The examples of chemical genetics studies using S. cerevisiae.
\r\n\tThe eye is our window to the brain. Vision is the ability to interpret and understand the information that comes in through the eyes. The visual system utilizes brain pathways to process and understand what the eyes sense. The dynamic process of vision is to identify, interpret and understand what the eyes see.
\r\n\tAn image is a sight which has been recreated. It is an appearance which has been detached from the place and time in which it first made its appearance. Sensing is not the same as seeing. The eyes and the nervous system do the sensing, while the mind does the perceiving.
\r\n\t
\r\n\tMedical imaging is the process of using technology to view the human body in the interest of diagnosing, monitoring, and treating medical problems. It is especially beneficial when it comes to detecting cancer. Such a threatening disease requires very early detection to improve the chances of survival. Medical imaging is an extremely important element in medical practice in the world of today. While medical knowledge and discernment forms the basis of diagnoses and decisions, medical imaging plays a vital role in confirming any diagnosis. With scientific advancement and a continued effective use, medical imaging will continue to help with earlier detection of health issues and provide increased preventative care.
\r\n\tThis book intends to provide readers with a comprehensive overview of the latest and most advanced findings in several aspects of ophthalmic pathology, treatment and surgical strategies, ocular imaging, vision sciences, medical images and perception that focuses on the most important developments in these critically important areas. Enough has been achieved already to make it clear that these fields have enormous possibilities for improving the human health.
\r\n\t
The screening of bioactive small molecule compounds is the most important process in drug development. Natural products which have structural diversity isolated from microorganisms, plants, and animals are useful sources in the field of drug development [1]. Structurally, new natural products might show novel activities such as antimicrobial, antiviral, and antitumor activities. These natural products also provide useful information for medicinal chemistry, and allow the development of new synthetic compounds as novel medicines. For example, eribulin, a semi-synthetic derivative of halichondrin B, has been approved as an anti-cancer drug [2, 3, 4]. Therefore, the screening and identification of new small molecules open new avenues for drug development. There are two major ways to identify bioactive small molecules: phenotypic screening and target-based screening. Phenotypic screening is based on cytotoxicity [5, 6, 7], cell cycle arrest [8], immune-suppression [9], and morphological changes [10] of drug-treated cells, fungi, and bacteria. Target-based screening is performed based on measurable readouts such as enzymatic activity inhibition [11] or drug-protein interaction [12]. These approaches have identified useful small molecules and medicines.
\nTarget identification (Target ID) of small molecules is also quite important in order to develop safe and useful drugs [13]. Thalidomide, a cautionary example, was used as a sedative a half-century ago before it was found to be teratogenic and to cause multiple birth defects [14]. However, thalidomide is also used in the treatment of Hansen’s disease, myeloma [14], and so on. In addition, immunomodulatory drugs derived from thalidomide have been developed as a new class of anti-cancer drugs and novel medicines for treating ribosomopathies such as 5q-syndrome [15]. Recently, cereblon, a substrate receptor of the CRL4 E3 ubiquitin ligase, has been identified as a primary target of thalidomide teratogenic [16] and anti-cancer [15] activity. These lines of research provide useful information that cereblon may pose a risk of teratogenic activity and simultaneously serve as an attractive molecular target for immunomodulatory drug development. To identify the relevant target molecules and target pathways, indirect and direct approaches have been used [13]. The indirect approaches include phenotypic analysis and large-scale analysis such as proteomic and genome-wide analyses. Some specific changes in cell morphology, cell cycle arrest, and other phenotypes provide us useful information for predicting targets of the drugs. Based on this property, Morphobase, an encyclopedic database of the morphological changes that occur in drug-treated cells, has been constructed and applied to drug target discovery [17]. Large-scale analyses such as proteomics, metabolomics, and transcriptome analysis of drug-treated cells have been performed to predict the target pathways of bioactive small molecules [18]. Genome-wide genetic studies are also frequently used for drug target ID. For example, synthetic lethal/sick genetic interaction analyses [19, 20], genome-wide overexpression screening [21], and haploinsufficiency-chemical sensitive assays [22] have been used to analyze the mode of action of various drugs. On the other hand, direct approaches, such as affinity probe approaches and genetic analyses, are quite useful to identify the direct target molecules of drugs. By using affinity probe approaches, the targets of thalidomide [16] and FK506 [23] have been identified. Genetic analysis is another powerful method of identifying not only drug targets [24, 25, 26, 27, 28, 29] but also the signaling pathway affected by a drug. Genetic studies using model organisms such as yeast have contributed to identification of the target molecules of bioactive compounds.
\nThe identification of new bioactive small molecules and elucidation of their target molecules/signaling pathways are important not only for developing medicines but also for basic science. Such compounds are a useful tool for understanding the fundamental protein functions in cells. Well-known examples are famous immunosuppressants such as FK506, cyclosporine, and rapamycin. These compounds inhibit immunophilin and T-cell activation through different mechanisms [30]. Studies of these compounds have revealed their detailed immunoreaction mechanisms [30]. Mitotic inhibitors are another example. Mitotic spindle formation and chromosome segregation are fast processes that are completed within approximately 1 hour. Therefore, by taking advantage of rapid pharmacological intervention, studies using microtubule inhibitors (αβ-tubulin inhibitors [31, 32, 33] or γ-tubulin inhibitor [12]), mitotic kinesins (Eg5 [34, 35]), and mitotic kinase inhibitors (aurora kinases [36, 37], Cdk1 [38], Plk1 [39, 40], Mps1 [41, 42]) highlighted useful information regarding the temporal regulation of mitotic spindle architecture and faithful chromosome segregation. These findings could in turn contribute to further drug development. Therefore, target ID of newly found useful bioactive compounds is quite an important process in both basic science and medicine development.
