Proportion of LVV-h7 in total area of peptides after extraction process.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"},{slug:"intechopen-s-chapter-awarded-the-guenther-von-pannewitz-preis-2020-20200715",title:"IntechOpen's Chapter Awarded the Günther-von-Pannewitz-Preis 2020"}]},book:{item:{type:"book",id:"5864",leadTitle:null,fullTitle:"Different Types of Field-Effect Transistors - Theory and Applications",title:"Different Types of Field-Effect Transistors",subtitle:"Theory and Applications",reviewType:"peer-reviewed",abstract:'In 1959, Atalla and Kahng at Bell Labs produced the first successful field-effect transistor (FET), which had been long anticipated by other researchers by overcoming the "surface states" that blocked electric fields from penetrating into the semiconductor material. 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These antibiotics are bacteriostatic in nature and act by inhibiting protein synthesis of bacteria. These are obtained mainly from certain actinomycetes genus, such as Streptomyces and related species. The original macrolide complex, erythromycin A, was isolated in 1952 as a natural product of Saccharopolyspora erythraea (formerly Streptomyces erythreus). Other examples include clarithromycin, azithromycin, telithromycin, cethromycin, modithromycin, etc. Macrolides structurally contain three characteristic parts in every molecule, that is, a macrocyclic lactone ring, multiple ketone & hydroxyl group, and two deoxy sugars attached by glycosidic bond. According to the carbon number of lactone ring, macrolides are classified into several types. That is, 12-membered ring, 13-membered ring, 14-membered ring, 15-membered ring, 16-membered rings, etc. (Figure 1). Out of these, most of the antibiotic drugs comprised of 14-membered and 16-membered lactone rings.
Classification of macrolide antibiotics.
The construction of macrocyclic structures is a recurrent and challenging problem in synthetic organic chemistry. Theoretically, macrocyclic systems can be generated by cyclization of open, long chain precursors or by cleavage of internal bonds in polycyclic systems. In the course of synthesis, numerous problems are encountered to achieve target molecules. Despite the several problems, however, recent interest in the chemistry of macrolide antibiotics and other biologically active macrolactones and macrolactams resulted in the discovery and development of several new synthetic methods for macrolide formation. In this chapter, total synthesis of some of the macrolides is discussed with scrupulous emphasis on the key macrolide ring forming reactions.
In the polyoxomacrolide ring, generally we will observe the 1,3-diol systems as a core. There are two synthetic approaches for the edifice of 1,3-diols which are illustrated here. They are asymmetric aldol reaction and the other one is asymmetric epoxide and epoxide ring-opening.
Asymmetric synthesis of β-hydroxy ketones by aldol reactions of ketones with aldehydes is the general and efficient method for the synthesis of 1,3-diol systems and is of great interest in the field of total synthesis. By using the range of chiral ketones, highly diastereoselective syn and anti aldol products are produced using various boron enolates [1, 2, 3]. Some of the reagents shown below (Figure 2) direct the relative and absolute stereochemistry of C▬C bond formation between various achiral and chiral ketones, thus providing a ubiquitous synthetic tool for macrolide synthesis (Figure 3).
Reagents for asymmetric Aldol reactions.
Macrolide antibiotics: evidence for the chemists interested in the stereochemistry of the Aldol reaction.
A highly efficient and extensively used method for diastereoselective aldol reactions is the Evans aldol reaction using boron enolate derived from a chiral imide [4, 5]. Upon treatment of imide 1 with n-Bu2BOTf and i-Pr2NEt in CH2Cl2 followed by addition of aldehyde, aldol reaction proceeds smoothly in stereoselective manner through the chelation transition state to attain 1,2-syn-aldol adduct 2 in high yield and with excellent diastereoselectivity. After the reaction, the chiral auxiliary is cleaved by hydrolysis to acid, then reduction to aldehyde or alcohol, conversion to Weinreb amide, etc. In contrast, addition of a Lewis acid to the boron enolate provides either anti-diol 3 or non-Evans 1,2-syn-aldol 4 with excellent diastereoselectivity [6] (Figure 4).
Evan’s Aldol strategy.
The asymmetric epoxidation of allylic alcohols introduced by Katsuki and Sharpless in 1980 has tremendous applications in the synthesis of various compounds [7]. The Sharpless asymmetric epoxidation (AE) is the efficacious reagent in the synthetic organic chemistry particularly in the synthesis of variety of natural products. Epoxidation is carried out from allylic alcohols 5 with tert-butyl hydroperoxide in the presence of Ti(OiPr)4. The resulting epoxide stereochemistry is determined by the enantiomer of the chiral tartrate ester (usually diethyl tartrate or diisopropyl tartrate) employed in reaction. When (−)-diester is used, β-epoxide 6 is obtained, while (+)-diester produces α-epoxide 7 (Figure 5).
Sharpless asymmetric epoxidation strategy.
The Sharpless dihydroxylation [8] is another tool used in the enantioselective preparation of 1,2-diols (9a/9b) from olefins (8). This reaction is performed with osmium catalyst and a stoichiometric oxidant (e.g., K3Fe(CN)6 or NMO). Enantioselectivity is produced by the addition of enantiomerically-enriched chiral ligands [(DHQD)2PHAL also called AD-mix-β, (DHQ)2PHAL also called AD-mix-α or their derivatives] (Figure 6). These reagents are also commercially available as stable and not so expensive.
Sharpless asymmetric dihydroxylation.
Stereoselective ring-opening of 2,3-epoxy alcohols 10 is extremely valuable for the synthesis of different functionalized compounds [9]. A wide range of nucleophiles such as secondary amine, alcohol, thiol, azide and carboxylic acid predominantly at C-3 position to give 1,2-diol 11 (Figure 7).
Stereoselective ring-opening of epoxy alcohols.
