clay, etc., direct observations for flow and transport can be made using this system and that too in reservoir conditions. In this micromodel fabrication method, 3D tomography images of real fractures were used as micromodel template. This provided better representation of the pore space and fracture geometries in subsurface formations [61]. Several microfluidic devices can be used for detection and analysis based upon electrochemistry, surface enhanced Raman spectroscopy, chemiluminescence, absorbance and laser-induced fluorescence. These electrochemical and optical based systems can be conjugated on a single micro platform to perform environmental monitoring. These labs on chip systems can be used for real time tracking of pollutants in the environment. Major advantages of these systems are portable compact size, better process control, low-cost production, real-time analysis, low sample consumption and fast response. LOC is used for real-time analysis of pollutants in wastewater. Combining it with the wireless communication, make it a strong tool for modifying data acquisition parameters and data transfer [62].
Microfluidic systems are being used for detection of formaldehyde as well. Formaldehyde is the organic volatile compound found in many household products. It is associated with health risk factors and is also a cause of sick building syndrome. Therefore its detection at real-time in the surroundings is essential for a healthy living. Liu et al. developed a paper based microfluidic system for detection of formaldehyde. Acetoacetanilide reagent is used to implant paper-based chip at reaction site. Concentration of formaldehyde is detected using UV light which induces fluorescence intensity in the dihydropyridine. Dihydropyridine is the complex of formaldehyde with acetoacetanilide. This method was used to detect formaldehyde in the commercial food samples and proved to be an efficient method for detection of formaldehyde concentration [63]. Similarly, Czugala et al. developed a fully integrated microfluidic device to provide wireless and portable analytical platform. This system can be used for detection of nitrite anions in the water. Nitrite anions are one of the water contaminants along with lead, cadmium and nitrate. In this system detection is done through analysis of color intensity of complex formed between nitrite anions and Griess reagent. This color intensity was assessed using low cost Paired Emitter Detector Diode. Biomimetic photoresponsive ionogel microvalve controlled by LED was used for manipulation of on-chip fluid. This system was one of its type that conjugated fully functional microfluidics with photobased valving and photo detection [64]. Microfluidic devices along with porous plugs have also been developed. This device can be used for size based separation of particles including microorganisms and therefore have implications as miniature filter for analysis of water samples. Living radical photo-polymerization technique using wide range of polymers was used for fabrication of these devices. Salt-leaching technique was used for placement of porous plug in the microfluidic channels. Pore size of the porous plug in this device was determined using flow field-flow fractionation. It is a new and cost efficient simple tool for water assessment [65]. Research is moving at a fast pace for development and commercialization of such paper based microfluidic devices that can be conjugated with other existing techniques.
Surface wettability or wetting is the ability of the liquid to maintain contact and interact with the solid surface over which it is flowing. It results from the interaction of intermolecular forces between the molecules of liquid and molecules over the surface of the solid. Surface wettability measurement is a very critical technique to measure the flow of micro fluid in microfluidic applications. In microfluidic devices the detection of small volume change with change in fluid properties is very small because of the micrometer range. In order to detect this small change in micrometer range in situ wetting measurement is required. Microfluidic devices offer innumerable application in the field of science and technology. The scopes of these types of devices have been increasing for recent decades. For example, in clinical trials for drug development the amount of antibodies used is very high and cover large cost. On the other hand microfluidic devices reduce amount and cost of antibodies as well as time.
In microfluidic devices the motion of chemical reaction governed by chemo taxis gradient and this gradient is responsible for the motion of droplet. The motion of droplet generally measured with the help of wettability and wettability of droplet depends upon the surface. Wettability has a dynamic impact on the displacement of fluid inside micro fluidic device. The change in displacement of any fluid inside any microfluidic device measured in term of spreading of fluid. The spreading behavior of any flowing liquid measured with its wetting behavior and it is generally measured in term of contact angle. The magnitude of contact angle formed by micro fluid with micro-channel wall has great importance to study the characteristics of micro fluidic device.
Example: Suppose a static fluid is placed at the center of any plate and we apply taxis gradient at the two end of plate. The taxis gradient (magnetic, chemotaxis) is responsible for the displacement of fluid inside. The fluid try to spread both in linear (parallel to gradient axis) and lateral (perpendicular to direction of applied gradient) direction. The two directional spreading of liquid makes difficulty in the quantitative measurement in displaced liquid. In order to overcome this issue microfluidic devices play the important role in various scientific testing applications.
The contact angle measurement is carried out using young’s equation is given in Eq. (1). The equation is derived by balancing different interfacial energy in all direction.
where θ = contact angle
σsv = solid/vapor interfacial energy
σsl = solid/liquid interfacial energy
σlv = liquid/vapor interfacial energy.
Wettability of fluid over the solid surface is measured in terms of contact angle (θ). The higher value of contact angle leads to lower wettability (low spreading area of displaced fluid) as shown in Figure 1c. The contact angle close to 0°, as droplet turns into flat puddle shows complete wetting (highest spreading area) as shown in Figure 1e, if angle exceeds zero but is less than 90° as shown in Figure 1d shows wetting [66].