\nSaccharomyces cerevisiae is one of the most frequently used model organisms in chemical genetics. The properties of S. cerevisiae along with easy-to-use genetic analyses, mutational analyses, gene disruption, and genome modification have facilitated both chemical screening and target ID (Table 1). For example, the target of rapamycin (TOR) has been found by genetics using S. cerevisiae [29]. In addition, S. cerevisiae is useful for chemical screening [43, 44]. However, S. cerevisiae generally shows higher resistance against various compounds compared with mammalian cells, except in the case of a few compounds such as rapamycin (Table 2). This disadvantage limits the application of S. cerevisiae in chemical screening. Therefore, S. cerevisiae showing sensitivities against drug of interest has been quite useful. For example, S. cerevisiae quadruple deletion mutant lacking yrr1, yrs1, pdr1, and pdr3 was constructed for the analyses of target molecule of reveromycin A. However, construction of sensitive yeast suitable for each compound is a time-consuming process. To overcome this drawback, we developed two multidrug-sensitive strains which have proven quite useful for research in chemical biology. There are two major systems conferring multidrug resistance in S. cerevisiae: one is the drug efflux system, which exports drugs into vacuoles or outside of cells, and the other is the permeability barrier, which blocks the penetration of drugs into the cells (Figure 1). The drug efflux system consists of ATP-binding cassette (ABC) transporters that export xenotoxic compounds outside of cells or inside of vacuoles, and their transcriptional factors [45, 46, 47]. S. cerevisiae has at least 16 ABC transporters, of which Pdr5p, Snq2p, and Yor1p confer multidrug resistance by exporting bioactive small molecules out of cells. Four transcriptional factors (Pdr1p, Pdr3p, Pdr8p, and Yrr1p) up-regulate the transcription of most of the ABC transporters [45, 46, 47]. A permeability barrier is conferred by ergosterol in the yeast plasma membrane. Therefore, ABC transporter-related genes and ergosterol synthesis genes were frequently disrupted to construct drug-sensitive strains. For instance, a strain in which pdr1, pdr3 (genes encoding transcriptional factors for ABC transporters), and erg6 (a gene involved in ergosterol synthesis) were disrupted was used for drug screening [43]. However, the erg6 deletion mutant shows decreased transformation and sporulation efficiencies that are essential for yeast genetic analysis. In addition, some of the transporters located in the vacuole membrane are involved in the detoxination of metabolites as well as xenotoxins, and their disruption results in growth defects. Therefore, to make a yeast strain sensitive to a wide range of drugs, it is necessary to suppress both efflux and barrier systems without affecting the genetic properties and growth rate. Hence, we speculated that the disruption of all ABC transporters located on the plasma membrane that are not important for viability and genetic experiments or for the conditional expression regulation of the ERG6 gene could increase the drug sensitivity without influencing the transformation, mating, or sporulation efficiency.
\nCompound | \nApproach | \nFinding | \nRef. | \n
---|---|---|---|
Benomyl | \nPathway analysis | \nIdentification of Mad1, Mad2, Mad3 as mitotic spindle checkpoint proteins by using benomyl sensitive mutants | \n[31] | \n
Benomyl | \nPathway analysis | \nIdentification of Bub1, Bub2, Bub3 as mitotic spindle checkpoint proteins by using benomyl sensitive mutants | \n[32] | \n
Reveromycin A | \nTarget ID | \nIdentification of ILS1 as a target of reveromycin A | \n[27] | \n
Curvularol | \nTarget ID | \nIdentification of RPL3 as a target of curvularol | \n[28] | \n
Rapamycin | \nTarget ID | \nIdentification of TOR as a target of rapamycin | \n[29] | \n
Eudistomin C | \nTarget ID | \nIdentification of RPS14 as a target of eudistomin C | \n[50] | \n
Splitomicin | \nScreening | \nIdentification of splitomicin as a NAD+-dependent histone deacetylase inhibitor | \n[51] | \n
The examples of chemical genetics studies using S. cerevisiae.
\n | Mammalian cell line (HeLa) | \nBudding yeast (BY4741) | \n
---|---|---|
Cycloheximide (μM) | \n0.2 | \n270 | \n
Digitonin (μM) | \n0.4 | \n1.9 | \n
Fluphenazine (μM) | \n13 | \n51 | \n
Latrunculin A (nM) | \n0.2 | \n>240 | \n
4-Nitroquinoline 1-oxide (μM) | \n0.1 | \n7.1 | \n
Rapamycin (nM) | \n>300 | \n7.1 | \n
Staurosporine (μM) | \n0.1 | \n15.1 | \n
Tunicamycin (μM) | \n1.8 | \n>120 | \n
The IC50 values of compounds against HeLa cells and S. cerevisiae.
HeLa cells (3 × 103 cells/well in 96 well plate) and BY4741 cells (3.8 × 105 cells/well in 96 well plate) were treated with various concentrations of compounds for 48 and 8 h, respectively. Cell viabilities were determined by WST-8 (Dojindo, Kumamoto, Japan) and IC50 values were calculated.
The work flow of the construction of multidrug-sensitive strains. (A) The parental strain, BY4741, possesses high genetic manipulation availability, but shows high drug resistance. (B) 12geneΔ0HSR, created by disruption of the drug efflux system and introduction of the RME1(ins-308A) mutation, achieves drug-sensitivity without compromising the genetic manipulation availability. (C) 12geneΔ0HSR-iERG was created by the insertion of a gal1 promoter into ERG6. This strain shows high drug sensitivity but drastically decreased genetic manipulation availability under the glucose condition, because ERG6p expression is repressed. Instead, genetic manipulation is available under the galactose condition through enhancement of the ERG6p expression.
In this review, we discuss the construction of two multidrug-sensitive yeast strains, 12geneΔHSR [48] and 12geneΔHSR-iERG [49], which are available for genetic analysis. We also discuss the application of these strains in drug screening and target ID [50].
\nWe constructed a multidrug-sensitive yeast strain by disrupting 12 ABC transporter-related genes and suppressing the ERG6 gene. The work flow is shown in Figure 1. As a first step, we focused on drug efflux systems. The drug efflux system composed of ABC transporters confers resistance against a wide variety of compounds [45, 46, 47]. Therefore, it is difficult to predict which transporters will confer drug resistance against the drug of interest. We thus decided to construct the 12geneΔ0 strain through the disruption of all of the ABC transporters involved in drug export located on the plasma membrane and transcription factors involved in multidrug resistance specifically on a BY4741 background [48]. Gene disruption of eight gene-encoding ABC transporters (AUS1, PDR5, PDR10, PDR11, PDR12, PDR15, SNQ2, and YOR1) and four genes encoding transcriptional factors (PDR1, PDR3, PDR8, and YRR1) was carried out using a PCR-based markerless gene disruption method modified from the delitto perfetto method [52]. Because 12geneΔ0 leaves no marker genes in the genome, auxotroph markers which the parental strain originally possesses can be used for further studies. To use 12geneΔ0 for chemical genetics, it is important to show not only its multidrug sensitivity but also its transformation, mating, and sporulation efficiencies, which are necessary for genetic analysis. The transformation and mating efficiency of 12geneΔ0 were on the same order as those of the parental strain BY4741 (Table 3). However, the sporulation efficiency was drastically decreased in 12geneΔ0 (Table 3). It was reported that single-nucleotide polymorphisms of three genes (a noncoding regulatory region of RME1(ins-308A), and two missense mutations in TAO3 and MKT1) are involved in sporulation efficiency, and when these mutations were introduced in S288c, the parental strain of BY4741, the sporulation efficiency increased [53]. We therefore introduced the RME1(ins-308A) and MKT1(D30G) mutations into 12geneΔ0. Although both mutations increased the sporulation efficiencies, the MKT1(D30G) mutant formed petite colonies as reported previously [54]. Therefore, we decided to use the RME1 mutant for our studies, and the strain created was named 12geneΔ0HSR (12geneΔ0 strain showing
\n | Transformation efficiency (Cfu/μg) | \nMating efficiency (%) | \nSporulation efficiency (%) | \n
---|---|---|---|
BY4741 | \n9.6 × 105 ± 2.2 × 105 | \n17.7 ± 7.5 | \n21.9 ± 6.8 | \n
Δerg6 | \n55.0 ± 51.3 | \n4.8 ± 1.7 | \n9.4 ± 4.7 | \n
12geneΔ0 | \n1.2 × 105 ± 2.0 × 104 | \n15.7 ± 5.3 | \n5.0 ± 2.9 | \n
12geneΔ0HSR | \nN.D. | \nN.D. | \n28.8 ± 4.6 | \n
12geneΔ0HSR-iERG6 (under glucose condition) | \n7.0 ± 8.2 | \n6.4 ± 2.2 | \n0.0 ± 0.0 | \n
12geneΔ0HSR-iERG6 (under galactose condition) | \n3.0 × 104 ± 2.4 × 104 | \nN.D. | \n10.7 ± 3.0 | \n
Comparison of the efficiencies of transformation, mating and sporulation between BY4741, erg6 disruptant and 12geneΔ0HSR.