The logic of macrocyclization in natural product synthesis can be investigated by different strategies; some of them are Prins reaction [10], lactonization [11, 12], ring closing metathesis [13], Wittig reaction [14], Horner Wadsworth Emmons (HWE) reaction [15], Julia-Kocienski reaction [16], metal-mediated cross coupling reaction [17], etc. However, it is true that there is no universal macrocyclization method is reliable in the total synthesis of natural products.
Macrolactonization is the one of the effective and popular methods in the synthesis of macrolactones. The method is based on the lactonization of the corresponding seco-acid. Thus various methods are reported in the literature for the macrolactone synthesis, some of the most commonly used methods are Corey-Nicolaou [18], Shiina [19], Yamaguchi [20], Mitsunobu [21], Keck-Boden [22], and Mukaiyama [23] macrolactonizations (Figure 8).
Some of the popular methods used for macrolactonization.
Hansen et al. [24] reported the synthesis of (−)-aplyolide A from 12 in which they adopted the Corey-Nicolaou macrolactonisation as the key step with 78% yield (Figure 9).
Application of Corey-Nicolaou macrolactonisation.
Narasaka et al. [25] used the Mukaiyama method for the effective construction of macrocycle ring from corresponding seco-acid 13 in the synthesis of Prostaglandin F-lactone (Figure 10).
Mukaiyama method in the synthesis of prostaglandin F-lactone.
Enev et al. [26] in his studies towards the total synthesis of laulimalide, crucial Yamaguchi macrolactonization was employed on the ynoic seco-acid 14 and then reducing the triple bond obtained the desired macrolactone 15 (Figure 11).
Yamaguchi protocol in the synthesis of laulimalide.
In the synthetic studies towards the synthesis of colletodial, Keck et al. [27] effectively used DCC-DMAP protocol for the macrolactonization of 16 to precursor of colletodial 17 (Figure 12).
Keck et al. lactonisation for the synthesis of colletodial.
Mitsunobu macrolactonization protocol based on the activation of the seco-acid alcohol 18 to 19 using diisopropyl azodicarboxylate (DIAD) and triphenylphosphine is used in the total synthesis of natural product (+)-amphidinolide K by Williams and Meyer [28] (Figure 13).
Mitsunobu esterification in the total synthesis of (+)-amphidinolide K.
In the total synthesis of iejimalide by Schweitzer et al. [29], Shiina macrolactonization (2-methyl-6-nitro benzoic anhydride/DMAP) is used as the key step for the construction of macrolactone 21 in moderate yield. Even the yield is somewhat low, other methods failed to construct the lactone while Shiina protocol worked successfully from 20 (Figure 14).
Shiina macrolactonization towards the synthesis of iejimalide B.
In recent years, ring closing metathesis (RCM) has become one of the most paramount tools in synthetic organic chemistry especially in the field of total synthesis of macrolide natural products [13, 30, 31]. Furthermore, RCM is becoming the most popular way to construct large rings and has the advantage of being compatible with a wide range of functional groups such as ketones, ethers, esters, amides, amines, epoxides, silyl ethers, alcohols, thioesters, etc. In view of this, among the several reagents developed by Grubbs, Shrock, and Chauvin, the catalysts A–D represents two generations of ruthenium complexes, while E is the molybdenum Shrock catalyst (Figure 15). A is popularly known as Grubbs first generation catalysts, B and C are Grubbs second generation catalysts and D is Hoveyda-Grubbs catalyst. The choice of the catalysts can be used in the synthetic organic transformations based on the reactivity of the substrate, and other reaction condition parameters. Substitution in the aromatic ring of D has given rise to a new family of third generation catalyst.
Various catalysts for ring closing metathesis.
Here, some of the applications of ring closing metathesis in the total synthesis of macrolides salicylihalamide A [32], trans-resorcylide [33], (+)-lasiodiplodin [34], oximidine III [35], and Sch 38516 [36] by various metathesis catalysts have been illustrated (Figure 16).
Some of the applications of ring closing metathesis in total synthesis of macrolides.
Palladium-catalyzed coupling reactions have gained more attention in recent years in the field of organic chemistry. In this course, Suzuki reaction using organoboron compounds [37], Heck reaction using alkenes [38], Stille reaction with organostannate [39, 40], Sonogashira reaction with terminal alkyne [41] and Tsuji-Trost reaction with π-allylpalladium intermediate [42, 43], etc. are the most frequently employed reactions in the total synthesis of macrolide natural products. Some of them are depicted here.
Tortosa and co-workers [44] in the synthesis of (+)-superstolide A, Suzuki macrocyclisation approach is used for the construction of 24-membered macrocyclic octane 23 (Figure 17).
Suzuki macrocyclisation in the synthesis of superstolide A.
The first application of the Heck cyclisation to a macrocyclic substrate was reported by Ziegler and co-workers [45] in 1981 during the synthesis of aglycone of the macrocyclic antibiotic carbomycin B. They achieved the cyclisation to the model substrate 25 in 55% yield, by slow addition to a solution of PdCl2(MeCN)2, Et3N and formic acid in MeCN at ambient temperature (Figure 18).
Heck cyclisation in the synthesis of carbomycin B.
Stille macrocyclisation as illustrated below used as the key step in the total synthesis of the biselyngbyolide A by Tanabe et al. [46] using Pd2(dba)3 and lithium chloride in DMF (Figure 19).
Stille macrocyclisation in the total synthesis of biselyngbyolide A.
The utility of Sonogashira macrocyclisation in the first total synthesis of penarolide sulfate A1, an α-glucosidase inhibitor is demonstrated by Mohapatra and co-workers [47]. The macrocyclisation was successfully achieved from compound 28 with catalytic Pd(PPh3)4 and CuI in Et2NH at room temperature (Figure 20).
Sonogashira macrocyclisation in the synthesis of penarolide sulfate A1.