In microfluidic devices the fluid displacement takes place only in linear direction because of micro channel cavity. The quantitative measurement of displaced fluid inside micro channel can be made by measuring the dimension of micro channel and displace length of fluid. The measurement of displace volume with little change in taxis gradient improves the overall sensitivity of device. Sensitivity of device is defined as the measurement of small change in the system by varying input parameter.
The existing process of antibiotic susceptibility measurement uses Petri dish coated with bacteria and divides the Petri dish into required number of segment using marker. An antibiotic dish (different concentrations) is then placed over the bacterial coated Petri dish. The petri dish is then placed over incubator for 24–48 hours. The reaction of bacteria with antibiotic takes place in petri dish and reaction takes place in radial outward direction as shown in Figure 1a. The measurement of reaction in radial direction is difficult to quantify in required scale. To overcome this issue a microfluidic device can be used as antibiotic susceptibility testing device. In this type of device, glass slide micro channel is coated with bacterial coating like petri dish as shown in Figure 1b. Different antibodies are then placed over bacterial coated micro channel for measuring the spreading of reaction due to chemo taxis in one direction and chemo taxis spreading phenomenon can be quantify using microfluidic chip time lapse microscopy as shown in Figure 1d. The spreading of reaction is then measured by the dimension of micro channel as shown in Figure 1c.
In this study, microfluidic device for mixing three liquid is used. In this device, three different liquid A, B and C is used to mix in different concentration and their mixing reaction is measured with the range of output mixing micro channel as shown in Figure 3. In this type of device the change in output parameter can be detect significantly my using small volume of liquid droplet. These devices are very useful to measure mixing behavior of two or more liquid for various chemical mixing applications.
Microfluidic device for mixing different liquid.
The wettability is generally are properties of displaced liquid measured in term of contact angle. The surface morphology, material impurity and porosity are the properties which affect the wettability.
Effect of surface roughness: All smother surfaces look rough in microscopic level. The rough surface of solid specimen affects the wettability of liquid over the solid surface. The contact angle formed with flat surface is called apparent contact angle θa and it is consider by considering ideal surface condition. The actual contact angle θA is generally higher than that of apparent contact angle θa as shown in Figure 4a,b. To calculate real surface free energies of liquid actual contact angle is used. Generally hydrophilic surface is considered to be the best surface where lower value of contact angle is obtain. The wettability of liquid surface generally increases as we decrease the surface roughness of solid surfaces. The relation between roughness and wettability was explained by Wenzel and stated that if the surface is chemically hydrophobic it will become more hydrophobic when surface roughness is added. According to Wenzel,
Effect of surface roughness on the wettability of fluid.
R is the surface ratio between actual and projected area of solid surface over which fluid is flowing. For smother surface R = 1 and apparent contact angle becomes equal to actual contact angle. Other than surface roughness, impurity and porosity in solid surface effect wettability.
In microfluidic device, the displacement of fluid takes place continuously, and it is very difficult to measure wettability (contact angle formed by moving fluid with the wall of micro channel). The Sessile drop method and image analysis techniques are the method used only for measuring the static contact angle of liquid in micro channel device. For biomedical and clinical application the chemotaxis reaction takes place continuously and required continuous monitoring of contact angle in situ image capturing system is used. In this technique the position of chemical reaction captured with the help of microscope and high speed camera installed over the viewing point of microscope [67]. The camera records the position of reaction in different time interval and measured the contact angle and contact angle is further used to measure interfacial energy of fluid in microfluidic devices. The schematic of in situ image capturing system is as shown in Figure 5.
In situ image capturing system for measuring wettability of microfluid devices.
In this system a microscope is just place at the top of microfluidic device and it captures the motion of chemical reaction change in micro channel. A light source is applied from the side to capture the video with more celerity with the help of high speed camera and store video into computer. The video is than sliced into image in required time interval as shown in lower left corner of figure. The Enlarge version of captured screen is shown in lower right corner of Figure 5 which shows the measurement of contact angle variation at different time interval.
The selection of microfluidic fabrication process is dependent on type of material selection for different microfluidic application. The special grade stainless steel, borosilicate glass, PDMS (polydimethylsiloxane), PMMA(Poly methyl metacrylate) copper, aluminum and Acrylic have been used as solid material for microfluidic device fabrication. Chemical etching, 3D printing, Additive manufacturing, micromachining are the common manufacturing practices for the development of different microfluidic devices [68, 69, 70].
Microfluidic devices are one of the most widely used devices of twenty-first century. They are being used in almost all the fields including biomedical, energy, chemical, environmental, etc. Microfluidics is the technology based upon various types of taxis, specifically chemotaxis. Surface wettability is an essential factor in the development of microfluidics. Elucidating mechanisms to improve surface wettability will help in the betterment of microfluidic devices. There are still unexplored applications of microfluidics such as in paint industry: to study the mixing and spreading of paints. Initially, microfluidics developed due to advancement in the field of silicon etching and molding of micro channels technique. The further advancement in the fabrication techniques will pave way for development of high-leveled microfluidic devices that will open a new era of research in all the fields.
We would like to acknowledge DARVUN India for providing us the opportunity of working for them.
The authors declare no conflict of interest.
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