Drugs to which resistance was conferred by ABC transporters, ergosterol or both systems (indicated by underlining), respectively.
In general, S. cerevisiae exhibits high levels of drug resistance, which is an obstacle for drug screening. In fact, most of the compounds used for clinical or basic research show higher IC50 values against S. cerevisiae than against mammalian cells (Table 2). Therefore, multidrug-sensitive strains of S. cerevisiae—for example, the pdr1 pdr3 erg6 triple mutant or pdr1 pdr3 yrs1 yrr1 quadruplex mutant—have been used for drug screening [43, 55]. To test the superiority of our strain, we screened mitochondrial inhibitors from microbial secondary metabolites and compared the hit ratio of 12geneΔ0HSR-iERG6 with that of BY25929 (yrs1::HIS3 yrr1::TRP1 pdr1::hisG pdr3::hisG), a multidrug-sensitive quadruplex mutant (Tables 4 and 5).
\n\n | Number of broth | \nNumber of hit broth | \nHit ratio (%) | \n
---|---|---|---|
Origin | \n|||
Fungus | \n2664 | \n149 | \n5.6 | \n
Actinomycetes | \n5617 | \n289 | \n5.1 | \n
Total | \n8281 | \n438 | \n5.3 | \n
Hit ratio of screening of mitochondrial inhibitor using quadruplex mutant, BY25929.
\n | Number of broth | \nNumber of hit broth | \nHit ratio (%) | \n
---|---|---|---|
Origin | \n|||
Fungus | \n3144 | \n270 | \n8.6 | \n
Actinomycetes | \n3067 | \n253 | \n8.2 | \n
Total | \n6211 | \n523 | \n8.4 | \n
Hit ratio of screening of mitochondrial inhibitor using 12geneΔ0HSR-iERG6.
To identify the mitochondrial inhibitors, we used the difference in cell growth between the glucose medium and the glycerol medium. Yeast can use glycerol as a respiratory substance after the conversion to dihydroxyacetone phosphate via glycerol-3-phosphate by cytosolic and mitochondrial enzymes, GUT1p and GUT2p, respectively. Therefore, yeast could grow even in the presence of a mitochondrial inhibitor in glucose medium because of anaerobic respiration, but not in glycerol medium in which one of the metabolites in glycolysis, dihydroxyacetone phosphate, could not be produced. Therefore, we compared the growth inhibition induced by microbial broth samples on glucose medium (1% yeast extract, 2% polypeptone, 2% glucose, 1.5% agar) with that on glycerol medium (1% yeast extract, 2% polypeptone, 3% glycerol, 1.5% agar), and chose the broth which inhibited yeast growth on glycerol medium but not on glucose medium [55]. Growth inhibition activities of microbial broth samples were evaluated using the paper disc method on agar plates inoculated with recombinant S. cerevisiae strains. In detail, 6 mm sterile filter discs impregnated with each compound solution (10 μl) were placed on the agar plate using a forceps (medium volume; 30 ml/plate, cell number; 1.5 × 106 cells/plate, plate dimension; 144 × 100 × 14.5 mm, square shape), and the plates were incubated at 30°C for 48 h. After incubation, the diameters of the zone of inhibition were measured with a vernier caliper. As shown in Table 4, the hit ratio using the quadruplex mutant, BY25929, was about 5%. Because the hit ratio when wild-type yeasts (W303-derived yeast strains) were used in a similar screening system was 1.4% (fungus samples 0.5% (44 total hits among 8610 samples), actinomycetes samples 3.2% (125 total hits among 3912 samples), this result suggests that the quadruplex mutant is useful for drug screening with a high hit ratio. Indeed, a novel compound, decatamariic acid, was isolated as a mitochondrial inhibitor using the quadruplex mutant [55]. Moreover, the hit ratio using 12geneΔ0HSR-iERG6 increased to about 8% (Table 5).
\nTo determine whether it is possible to isolate the novel compounds or not, we selected the microbial broths which were detected using 12geneΔ0HSR-iERG6 but not using the quadruplex mutant. We found a total of 46 broths (fungus origin: 16 broths; actinomycetes origin: 30 broths) which inhibited the growth of 12geneΔ0HSR-iERG6 specifically. Among these broths, we selected two fungus broths for further purification of active metabolites, and isolated 4,6′-anhydrooxysporidinone (1, fusoxypyridone [56]), pestalotic acid A (2), and three novel compounds (manuscript in preparation) (Figure 3). 4,6′-Anhydrooxysporidinone has been isolated from Fusarium oxysporum in the course of the screening of anti-angiogenesis inhibitors [57], but showed weak cytotoxicity against mammalian cell cultures (IC50 > 100 μM) and anti-MRSA activity (MIC = 100 μg/ml) [58]. Pestalotic acid A has been isolated from a Pestalotiopsis sp. as an antimicrobial compound containing a furylidine tetronic acid core [59]. Because of the lack of biological activity other than antimicrobial activities, the observation of antifungal activity is a novel insight. These results strongly suggest that 12geneΔ0HSR-iERG6 would be useful for drug screening.
\nStructure of 4,6′-anhydrooxysporidinone (1) and pestalotic acid A (2).