Towards the total synthesis of antibiotic natural product A26771B, Trost and co-workers [48] effectively constructed the macrolactone 31 (Figure 21) by the use of bidentate phosphine ligand (1,4-bis(diphenylphosphino)butane (DPPB)).
Tsuji-Trost lactonization for the synthesis of A26771B.
In the end game of total synthesis of macrolides, glycosidation to the aglycon also have more significance. Thus, a wide variety of methods are reported for glycosidation in the literature [49, 50].
In this section, the total synthesis of selected macrolides is discussed: (+)-neopeltolide (32), aspergillide D (33) and briefly about miyakolide (34) and acutiphycin (35).
(+)-Neopeltolide is a 14-membered macrolide isolated from north coast of Jamaica by Wright and coworkers from a deep water sponge [51]. It was tested for in vitro antiproliferative activity against several cancer cell lines comprising A549 human lung adenocarcinoma, NCI/ADR-RES ovarian sarcoma and P388 murine leukemia and shows IC50 values 1.2, 5.1 and 0.56 nM. Besides this, neopeltolide also exhibits anti-fungal activity against Candida albicans [52]. The complexity of the structure with six chiral centres, tetrahydropyran ring, and an oxazole-bearing unsaturated side chain and its efficacious biological activity led to several total syntheses, few of them are discussed below.
In 2013, Ghosh et al. [53] in their total synthesis adopted the retrosynthetic pathway as follows. Disconnection of O▬C bond of the oxazole side chain would give acid which can undergo Mitsunobu esterification. Yamaguchi macrolactonization of acid would in turn give the desired macrolactone. The tetrahydropyran ring in acid could be constructed via a hetero Diels-Alder reaction between aldehyde and silyloxy diene ether using Jacobsen’s chromium catalyst.
The synthesis of the macrolactone ring of (+)-neopeltolide began with commercially available 3-methyl glutaric anhydride as shown in the scheme. 3-methyl glutaric anhydride, 36 was desymmetrized using PS-30 ‘Amano’ lipase to obtain acid. The resulting acid was treated with borane-dimethyl sulfide complex to afford alcohol, 37. Alcohol 37 was oxidized to corresponding aldehyde by Swern oxidation and then protected to its acetal, 38. Ester of 38 was then reduced to alcohol and on Swern oxidation obtained aldehyde and the resulting aldehyde was subjected to Brown’s allylation protocol using (+)-Ipc2BOMe and allyl magnesium bromide to attain alcohol, 39. Alcohol 39 was methylated with MeI, and on Lemieux-Johnson oxidation gave aldehyde and on Brown’s allylation protocol afforded alcohol, 40. Acetal protection was deprotected and the aldehyde was converted to α,β-unsaturated ketone, 41 using standard Horner-Wadsworth-Emmons olefination conditions. Secondary alcohol in 41 was then protected with TESOTf to obtain the silyloxy diene, 42 in excellent yield (Figure 22).
Synthesis of silyloxy diene 42 fragment.
After the completion of requisite silyloxy diene, hetero-Diels Alder reaction of tosyl oxyacetaldehyde, 43 with 42 using chiral chromium catalyst (44) gave tetrahydropyranone, 45 in 83% yield (Figure 23). After protection of ketone group in 45 as ketal and displaced the tosylate to nitrile 46 using NaCN in DMF. Nitrile 46 was hydrolysed to acid and on deprotection of ketone to afford ketone 47. Intramolecular Yamaguchi macrolactonization attained the key macrolactone 48 in 40% yield. Olefin 48 was subjected to hydrogenation with 10% Pd/C to give saturated compound and on reduction with NaBH4/EtOH to attain alcohol 49. Next, the synthesis of unsaturated oxazole side chain 50 is started with known alkyne with LDA and Bu3SnCl to obtain the alkynyl stannate, which on hydrozirconation gave the carbamate in 38% yield. Crucial Stille cross coupling of carbamate with iodooxazole using Pd(MeCN)2Cl2 in DMF gave oxazole which can be easily converted to desired side chain 50. The target neopeltolide compound was furnished by standard Mitsunobu esterification of 49 with acid 50 (Figure 24).
Hetero-Diels-Alder reaction for the synthesis of tetrahydropyrarone moiety.
Completion of synthesis of (+)-neopeltolide.
Paterson and coworkers [54] reported the synthesis of neopeltolide as follows. Aldehyde was synthesized starting from known β-keto ester, 51, which on treatment with (S)-BINAP-Ru (II) catalyst under Noyori asymmetric hydrogenation to afford (13S)-alcohol. The alcohol on TBS protection and DIBAL reduction of the ester produced the enantiopure aldehyde 52. Aldehyde 52 was subjected to Brown’s methallylation using 2-methyl propene and (−)-Ipc2BOMe furnished the desired C11 alcohol with 94:6 dr, and the alcohol was methylated into the methyl ether 53 by NaH, MeI. Methyl ether 53 was subjected to ozonolysis to obtain methyl ketone and on Horner Wadsworth Emmons reaction with trimethyl phosphonoacetate to attain ester 54 in E/Z isomers (75,25). Esters 54 were reduced to its alcohol by DIBAL-H and on subsequent oxidation with Dess-Martin periodinane produced aldehyde 55. Next, organo catalytic hydride reduction of enal 55 using MacMillan strategy with imidzolidinone catalyst 56. TFA (20 mol%) and Hantzch ester furnished as 1,4-reduction product 57 with 76:24 of epimers at C9 stereocentre (Figure 25). Further, Jacobsen asymmetric hetero Diels-Alder reaction between 57 and known 2-silyloxy diene 58 produced cis-tetrahydropyranone 60 in 60% yield using chiral tridentate chromium (III) catalyst 59. On PMB deprotection and further oxidation of alcohol to corresponding acid followed by TBS deprotection furnished seco-acid 61. Macrolactonization of 61 under standard Yamaguchi conditions afforded macrolactone 62 in 80% yield. Reduction of macrolactone 62 to the alcohol with NaBH4 in MeOH followed by Mitsunobu esterification with the oxazole side chain 50 achieved (+)-neopeltolide (32) in 52% yield (Figure 26).