Because the usefulness of our strains was confirmed, we next performed the preliminary screening of compounds that show readthrough activities. Readthrough compounds allow the translational machinery to skip nonsense mutations encoding premature termination codons (PTCs) and could become medicines for hereditary diseases caused by PTCs (Figure 4). To date, many small molecules have been developed as readthrough drug candidates. Several forms of aminoglycoside antibiotics, such as gentamicin (3), G418 (4), and its analogues, have been reported to show readthrough activities (Figure 5) [60]. Barton-Davis et al. revealed that the dystrophin expression in mdx mice, an animal model of duchenne muscular dystrophy (DMD) is increased after the administration of gentamicin (3) [61]. Novel aminoglycosides derived from gentamicin, which showed readthrough activity against four different nonsense DNA constructs underlying genetic diseases, were also recently reported [62]. However, long-term treatment with aminoglycosides showed serious side effects such as nephrotoxicity [63] and ototoxicity [64]. As a non-aminoglycoside readthrough compound, ataluren (5), which is a 1,2,4-oxadiazole derivative developed from a chemical library, promotes dystrophin production in primary muscle cells from humans and mdx mice (Figure 5) [65]. It was also found that (+)-negamycin (6), which is a dipeptide-like antibiotic containing a hydrazide structure [66], has readthrough activity and restores dystrophin expression in the muscles of mdx mice (Figure 5) [67]. In our structure-activity relationship study of (+)-negamycin, we discovered several more potent derivatives, including Leucyl-3-epi-deoxynegamycin (TCP-126, 7) and TCP-112 (8) (Figure 5) [68, 69]. However, the activities of these compounds are not sufficient for medicine, and the mechanism of action of the readthrough activity remains to be elucidated.
\nNonsense mutation as a premature termination codon (PTC) and readthrough compounds. (A) mRNAs containing no PTC are translated into full-length and functional proteins. (B) In the case of mRNAs containing PTC, translation stops at PTC and non-functional truncated proteins are synthesized. (C) In the presence of readthrough compounds, even mRNAs containing PTC are translated into full-length and functional proteins.
Structure of readthrough compounds. Gentamicin (3) and G418 (4) are aminoglycoside-type readthrough compounds. Aataluren (5), (+)-negamycin (6), and negamycin derivatives (Leucyl-3-epi-deoxynegamycin (TCP-126, 7), TCP-112 (8)) are non-aminoglycoside-type readthrough compounds.
To discover novel readthrough compounds, we constructed yeast strains for the screening of readthrough compounds using 12geneΔ0HSR. ADE2 is an enzyme that is essential to producing adenine in live yeast systems, and its mutation induced the accumulation of red pigment in vacuoles [70]. One of the ade2 auxotroph markers, ade2–101, has a nonsense mutation (ochre) at 190 bp [71]. Therefore, we introduced PTCs at the same site as in the ADE2 gene and inserted the ADE2 loci of 12geneΔ0HSR by pop-in/pop-out. The resulting strains 12geneΔ0HSR ade2-E64X required adenine for growth and formed red colonies in adenine-limited medium (Figure 6A). In contrast, most of the colonies appeared white on medium containing TCP-126 (Figure 6B), suggesting that TCP-126 evoked readthrough in ade2-E64X. In addition, DMSO solution (3 μl) containing readthrough compounds (G418 or negamycin analogues including TCP-126) induced the white halo on the 12geneΔ0HSR ade2-E64X strain-inoculated plate after 4 days incubation (Figure 6C). These results indicated that 12geneΔ0HSR ade2-E64X is suitable for use in the qualitative analysis of readthrough activity.
\nThe color of 12geneΔ0HSR ade2-E64X strains turned from red to white in the presence of readthrough compounds. (A) 12geneΔ0HSR ade2-E64X strains were plated on YPD containing 0.0005% adenine for 4 days. The wild-type strain (12geneΔ0HSR) formed white colonies, but 12geneΔ0HSR ade2-E64X strains formed red colonies. (B) 12geneΔ0HSR ade2-E64X strains were plated on SC-ADE + 0.0045% adenine with or without luecyl-3-epi-deoxy-negamycin (TCP-126) for 4 days. The colonies formed on medium containing TCP-126 were white, suggesting that TCP-126 evoked readthrough activity in the 12geneΔ0HSR ade2-E64X (TGA) strain. (C) DMSO and G418 were spotted on 0.5% agar containing 12geneΔ0HSR ade2-E64X strains overlaid on YPD containing 0.0005% adenine. After 4 days incubation, the halo that formed around the G418 was white.
Next, we initiated a high-throughput screening of the readthrough compounds based on the halo assay using chemical library. This screening is underway, but already several hit compounds have been found, including rapamycin (9) [72], wortmannin (10) [72], and A23187 (11) [73] (Figure 7). These data provided further evidence of the usefulness of the 12geneΔ0HSR ade2-E64X strains for identifying and elucidating the mechanism of action of readthrough drugs.
\nCompounds showing readthrough activities in our screening. Rapamycin (9), wortmannin (10), and A23187 (11) were found as readthrough compounds in our assay system. The structures and haloes of these compounds are shown.
Since our strains show multidrug sensitivity without a decrease in genetic availability, they should also be useful for performing target ID for drugs and the mechanism evaluation of compounds, especially those which are only available in limited amounts, such as natural products. Here we show an example of target ID [50]. Eudistomin C (EudiC, Figure 8), a natural product isolated from the Caribbean tunicate Eudistoma olivaceum [74, 75] shows broad-spectrum antiviral activity [76]. Because of a unique structural feature, oxathiazepine ring attached to a tetrahydro-β-carboline, EudiC has attracted attention as a lead compound for antiviral medicines. However, several trials for its clinical development have failed due to the strong cytotoxicity of EudiC. To reveal the cause of the cytotoxicity of EudiC, it is important to identify the target molecule responsible for the cytotoxicity of EudiC. By using the yeast genetic approach, we found that a mutation in the RPS14A gene confers EudiC-specific resistance [50]. The work flow is shown in Figure 9. We used dTC033, one of the multidrug-sensitive yeast strains which lacks 12 genes of the drug-efflux system. The sensitivity of dTC033 against EudiC was 25-fold higher than that of the parental strain BY4741. We isolated the 59 spontaneous mutants that show EudiC resistance. We then crossed these 59 EudiC-resistant strains with OTA014, which has the same genotype as dTC033 (except for the mating type and RME1(ins-308A) mutation), and confirmed that 34 of the strains showed dominant resistance. Dominant resistance is predicted to be the mutation in target molecules which inhibits drug-target interaction rather than a lack of cell death signals activated by EudiC treatment (Figure 9). These 34 strains were further tested for their EudiC resistance under a higher concentration of EudiC, and 11 strains were selected as strongly resistant mutants. To confirm that the EudiC-resistant mutations of these mutants were not related to multi-drug-resistance mechanisms such as drug efflux pump up-regulation, we checked the sensitivity of these mutants against several compounds. These strains did not show cross-resistance against 4-nitroquinoline 1-oxide, digitonin, cycloheximide, or rhodamine 6G, suggesting that these mutants obtained specific resistance against EudiC. We speculate that our strain cannot obtain cross-resistance easily due to its lacking all ABC transporters on the plasma membrane. To select mutants which have a single mutation responsible for EudiC resistance, we performed a tetrad analysis of the spores derived from the diploid of the 11 selected mutants and confirmed that 8 of the strains showed a 2:2 segregation pattern for EudiC resistance. These eight strains were classified into three complementation groups, which we named YER1 (1 strain), YER2 (2 strains), and YER3 (5 strains). “YER” stands for Yeast Eudistomin C Resistance. Whole-genome sequence analysis of the YER strains and further confirmatory analyses, including the disruption of mutated genes in YER strains and the re-introduction of identified mutations into wild-type strains (Figure 9), revealed that YER1 is RPS14A(E54K). Unless we checked all of the gene mutations found in the coding region, we failed to identify the mutations in YER2 and YER3, suggesting that the YER2 and YER3 mutations were located on the noncoding region or repetitive sequences—for example, rDNA. RPS14A encodes a component of the 40S ribosome, uS11, which participates not only in protein translation but also in 18S ribosomal RNA (rRNA) maturation (20S to 18S processing) in ribosome biogenesis with Fap7p [77]. To distinguish the effect of EudiC on uS11, we performed biochemical analysis using biotinylated EudiC and purified ribosome complexes. Because biotinylated EudiC failed to pull Fap7p down and no effect on 18S maturation processes was observed, it was confirmed that EudiC targets the matured 40S ribosome and inhibits protein translation but not rRNA maturation [50].
\nChemical structure of eudistomin C (EudiC).
The work flow of the identification of RPS14A as a target of EudiC.
Collectively, our target ID studies of EudiC suggested the mode of action of EudiC cytotoxicity and indicated that our sensitive strains would be quite useful for performing drug target IDs in a relatively short period.
\nIn the field of chemical biology, several model organisms, including yeast, worms, flies, and mice, have been used. Yeast is one of the most-used model organisms due to its ease of handling and its genetic availability, but its drug resistance is sometimes an obstacle to investigation. To overcome this problem, we constructed two multidrug-sensitive yeast strains, 12geneΔ0HSR and 12geneΔ0HSR-iERG6. These strains not only show a broad spectrum of drug sensitivities against compounds for which resistance is shown by both ABC transporters and ergosterol without influencing transformation, mating, or sporulation efficiency, but they are also useful for drug screening. Indeed, we performed a screening of antifungal compounds and protein translation regulators which skip stop codons and found some promising candidates. Using 12geneΔ0HSR-iERG6, we succeeded in improving the hit rate of drug screening from microbial broth. The screening of microbial broth which inhibits the growth of 12geneΔ0HSR-iERG6 but not of the quadruplex mutant identified novel compounds suggested that our multidrug-sensitive strain-based screening using previously tested chemical sources in yeast screening could identify new bioactive compounds. Furthermore, as our screening system for readthrough compounds, genetically modified multidrug-sensitive strains can be applied for several types of screening such as a yeast 2-hybrid system-based protein-protein interaction modulators screening. Recently, a yeast 3-hybrid system has been applied for drug-protein interaction analysis [78]. In this study, the pdr5 snq2 yor1 triple mutant was used to increase the sensitivity of the system [78]. Our multidrug-sensitive yeast strain was thus shown to be useful for this kind of analysis. Moreover, we expect that the 12geneΔ0HSR and 12geneΔ0HSR-iERG6 strains will also be useful tools for genome-wide chemical biology studies such as synthetic lethal/sick genetic interaction analyses [19, 20], genome-wide overexpression screening [21], and haploinsufficiency-chemical sensitive assays [22]. In addition, the genetic approach using our strains identified the 40S ribosome component uS11 as a target molecule of the cytotoxicity caused by the antiviral compound EudiC. Because it has been reported that protein translation is one of the targets for antiviral agents [79, 80, 81], the effect on the 40S ribosome and the inhibition of translation by EudiC may cause both the cytotoxicity and the antiviral activity. In contrast, it has also been reported that the uS11 protein interacts with the eS1 and eS26 proteins, which form part of the mRNA exit tunnel [82], and that the eS1 protein is one of the contact sites for hepatitis C virus internal ribosome entry sites (IRES) [83, 84]. These reports might suggest that EudiC decreases the interaction between ribosomes and some of the viral IRES, and efficiently inhibits the translation of viral proteins compared to that of host mRNA. Elucidating the detailed inhibitory mechanism of EudiC on protein translation and its effects on IRES-dependent translation might promote the development of EudiC as a novel antiviral medicine.
\nRecently, it has been reported that RNAseq combined with Crisper/Cas9-based genome-editing technologies is useful for target ID in mammalian cells [25]. Identification of the drug target using our multidrug-sensitive strains and confirmation of the identified mutation in mammalian cells by Crisper/Cas9-based genome editing will reveal the mechanisms of drugs in more detail. Our multidrug-sensitive strains have the potential to facilitate chemical genetic studies and contribute to the development of medicines in the future.
\nStability constant of the formation of metal complexes is used to measure interaction strength of reagents. From this process, metal ion and ligand interaction formed the two types of metal complexes; one is supramolecular complexes known as host-guest complexes [1] and the other is anion-containing complexes. In the solution it provides and calculates the required information about the concentration of metal complexes.
Solubility, light, absorption conductance, partitioning behavior, conductance, and chemical reactivity are the complex characteristics which are different from their components. It is determined by various numerical and graphical methods which calculate the equilibrium constants. This is based on or related to a quantity, and this is called the complex formation function.
During the displacement process at the time of metal complex formation, some ions disappear and form a bonding between metal ions and ligands. It may be considered due to displacement of a proton from a ligand species or ions or molecules causing a drop in the pH values of the solution [2]. Irving and Rossotti developed a technique for the calculation of stability constant, and it is called potentiometric technique.
To determine the stability constant, Bjerrum has used a very simple method, and that is metal salt solubility method. For the studies of a larger different variety of polycarboxylic acid-, oxime-, phenol-containing metal complexes, Martel and Calvin used the potentiometric technique for calculating the stability constant. Those ligands [3, 4] which are uncharged are also examined, and their stability constant calculations are determined by the limitations inherent in the ligand solubility method. The limitations of the metal salt solubility method and the result of solubility methods are compared with this. M-L, MLM, and (M3) L are some types of examples of metal-ligand bonding. One thing is common, and that is these entire types metal complexes all have one ligand.
The solubility method can only usefully be applied to studies of such complexes, and it is best applied for ML; in such types of system, only ML is formed. Jacqueline Gonzalez and his co-worker propose to explore the coordination chemistry of calcium complexes. Jacqueline and et al. followed this technique for evaluate the as partial model of the manganese-calcium cluster and spectrophotometric studies of metal complexes, i.e., they were carried calcium(II)-1,4-butanediamine in acetonitrile and calcium(II)-1,2-ethylendiamine, calcium(II)-1,3-propanediamine by them.
Spectrophotometric programming of HypSpec and received data allows the determination of the formation of solubility constants. The logarithmic values, log β110 = 5.25 for calcium(II)-1,3-propanediamine, log β110 = 4.072 for calcium(II)-1,4-butanediamine, and log β110 = 4.69 for calcium(II)-1,2-ethylendiamine, are obtained for the formation constants [5]. The structure of Cimetidine and histamine H2-receptor is a chelating agent. Syed Ahmad Tirmizi has examined Ni(II) cimetidine complex spectrophotometrically and found an absorption peak maximum of 622 nm with respect to different temperatures.