Synthesis of aldehyde 57.
Total synthesis of (+)-neopeltolide.
The synthesis of neopeltolide by Ulanovskaya et al. [55] is depicted as follows, Prins desymmetrization of diene 63 followed by benzyl protection and Wacker oxidation of alkene afforded ketone 64. Formation of boron enolate from ketone and on addition of aldehyde 65 gave the anticipated aldol product with >98:2 diastereoselectivity, which was treated with Ph3P=CH2 (Wittig methylenation) followed by cleavage of dioxolone by acidic work-up afforded ketone 66 in 75% yield. Ketone 66 was selectively reduced to syn-alcohol using Et2BOMe and NaBH4 followed by ester hydrolysis gave acid which was subjected to Yamaguchi macrolactonization to furnish desired macrolactone 67. Alkene in 67 was hydrogenated using Pd/C to afford desired alcohol 68 as a major product. Alcohol 68 was subjected to Mitsunobu conditions, followed by hydrolysis with K2CO3 in MeOH to get the inversion product. Subsequent methylation with MeO3BF4 & hydrogenolysis of benzyl ether achieved desired macrolide 49. The final coupling of fragment 49 with oxazole side chain 50 with standard Mitsunobu conditions furnished target (+)-neopeltolide 32 (Figure 27).
Alternate synthesis of (+)-neopeltolide.
Bao and coworkers in 2013 isolated 16-membered macrolide, aspergillide D, from the extract of Aspergillus sp. SCSGAF 0076 [56]. Aspergillide D macrolactone contains four chiral centres, α,β-unsaturation, three hydroxyl groups and the first total synthesis was reported by Jena et al. in 2017 as follows [57].
The retrosynthetic analysis of aspergillide D was depicted as shown above, macrolactone could be synthesized from seco acid via intramolecular Shiina esterification. For the total synthesis of Aspergillide D, the acid fragment was synthesized from commercially available D-ribose which was transformed to lactol 69 by using three step sequence, that is, catalytic amount of H2SO4 & acetone to form acetonide which on reduction with NaBH4 and on oxidative cleavage of the diol with NaIO4. The lactol was subjected to Wittig type olefination using PPh3=CH2 and the obtained primary alcohol 70 was oxidized to carboxylic acid 71 by using TEMPO/BAIB conditions (Figure 28). The synthesis of alcohol fragment was started with mono-PMB protection 73 of commercially available 1,8-octane diol 72 and the other alcohol was converted to racemic allyl alcohol 74 by Swern oxidation and subsequent treatment of aldehyde with vinyl magnesium bromide in the presence of CuI. The allylic alcohol 74 was subjected to standard Sharpless kinetic resolution conditions by using (−)-DIPT & Ti(OiPr)4 to obtain enantiomeric epoxy alcohol 75. Upon MOM protection 76 to the secondary alcohol 75 and PMB deprotection produced 77, which on oxidation with Dess-Martin periodinane to afford aldehyde. Aldehyde was converted to olefin 78 by treating PPh3=CH2 in THF. 78 was cleaved to alcohol 79 by reduction with LAH in THF (Figure 29).
Synthesis of acid fragment 71.
Synthesis of alcohol fragment 79.
Acid 71 and alcohol 79 fragments were coupled together under Yamaguchi esterification conditions afforded diene ester 80 in 65% yield. Intramolecular RCM was employed on diene ester by using Grubbs’ second generation catalyst in refluxing CH2Cl2 to produce the requisite macrolactone 81. Double bond in 81 was hydrogenated by using PtO2 in MeOH to attain saturated lactone 82. Lactone 82 was reduced with DIBAL-H to afford lactol which on further treatment with Ph3P=CHCO2Et in C6H6 afforded α,β-unsaturated ester 83. The ester was converted to carboxylic acid 84 by LiOH in THF/H2O which on adopting key Shiina’s macrolactonization protocol to provide the desired mactrolactone 85 in 51% yield. On deprotection of acetonide with CuCl2.2H2O gave diol 86 and removal of MOM group, the synthesis of aspergillide D 33 was achieved (Figure 30).
Completion of synthesis of aspergillide D.
Evan’s strategy of bond connections & key reactions in the synthesis of 34 is illustrated [58].
A number of new macrolide antibiotics with fascinating biological activities have been isolated everyday with the unique and complex structures have been determined with extensive spectroscopic studies. Toward the total synthesis of such macrolide antibiotics, very efficient synthetic strategies and various new methodologies are also developed. Recent advances in macrolide synthesis based on newly developed strategies and methodologies are noteworthy. Further synthetic studies on macrolide antibiotics will make an immense contribution to progress in both organic and medicinal chemistry.
The author wishes to thank Vice Chancellor, Dean R & D, VFSTRU for constant support and encouragement. The author wishes to express his gratitude to Prof. V. Anuradha and other staff members of chemistry department, Vignan for the fruitful discussion. IntechOpen OAPF is greatly acknowledged.
Intensification of process is considered as an indispensable part in the development of approach for obtaining product with high added value. The improvement of a process could concern the technology used, the safety or also the source of raw material employed. Among these sources, wastes of agricultural and food processing are considered as a cheap source of valuable components since the existent technologies allow the recovery of target compounds and their recycling [1]. The process was developed at industrial scale to valorise these kinds of products [2]. In this work, animal blood was studied as a source of bioactive peptides [3, 4, 5, 6]. Some of these peptides revealed their potential as antimicrobial [7], opioid [8], antihypertensive [8] or antioxidative activities [9]. These peptides are generally obtained by enzymatic degradation of haemoglobin alpha and beta chains [3]. Among these peptides, one opioid peptide was studied, known as LVV-haemorphin-7. LVV-h7 corresponds to the amino acid sequence LVVYPWTQRF (Leu-Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-Phe), obtained from β chain of haemoglobin (β 31–40) by pepsin hydrolysis and well known as bioactive peptides involved in the treatment of humans diseases [8, 10, 11, 12].