Syed Ahmad Tirmizi have been used to taken 1:2 ratio of metal and cimetidine compound for the formation of metal complex and this satisfied by molar ratio data. The data, 1.40–2.4 × 108, was calculated using the continuous variation method and stability constant at room temperature, and by using the mole ratio method, this value at 40°C was 1.24–2.4 × 108. In the formation of lead(II) metal complexes with 1-(aminomethyl) cyclohexene, Thanavelan et al. found the formation of their binary and ternary complexes. Glycine,
Using the stability constant method, these ternary complexes were found out, and using the parameters such as Δ log K and log X, these ternary complex data were compared with binary complex. The potentiometric technique at room temperature (25°C) was used in the investigation of some binary complex formations by Abdelatty Mohamed Radalla. These binary complexes are formed with 3D transition metal ions like Cu2+, Ni2+, Co2+, and Zn2+ and gallic acid’s importance as a ligand and 0.10 mol dm−3 of NaNO3. Such types of aliphatic dicarboxylic acids are very important biologically. Many acid-base characters and the nature of using metal complexes have been investigated and discussed time to time by researchers [7].
The above acids (gallic and aliphatic dicarboxylic acid) were taken to determine the acidity constants. For the purpose of determining the stability constant, binary and ternary complexes were carried in the aqueous medium using the experimental conditions as stated above. The potentiometric pH-metric titration curves are inferred for the binary complexes and ternary complexes at different ratios, and formation of ternary metal complex formation was in a stepwise manner that provided an easy way to calculate stability constants for the formation of metal complexes.
The values of Δ log K, percentage of relative stabilization (% R. S.), and log X were evaluated and discussed. Now it provides the outline about the various complex species for the formation of different solvents, and using the concentration distribution, these complexes were evaluated and discussed. The conductivity measurements have ascertained for the mode of ternary chelating complexes.
A study by Kathrina and Pekar suggests that pH plays an important role in the formation of metal complexes. When epigallocatechin gallate and gallic acid combine with copper(II) to form metal complexes, the pH changes its speculation. We have been able to determine its pH in frozen and fluid state with the help of multifrequency EPR spectroscopy [8]. With the help of this spectroscopy, it is able to detect that each polyphenol exhibits the formation of three different mononuclear species. If the pH ranges 4–8 for di- or polymeric complex of Cu(II), then it conjectures such metal complexes. It is only at alkaline pH values.
The line width in fluid solutions by molecular motion exhibits an incomplete average of the parameters of anisotropy spin Hamilton. If the complexes are different, then their rotational correlation times for this also vary. The analysis of the LyCEP anisotropy of the fluid solution spectra is performed using the parameters determined by the simulation of the rigid boundary spectra. Its result suggests that pH increases its value by affecting its molecular mass. It is a polyphenol ligand complex with copper, showing the coordination of an increasing number of its molecules or increasing participation of polyphenol dimers used as ligands in the copper coordination region.
The study by Vishenkova and his co-worker [8] provides the investigation of electrochemical properties of triphenylmethane dyes using a voltammetric method with constant-current potential sweep. Malachite green (MG) and basic fuchsin (BF) have been chosen as representatives of the triphenylmethane dyes [9]. The electrochemical behavior of MG and BF on the surface of a mercury film electrode depending on pH, the nature of background electrolyte, and scan rate of potential sweep has been investigated.
Using a voltammetric method with a constant-current potential sweep examines the electrical properties of triphenylmethane dye. In order to find out the solution of MG and BF, certain registration conditions have been prescribed for it, which have proved to be quite useful. The reduction peak for the currents of MG and BF has demonstrated that it increases linearly with respect to their concentration as 9.0 × 10−5–7.0 × 10−3 mol/dm3 for MG and 6.0 × 10−5–8.0 × 10−3 mol/dm3 for BF and correlation coefficients of these values are 0.9987 for MG and 0.9961 for BF [10].
5.0 × 10−5 and 2.0 × 10−5 mol/dm3 are the values used as the detection limit of MG and BF, respectively. Stability constants are a very useful technique whose size is huge. Due to its usefulness, it has acquired an umbrella right in the fields of chemistry, biology, and medicine. No science subject is untouched by this. Stability constants of metal complexes are widely used in the various areas like pharmaceuticals as well as biological processes, separation techniques, analytical processes, etc. In the presented chapter, we have tried to explain this in detail by focusing our attention on the applications and solutions of stability of metal complexes in solution.
Stability or formation or binding constant is the type of equilibrium constant used for the formation of metal complexes in the solution. Acutely, stability constant is applicable to measure the strength of interactions between the ligands and metal ions that are involved in complex formation in the solution [11]. A generally these 1-4 equations are expressed as the following ways:
Thus
K1, K2, K3, … Kn are the equilibrium constants and these are also called stepwise stability constants. The formation of the metal-ligand-n complex may also be expressed as equilibrium constants by the following steps:
The parameters K and β are related together, and these are expressed in the following example:
Now the numerator and denominator are multiplied together with the use of [metal-ligand] [metal-ligand2], and after the rearranging we get the following equation:
Now we expressed it as the following:
From the above relation, it is clear that the overall stability constant βn is equal to the product of the successive (i.e., stepwise) stability constants, K1, K2, K3,…Kn. This in other words means that the value of stability constants for a given complex is actually made up of a number of stepwise stability constants. The term stability is used without qualification to mean that the complex exists under a suitable condition and that it is possible to store the complex for an appreciable amount of time. The term stability is commonly used because coordination compounds are stable in one reagent but dissociate or dissolve in the presence of another regent. It is also possible that the term stability can be referred as an action of heat or light or compound. The stability of complex [13] is expressed qualitatively in terms of thermodynamic stability and kinetic stability.
In a chemical reaction, chemical equilibrium is a state in which the concentration of reactants and products does not change over time. Often this condition occurs when the speed of forward reaction becomes the same as the speed of reverse reaction. It is worth noting that the velocities of the forward and backward reaction are not zero at this stage but are equal.
If hydrogen and iodine are kept together in molecular proportions in a closed process vessel at high temperature (500°C), the following action begins:
In this activity, hydrogen iodide is formed by combining hydrogen and iodine, and the amount of hydrogen iodide increases with time. In contrast to this action, if the pure hydrogen iodide gas is heated to 500°C in the reaction, the compound is dissolved by reverse action, which causes hydrogen iodide to dissolve into hydrogen and iodine, and the ratio of these products increases over time. This is expressed in the following reaction:
For the formation of metal chelates, the thermodynamic technique provides a very significant information. Thermodynamics is a very useful technique in distinguishing between enthalpic effects and entropic effects. The bond strengths are totally effected by enthalpic effect, and this does not make any difference in the whole solution in order/disorder. Based on thermodynamics the chelate effect below can be best explained. The change of standard Gibbs free energy for equilibrium constant is response:
Where:
R = gas constant
T = absolute temperature
At 25°C,
ΔG = (− 5.708 kJ mol−1) · log β.
The enthalpy term creates free energy, i.e.,
For metal complexes, thermodynamic stability and kinetic stability are two interpretations of the stability constant in the solution. If reaction moves from reactants to products, it refers to a change in its energy as shown in the above equation. But for the reactivity, kinetic stability is responsible for this system, and this refers to ligand species [14].
Stable and unstable are thermodynamic terms, while labile and inert are kinetic terms. As a rule of thumb, those complexes which react completely within about 1 minute at 25°C are considered labile, and those complexes which take longer time than this to react are considered inert. [Ni(CN)4]2− is thermodynamically stable but kinetically inert because it rapidly exchanges ligands.
The metal complexes [Co(NH3)6]3+ and such types of other complexes are kinetically inert, but these are thermodynamically unstable. We may expect the complex to decompose in the presence of acid immediately because the complex is thermodynamically unstable. The rate is of the order of 1025 for the decomposition in acidic solution. Hence, it is thermodynamically unstable. However, nothing happens to the complex when it is kept in acidic solution for several days. While considering the stability of a complex, always the condition must be specified. Under what condition, the complex which is stable or unstable must be specified such as acidic and also basic condition, temperature, reactant, etc.
A complex may be stable with respect to a particular condition but with respect to another. In brief, a stable complex need not be inert and similarly, and an unstable complex need not be labile. It is the measure of extent of formation or transformation of complex under a given set of conditions at equilibrium [15].
Thermodynamic stability has an important role in determining the bond strength between metal ligands. Some complexes are stable, but as soon as they are introduced into aqueous solution, it is seen that these complexes have an effect on stability and fall apart. For an example, we take the [Co (SCN)4]2+ complex. The ion bond of this complex is very weak and breaks down quickly to form other compounds. But when [Fe(CN)6]3− is dissolved in water, it does not test Fe3+ by any sensitive reagent, which shows that this complex is more stable in aqueous solution. So it is indicated that thermodynamic stability deals with metal-ligand bond energy, stability constant, and other thermodynamic parameters.
This example also suggests that thermodynamic stability refers to the stability and instability of complexes. The measurement of the extent to which one type of species is converted to another species can be determined by thermodynamic stability until equilibrium is achieved. For example, tetracyanonickelate is a thermodynamically stable and kinetic labile complex. But the example of hexa-amine cobalt(III) cation is just the opposite:
Thermodynamics is used to express the difference between stability and inertia. For the stable complex, large positive free energies have been obtained from ΔG0 reaction. The ΔH0, standard enthalpy change for this reaction, is related to the equilibrium constant, βn, by the well thermodynamic equation:
For similar complexes of various ions of the same charge of a particular transition series and particular ligand, ΔS0 values would not differ substantially, and hence a change in ΔH0 value would be related to change in βn values. So the order of values of ΔH0 is also the order of the βn value.
Kinetic stability is referred to the rate of reaction between the metal ions and ligand proceeds at equilibrium or used for the formation of metal complexes. To take a decision for kinetic stability of any complexes, time is a factor which plays an important role for this. It deals between the rate of reaction and what is the mechanism of this metal complex reaction.
As we discuss above in thermodynamic stability, kinetic stability is referred for the complexes at which complex is inert or labile. The term “inert” was used by Tube for the thermally stable complex and for reactive complexes the term ‘labile’ used [16]. The naturally occurring chlorophyll is the example of polydentate ligand. This complex is extremely inert due to exchange of Mg2+ ion in the aqueous media.
The nature of central atom of metal complexes, dimension, its degree of oxidation, electronic structure of these complexes, and so many other properties of complexes are affected by the stability constant. Some of the following factors described are as follows.
In the coordination chemistry, metal complexes are formed by the interaction between metal ions and ligands. For these type of compounds, metal ions are the coordination center, and the ligand or complexing agents are oriented surrounding it. These metal ions mostly are the transition elements. For the determination of stability constant, some important characteristics of these metal complexes may be as given below.
Ligands are oriented around the central metal ions in the metal complexes. The sizes of these metal ions determine the number of ligand species that will be attached or ordinated (dative covalent) in the bond formation. If the sizes of these metal ions are increased, the stability of coordination compound defiantly decreased. Zn(II) metal ions are the central atoms in their complexes, and due to their lower size (0.74A°) as compared to Cd(II) size (0.97A°), metal ions are formed more stable.
Hence, Al3+ ion has the greatest nuclear charge, but its size is the smallest, and the ion N3− has the smallest nuclear charge, and its size is the largest [17]. Inert atoms like neon do not participate in the formation of the covalent or ionic compound, and these atoms are not included in isoelectronic series; hence, it is not easy to measure the radius of this type of atoms.
The properties of stability depend on the size of the metal ion used in the complexes and the total charge thereon. If the size of these metal ions is small and the total charge is high, then their complexes will be more stable. That is, their ratio will depend on the charge/radius. This can be demonstrated through the following reaction:
An ionic charge is the electric charge of an ion which is formed by the gain (negative charge) or loss (positive charge) of one or more electrons from an atom or group of atoms. If we talk about the stability of the coordination compounds, we find that the total charge of their central metal ions affects their stability, so when we change their charge, their stability in a range of constant can be determined by propagating of error [18]. If the charge of the central metal ion is high and the size is small, the stability of the compound is high:
In general, the most stable coordination bonds can cause smaller and highly charged rations to form more stable coordination compounds.
When an electron pair attracts a central ion toward itself, a strong stability complex is formed, and this is due to electron donation from ligand → metal ion. This donation process is increasing the bond stability of metal complexes exerted the polarizing effect on certain metal ions. Li+, Na+, Mg2+, Ca2+, Al3+, etc. are such type of metal cation which is not able to attract so strongly from a highly electronegative containing stable complexes, and these atoms are O, N, F, Au, Hg, Ag, Pd, Pt, and Pb. Such type of ligands that contains P, S, As, Br and I atom are formed stable complex because these accepts electron from M → π-bonding. Hg2+, Pb2+, Cd2+, and Bi3+ metal ions are also electronegative ions which form insoluble salts of metal sulfide which are insoluble in aqueous medium.
Volatile ligands may be lost at higher temperature. This is exemplified by the loss of water by hydrates and ammonia:
The transformation of certain coordination compounds from one to another is shown as follows:
A ligand is an ion or small molecule that binds to a metal atom (in chemistry) or to a biomolecule (in biochemistry) to form a complex, such as the iron-cyanide coordination complex Prussian blue or the iron-containing blood-protein hemoglobin. The ligands are arranged in spectrochemical series which are based on the order of their field strength. It is not possible to form the entire series by studying complexes with a single metal ion; the series has been developed by overlapping different sequences obtained from spectroscopic studies [19]. The order of common ligands according to their increasing ligand field strength is
The above spectrochemical series help us to for determination of strength of ligands. The left last ligand is as weaker ligand. These weaker ligand cannot forcible binding the 3d electron and resultant outer octahedral complexes formed. It is as-
Increasing the oxidation number the value of Δ increased.