\nLVV-h7 presents also interesting physical properties, especially hydrophobic character which makes it able to transfer from aqueous to organic media in liquid/liquid extraction process [13]. Previous studies were interested to extract this peptide during haemoglobin hydrolysis using water/butan-2-ol-octan-1-ol liquid/liquid biphasic system [14, 15, 16]. Even if this process has shown the ability to extract selectively LVV-h7, its implementation was very complex and laborious, due to the long time of the process carried out (more than 10 h) to obtain low extraction yield of peptide (about 5%), the control of the immobilised enzyme stability during the process to avoid its inhibition by solvents and a high quantity of solvent.
\nKeeping in mind the economic and environmental impacts of a process development which requires the use of organic solvent, the microfluidic domain could bring solutions to reduce these disadvantages. First, reduction of scale allows to improve the surface/volume ratio and thus the molecular transfer capacity while reducing the volume of solvent used and energy [17, 18]. Second, the implementation for continuous flow platforms brings advantages of liquid-liquid transfer favoured by laminar flow [19, 20, 21], in the case of non-miscible liquids, for molecular transfer. Several studies revealed the real advantage of using LLE in microfluidic system [19, 22, 23].
\nPrevious study realised on the enzymatic hydrolysis of haemoglobin by pepsin in a microfluidic reactor has shown the influence of the microfluidic scale to the kinetics acceleration of bioactive peptides appearance, such as LVV-h7, comparing to bench scale [24]. This study shows also the potential of combining enzymatic microreactor with liquid/liquid biphasic system for LVV-h7 extraction. Therefore, the approach that we propose is based on continuous aqueous haemoglobin hydrolysis by pepsin, LVV-h7 extraction towards an intermediate organic phase and LVV-h7 DES extraction in a receiving aqueous phase, allowing the solvent recycling. This integrated process with solvent recycling is presented in Figure 1. Before fully designing the entire microfluidic process, where all the reactions are carried out simultaneously, we separately investigated each reaction to notably determine their respective optimal ranges of conditions before combination as follows: (1) haemoglobin hydrolysis by pepsin occurs in a primary aqueous feed phase, generating the LVV-h7 in a very complex peptide mixture with more than one hundreds of peptides with different primary sequences; (2) the as-formed LVV-h7 is then selectively extracted into an organic solvent (octan-1-ol); (3) eventually, the LVV-h7 is des extracted in a second aqueous phase (called receiving aqueous phase), which also allows the octan-1-ol recycling in the extraction step. Our approach is not only focused on the compatibility issues of enzymatic catalysis and opioid peptide extraction, but also pays particular attention to integrating all the steps to minimise separation and recycling burdens, which can be detrimental for the overall economics and efficiency of the process. The methodology envisioned to move from a sequential approach towards an integrated continuous process is schematised in Figure 2. Each step was optimised to obtain the best conditions concerning LVV-h7 concentration and purity, through residence time (i.e. flow rate) of both aqueous and organic phases inside the system. After optimisation, enzymatic hydrolysis and extractions steps were combined for a continuous approach to obtain final aqueous phase containing the bioactive peptide. Quantification and purity of LVV-h7 were determined to evaluate the efficiency of integrated process.
\nSimultaneous process applied to the haemoglobin hydrolysis by pepsin, the liquid/liquid extraction of LVV-h7 and the solvent recycling, to produce pure opioid peptide.
Methodology from a sequential approach towards an integrated continuous process.
Bovine haemoglobin (64.5 kDa, Sigma Chemicals Co.) was hydrolysed by porcine pepsin (E.C. 3.4.23.1, 3.440 U mg−1, 35 kDa, Sigma Chemicals Co.), protease from the family of aspartic acid proteases which preferentially catalyses the cleavage of peptide bonds at the carboxyl side of aromatic and hydrophobic amino acids. This proteolytic reaction leads to the appearance of product molecules called peptides. Haemoglobin was prepared under denaturing conditions at pH 3.0 by adding 2 M HCl for a 20 mg mL−1 final concentration. All aqueous solutions were prepared in 18.2 MΩ Milli-Q water (Millipore).
\nIn order to obtain a maximum concentration of LVV-h7 peptides for the extraction step studies, kinetic of reaction was implemented in microfluidic system (75 μm inner diameter, 2 m length). Denatured bovine haemoglobin (1% w/v) was hydrolysed by porcine pepsin at different flow rates (9, 4.5, 1, 0.4 and 0.2 μL min−1), which corresponded to a residence time of 15 s, 30 s, 2 min, 5 min and 10 min, respectively. Samples of peptidic solution were collected during the reaction and mixed with sodium hydroxide 1 M in order to inhibit the pepsin. Samples were conserved at 4°C for RP-HPLC analysis to determine the progress of the reaction.
\nPrevious studies have shown the choice of octan-1-ol as the better extraction solvent for hydrophobic peptides and particularly in the case of LVV-h7 [16, 25]. The haemoglobin hydrolysate was pumped using peristaltic pump (Minipulls 3, Gilson Inc., Middleton, WI, USA) and sent in co-flow with octan-1-ol solution in the same capillary (75 μm inner diameter, 10 cm length) for liquid-liquid extraction (LLE) of peptides from haemoglobin phase to the organic phase. The liquid-liquid extraction was performed with different flow rates to appreciate the impact of contact time on the opioid peptide extraction. The two phases were collected out of the capillary in a 2 mL Eppendorf, immediately separated and analysed by RP-HPLC.
\nOctan-1-ol phase obtained after the extraction procedure was pumped with peristaltic pump and fed in another capillary where acidic water (pH 3 obtained with acetic acid adjustment) was injected at different flow rates to perform a second liquid-liquid extraction from the octan-1-ol to the aqueous phase, called “DES extraction step”. In these conditions, the acidic water extracts peptides and favours the extraction without mixing of the two phases [26]. Phases were collected out of the capillary in a 2 mL Eppendorf, immediately separated and analysed by RP-HPLC.
\nA coupling between both extractions optimised method was implemented, and its efficiency on LVV-h7 peptide extraction selectivity was measured. The entire system was represented on scheme Figure 3 where the volume containing the peptidic hydrolysate and the octan-1-ol was pumped in the same capillary for extraction, followed by a pumping of octan-1-ol phase recovered in a second capillary, connected with acidic water for DES extraction of LVV-h7. For each part of the process, samples were collected for identification and quantification of species.
\nImplementation of microfluidic extraction and DES extraction steps of LVV-h7 from hydrolysate and recycling phases (black: employed method for extraction; green: recycling possibilities of solution).
The liquid chromatographic system is consisted of a Waters 600E automated gradient controller pump module, a Waters Wisp 717 automatic sampling device and a Waters 996 photodiode array detector. Spectral and chromatographic data were stored in a NECImage 466 computer. Detection of the produced peptides was carried out at 215 nm by reverse phase HPLC (RP-HPLC) on a C4-column (Vydak 0.46 × 25 cm, 3 mm I.D.). The mobile phase was water/trifluoroacetic acid (100, 0.1, v/v) and acetonitrile/water/trifluoroacetic acid (60, 40, 0.1, by vol.) at 0.4 mL min−1 flow rate. All common chemicals and reagents were of analytical grade and were purchased from Sigma Chemicals Co. and Flandres Chimie. Identification and quantification of LVV-h7 were performed using peptide standard (purity: 91.63% M.W. 1308.56 Da) purchased from GeneCust Society (Luxembourg).
\nThe sample was loaded on a ground steel MALDI target (Bruker Daltonics, Bremen, Germany) following the dried droplet method. The MS (positive reflectron mode) and MS/MS (lift mode) measurements were performed in an automatic mode on an AUTOFLEXTM Speed TOF/TOF mass spectrometer (Bruker Daltonics) running FlexControlTM3.0 software (Bruker Daltonics). Peptide fragmentation was performed by automatic method of the manufacturer. MS and MS/MS spectra were processed using FlexanalysisTM3.3 and BioTools 3.4 software packages (Bruker Daltonics). Fragmentation pattern of peptides was deduced from matching of amino acid sequences (Uniprot accession numbers: P02070 & P01966) of each chain of bovine haemoglobin to the MS/MS spectra using BioTools 3.4.
\nHaemoglobin 1% (w/v) was hydrolysed by porcine pepsin at room temperature, at pH 3 and at different residence time of substrate and enzyme in the microchannel. At the outlet of the capillary, samples were sent to an Eppendorf containing a disodium tetraborate buffer solution (0.32 M, pH 9.0), that caused enzyme denaturation and thus reaction stopping, and analysed by RP-HPLC.
\nFigure 4 shows the progressive decrease of alpha and beta chains of haemoglobin (between 40 and 60 min) to generate intermediate peptides (between 25 and 40 min) after 15 s of reaction. Next, after 30 s of reaction, there is an increase of peptide population between 25 and 30 min and an emergence of peptides between 15 and 25 min. For the last samples (5 and 10 min), there is a disappearance of peptides between 30 and 40 min to the profit of peptides between 5 and 25 min. This phenomenon was already described in the literature and was explained by an enzymatic hydrolysis of alpha and beta chains to produce a population of hydrophobic peptides with high molecular weight, observed between 30 and 35 min in Figure 3 [3, 5]. Next, this population is hydrolysed to produce other peptides with intermediate molecular weight, observed between 20 and 30 min. Finally, these intermediate peptides are hydrolysed to generate small peptides with hydrophilic character (retention time between 5 and 20 min). This mechanism is called “zipper” mechanism, which is characterised by a denatured state of the initial haemoglobin structure. Moreover, this mechanism is more suitable for obtaining intermediate bioactive peptides, such as LVV-h7 (retention time of about 29 min in Figure 4), compared to a “one by one” mechanism where initial haemoglobin structure is in a native state [3, 5]. LVV-h7 was used as a standard to evaluate the efficiency of extraction process by octan-1-ol. Thus, for studying of the extraction step in microfluidic system, we decided to stop the reaction after 30 s of hydrolysis by sodium hydroxide 1 M in order to obtain the maximum quantity of LVV-h7 (Figure 3c).
\nRP-HPLC chromatograms of haemoglobin 1% hydrolysed by porcine pepsin for different residence times of both haemoglobin and pepsin solutions. (a) Denatured haemoglobin without enzyme, (b) 15 s, (c) 30 s, (d) 2 min, (e) 5 min and (f) 10 min. Samples were analysed on C4 column.
Haemoglobin hydrolysate whose concentration of LVV-h7 was the more important (1%, 30 s of hydrolysis with pepsin) was injected in co-flow (using a T connector) with octan-1-ol at different flow rates (5, 10, 20 and 50 μL min−1). Samples were collected in Eppendorf, and octan-1-ol phase was analysed by RP-HPLC to highlight the extracted peptides. Results are shown in Figure 5.
\nHPLC chromatograms of octan-1-ol phase after extraction applied on haemoglobin hydrolysate in microfluidic system at different flow rates ((a) 10 μL min−1, (b) 20 μL min−1, (c) 40 μL min−1 and (d) 100 μL min−1).
The flow rates used for our analysis correspond to the additive flow rates of both solutions during the extraction step (i.e. initial flow rate multiplied by 2). Chromatograms show a good selectivity of the LLE method and octan-1-ol using microfluidic system. Indeed, we observe only three major peaks from the initial complex peptidic hydrolysate. Moreover, a predominance of LVV-h7 peptide is observed (RT of 29 min), which represents more than 55% of the peptides extracted by octan-1-ol. The selectivity of octan-1-ol for hydrophobic peptides such as LVV-h7 was previously confirmed by our team in batch and continuous reactors from enzymatic haemoglobin hydrolysates, but not in microfluidic system [14, 15, 16]. Two other peaks (RT of 27 and 31 min) are observed and supposed having a hydrophobic character.
\nThe three peaks identified in the octan-1-ol phase were analysed by MALDI mass spectroscopy to appreciate their composition (Figure 6).
\nMALDI-TOF spectra obtained for each peak (elution time (a) 27 min, (b) 29 min and (c) 31 min) collected after octan-1-ol extraction and separated by RP-HPLC.
Concerning the fraction eluted at a 29 min (Figure 6b), result from mass spectroscopy shows unique peak at m/z = 1308.930 Da corresponding to molecular weight for LVV-h7 (with one hydrogen more from mass analysis). No other components were observed, which shows that LVV-h7 peptide is pure. The other fractions collected were also identified. At retention time of 27 min, another pure peptide with 1195.933 Da for molecular weight was identified. It corresponds to the VV-h7 peptide, also obtained by haemoglobin hydrolysis with pepsin and characterised as a hydrophobic bioactive peptide [7]. The fraction eluted at 31 min was composed of two major compounds (1422.138 and 1733.23 Da). These peptides correspond to other peptides without known biological activity.
\nFinally, using standard concentration curve (R2 = 0.98) prepared with a pure standard of LVV-h7 (GeneCust, 91%), the quantity of pure LVV-h7 extracted from bovine haemoglobin hydrolysate was 6.12 ± 0.34 μg mL−1. With an initial concentration of LVV-h7 calculated at 16.12 ± 0.85 μg mL−1 in the hydrolysate, performance of our system is around 38% of peptide extracted with only one cycle of extraction.
\nTable 1 resumes the total area of peptides extracted and particularly for LVV-h7 depending on the flow rate and thus on the residence time of hydrolysate in the microsystem. The area of peptides extracted from peptidic hydrolysate increases with the decreasing of flow rate used, confirming the influence of the time of contact between both phases in the capillary. A relative high time of contact between peptidic hydrolysate and octan-1-ol favours the diffusion of peptides to the solvent phase. However, even if the quantity of LVV-h7 obtained between 10 and 20 μL min−1 was relatively proportional (×1.5), this difference was less marked for flow rates used up to 20 μL min−1.
\nFlow rate (μL min−1) | \nTime of contact (s) | \nTotal area of peptides (μV/*s) | \nLVV-h7 area (μV/*s) | \nTotal % of LVV-h71 | \n
---|---|---|---|---|
10 | \n2.65 | \n10,793,556 | \n6,292,478 | \n58 | \n
20 | \n1.32 | \n6,976,911 | \n4,064,156 | \n58 | \n
40 | \n0.66 | \n6,316,966 | \n3,599,507 | \n57 | \n
100 | \n0.26 | \n5,921,488 | \n3,181,856 | \n54 | \n
Proportion of LVV-h7 in total area of peptides after extraction process.
Total % LVV-h7 = (area of LVV-h7/total area) × 100)
Using the same process than in the first extraction (from peptidic hydrolysate to octan-1-ol), the octan-1-ol phase containing peptides was injected in co-flow with acidic aqueous phase in order to transfer these peptides from organic to receiving aqueous phase. Different flow rates were used to evaluate the impact of contact time between the two phases during the DES extraction process.
\nChromatograms (Figure 7) show clearly a transfer of peptides from the organic phase to the aqueous phase by liquid-liquid DES extraction in the microfluidic conditions. The three major fractions corresponding to the peptides previously described and mainly present in the initial octan-1-ol phase were found in the receiving aqueous phase. Moreover, a small proportion of these peptides were still present in octan-1-ol after the DES extraction step. Figure 8 illustrates the concentration of LVV-h7 in octan-1-ol and the receiving aqueous phase after the DES extraction for different flow rates.
\nRP-HPLC chromatograms of octan-1-ol phase before DES extraction of peptides (a) water phase, (b) and octan-1-ol phase (c) obtained after DES extraction in microfluidic system for a flow rate of 20 μL min−1.
Proportion of LVV-h7 (μg mL−1) in each phase after the DES extraction step in the microfluidic system for different flow rates.
The LVV-h7 concentration in the aqueous phase increases with the decrease of flow rate, indicating the influence of contact time between the two phases on the peptide diffusion. For 10 μL min−1, more than 82% of the initial concentration of LVV-h7 phase was transferred in the aqueous phase. The calculation of LVV-h7 proportion in the aqueous phase compared to the total quantity of peptides extracted was 50 ± 1%. LVV-h7 fraction was analysed by MALDI mass spectroscopy to verify its purity (result not shown). Mass analysis reveals the purity of the LVV-h7 fraction to recover from organic phase to the receiving aqueous phase using microfluidic system. Both fractions (27 and 31 min) were also analysed by mass spectroscopy. It confirmed the same composition than obtained during the extraction step that is, a pure VV-h7 peptide for 27 min of elution time and other peptides for 31 min. Thus, the DES extraction step of peptides from octan-1-ol phase to an acidic aqueous phase using microfluidic system was validated with a good efficiency (more than 82% of transfer yield).
\nIn the optimal conditions previously determined, a continuous integrated process was tested. The microfluidic system, phases and matter flows are presented in Figure 1. The experiment was conducted following the same approach than those in Figure 3 but with a feed aqueous phase formed by a haemoglobin solution, previously prepared under denaturing conditions at pH 3.0 (see part 3.1, haemoglobin final concentration of 1%, p/v), and a solution of pepsin with a E/S ratio of 1/11 (mol/mol). The introduction of these solutions in the microreactor (75 μm I.D. × 150 μm O.D.) was achieved by a syringe pump with a flow rate for both pepsin and haemoglobin solutions at about 4.5 μL min−1 for a capillary length of 2 m. The flow rates used correspond to the additive flow rates of both solutions, that is, initial flow rate multiplied by 2. The outlet fused silica capillary was in contact with a disodium tetraborate buffer solution (0.32 M, pH 9.0), thanks to a T-connection and a capillary (75 μm inner diameter, 10 cm length, flow rate of 5 μL min−1), that caused enzyme denaturation and thus reaction stopping. Consequently to the enzymatic reaction, the resulting peptidic hydrolysate was sent in co-flow in a T-connector with octan-1-ol solution in a new capillary (75 μm inner diameter, 10 cm length) for LVV-h7 extraction at 10 μL min−1. The two phases were collected out of the capillary in an Eppendorf. Octan-1-ol was pumped at 10 μL min−1 in a third capillary connected with acidic water for DES extraction of LVV-h7 thanks to a T-connector. Finally, the octan-1-ol phase remaining was pumped (10 μL min−1) and re-injected in the initial octan-1-ol phase for a new cycle of extraction-DES extraction. To avoid the pumping of the bad phase, an offset of 10 min was done between each extraction step to have sufficient volume of phases. For each step of the continuous process, samples were collected for identification and quantification of species (Figure 9 and Table 2).
\nRP-HPLC chromatograms obtained from each step of the continuous process in the microfluidic system. (a) Peptidic hydrolysate after 30 s of haemoglobin hydrolysis by pepsin, (b) octan-1-ol phase after the extraction, (c) water phase after the DES extraction and (d) octan-1-ol phase after the DES extraction.
Phases collected | \nLVV-h7 area (μV/*s) | \nLVV-h7 concentration (μg mL−1) | \n
---|---|---|
Octan-1-ol (extraction step) | \n6,354,896 | \n6.18 | \n
Octan-1-ol (DES extraction step) | \n1,687,646 | \n1.64 | \n
Water (DES extraction step) | \n4,982,647 | \n4.85 | \n
Concentrations of LVV-h7 in each phase during the complete process.
First, the peptidic profile obtained during the enzymatic hydrolysis step confirms the results previously obtained by Elagli et al. [24] and the presence of LVV-h7 in the reaction medium (Figure 9a). Then, extraction of the opioid peptide to octan-1-ol phase is also observed in Figure 9b, showing the good selectivity of the organic phase for the same hydrophobic peptides detected before, whose LVV-h7 (Figure 7). Finally, we observe the haemorphin in the acidic receiving aqueous phase, confirming the DES extraction step efficiency. A proportion of the peptidic fractions is also found in the octan-1-ol phase after the DES extraction, translating an incomplete transfer in the receiving aqueous phase. However, results validate the process of simultaneous enzymatic hydrolysis of haemoglobin with LVV-h7 extraction and DES extraction at the microscale level.
\nThe calculation of the different concentrations of LVV-h7 in each phase (Table 2) shows the transfer of 78% of the initial concentration of LVV-h7 from octan-1-ol to water. This result confirms the efficiency of the coupling approach of the extraction-DES extraction steps in microfluidic system after the enzymatic reaction. Moreover, after the DES extraction step, a low concentration of LVV-h7 remained in octan-1-ol phase (1.64 μg mL−1). Thus, the reuse of octan-1-ol for a new cycle of extraction allows to obtain an efficient method of peptide recovery with a minimal of organic solvent quantity. An optimisation of the process, particularly the time of contact between feed aqueous/organic phases during the extraction and receiving aqueous/organic phases during the DES extraction could certainly improve the final concentration of LVV-h7 recovered and consequently decrease peptide concentration remained in the organic phase.
\nIn this work, we have first provided the conditions of the key parameters in microfluidic systems (residence times, flow rates, and concentrations) applied for a sequential process from liquid/liquid extraction of LVV-h7, present in a very complex peptidic hydrolysate, in octan-1-ol to its DES extraction in a second acidic aqueous phase. The optimised conditions have been then applied to an unprecedented integrated process in a specifically microfluidic approach. Therein, enzymatic hydrolysis of denatured haemoglobin by pepsin in a first microfluidic system was coupled with LVV-h7 extraction in octan-1-ol. This organic phase was then put in contact with a second aqueous phase for LVV-h7 DES extraction. The microfluidic scale allowed to increase the ratio surface/volume in order to favour the transfer of hydrophobic peptide to the organic solvent. A very good selectivity of extraction of the opioid peptide is obtained, from a very complex peptidic population generated during the enzymatic hydrolysis of haemoglobin by pepsin, with more than 38% of LVV-h7 initial concentration transferred to the organic phase. The DES extraction reveals also a very good transfer of LVV-h7 from octan-1-ol to the acidic aqueous phase, with more than 80%. Thus, the simultaneous process allowed to recover until more than 6 μg mL−1 of LVV-h7 with an excellent purity measured by mass spectroscopy with only one cycle of process (2.65 s of contact for each LLE).
\nThe coupling of both extractions confirmed the feasibility of this process with a recycling of each phase to obtain a continuous process of extraction at microfluidic scale. An optimisation of the time of contact during the extraction is the key of peptide transfer between each phase and particularly for the recycling step. Currently, a study of a complete continuous process is in progress, where pepsin is immobilised in the microchannel and the outlet microcapillary is directly in contact with a solution of octan-1-ol, to avoid stopping the enzymatic reaction before extraction.
\nThis work was supported by the CPER Alibiotech project, which is financed by European Union, French State and the French Region of Hauts-de-France.
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