Δ increases from top to bottom.
However, when we consider the metal ion, the following two useful trends are observed:
Δ increases with increasing oxidation number.
Δ increases down a group. For the determination of stability constant, the nature of the ligand plays an important role.
The following factors described the nature of ligands.
The size and charge are two factors that affect the production of metal complexes. The less charges and small sizes of ligands are more favorable for less stable bond formation with metal and ligand. But if this condition just opposite the product of metal and ligand will be a more stable compound. So, less nuclear charge and more size= less stable complex whereas if more nuclear charge and small in size= less stable complex. We take fluoride as an example because due to their smaller size than other halide and their highest electro negativity than the other halides formed more stable complexes. So, fluoride ion complexes are more stable than the other halides:
As compared to S2− ion, O22− ions formed more stable complexes.
It is suggested by Calvin and Wilson that the metal complexes will be more stable if the basic character or strength of ligands is higher. It means that the donating power of ligands to central metal ions is high [20].
It means that the donating power of ligands to central metal ions is high. In the case of complex formation of aliphatic diamines and aromatic diamines, the stable complex is formed by aliphatic diamines, while an unstable coordination complex is formed with aromatic diamines. So, from the above discussion, we find that the stability will be grater if the e-donation power is greater.
Thus it is clear that greater basic power of electron-donating species will form always a stable complex. NH3, CN−, and F− behaved as ligands and formed stable complexes; on the other hand, these are more basic in nature.
We know that if the concentration of coordination group is higher, these coordination compounds will exist in the water as solution. It is noted that greater coordinating tendency show the water molecules than the coordinating group which is originally present. SCN− (thiocynate) ions are present in higher concentration; with the Co2+ metal ion, it formed a blue-colored complex which is stable in state, but on dilution of water medium, a pink color is generated in place of blue, or blue color complex is destroyed by [Co(H2O)6]2+, and now if we added further SCN−, the pink color will not appear:
Now it is clear that H2O and SCN− are in competition for the formation of Co(II) metal-containing complex compound. In the case of tetra-amine cupric sulfate metal complex, ammonia acts as a donor atom or ligand. If the concentration of NH3 is lower in the reaction, copper hydroxide is formed but at higher concentration formed tetra-amine cupric sulfate as in the following reaction:
For a metal ion, chelating ligand is enhanced and affinity it and this is known as chelate effect and compared it with non-chelating and monodentate ligand or the multidentate ligand is acts as chelating agent. Ethylenediamine is a simple chelating agent (Figure 1).
Structure of ethylenediamine.
Due to the bidentate nature of ethylenediamine, it forms two bonds with metal ion or central atom. Water forms a complex with Ni(II) metal ion, but due to its monodentate nature, it is not a chelating ligand (Figures 2 and 3).
Structure of chelating configuration of ethylenediamine ligand.
Structure of chelate with three ethylenediamine ligands.
The dentate cheater of ligand provides bonding strength to the metal ion or central atom, and as the number of dentate increased, the tightness also increased. This phenomenon is known as chelating effect, whereas the formation of metal complexes with these chelating ligands is called chelation:
or
Some factors are of much importance for chelation as follows.
The sizes of the chelating ring are increased as well as the stability of metal complex decreased. According to Schwarzenbach, connecting bridges form the chelating rings. The elongated ring predominates when long bridges connect to the ligand to form a long ring. It is usually observed that an increased a chelate ring size leads to a decrease in complex stability.
He interpreted this statement. The entropy of complex will be change if the size of chelating ring is increased, i.e., second donor atom is allowed by the chelating ring. As the size of chelating ring increased, the stability should be increased with entropy effect. Four-membered ring compounds are unstable, whereas five-membered are more stable. So the chelating ring increased its size and the stability of the formed metal complexes.
The number of chelating rings also decides the stability of complexes. Non-chelating metal compounds are less stable than chelating compounds. These numbers increase the thermodynamic volume, and this is also known as an entropy term. In recent years ligands capable of occupying as many as six coordination positions on a single metal ion have been described. The studies on the formation constants of coordination compounds with these ligands have been reported. The numbers of ligand or chelating agents are affecting the stability of metal complexes so as these numbers go up and down, the stability will also vary with it.
For the Ni(II) complexes with ethylenediamine as chelating agent, its log K1 value is 7.9 and if chelating agents are trine and penten, then the log K1 values are 7.9 and 19.3, respectively. If the metal ion change Zn is used in place of Ni (II), then the values of log K1 for ethylenediamine, trine, and penten are 6.0, 12.1, and 16.2, respectively. The log βMY values of metal ions are given in Table 1.
Metal ion | log βMY (25°C, I = 0.1 M) |
---|---|
Ca2+ | 11.2 |
Cu2+ | 19.8 |
Fe3+ | 24.9 |
Metal ion vs. log βMY values.
Ni(NH3)62+ is an octahedral metal complex, and at 25 °C its log β6 value is 8.3, but Ni(ethylenediamine)32+ complex is also octahedral in geometry, with 18.4 as the value of log β6. The calculated stability value of Ni(ethylenediamine)32+ 1010 times is more stable because three rings are formed as chelating rings by ethylenediamine as compared to no such ring is formed. Ethylenediaminetetraacetate (EDTA) is a hexadentate ligand that usually formed stable metal complexes due to its chelating power.
A special effect in molecules is when the atoms occupy space. This is called steric effect. Energy is needed to bring these atoms closer to each other. These electrons run away from near atoms. There can be many ways of generating it. We know the repulsion between valence electrons as the steric effect which increases the energy of the current system [21]. Favorable or unfavorable any response is created.
For example, if the static effect is greater than that of a product in a metal complex formation process, then the static increase would favor this reaction. But if the case is opposite, the skepticism will be toward retardation.
This effect will mainly depend on the conformational states, and the minimum steric interaction theory can also be considered. The effect of secondary steric is seen on receptor binding produced by an alternative such as:
Reduced access to a critical group.
Stick barrier.
Electronic resonance substitution bond by repulsion.
Population of a conformer changes due to active shielding effect.
The macrocyclic effect is exactly like the image of the chelate effect. It means the principle of both is the same. But the macrocyclic effect suggests cyclic deformation of the ligand. Macrocyclic ligands are more tainted than chelating agents. Rather, their compounds are more stable due to their cyclically constrained constriction. It requires some entropy in the body to react with the metal ion. For example, for a tetradentate cyclic ligand, we can use heme-B which forms a metal complex using Fe+2 ions in biological systems (Figure 4).
Structure of hemoglobin is the biological complex compound which contains Fe(II) metal ion.
The n-dentate chelating agents play an important role for the formation of more stable metal complexes as compared to n-unidentate ligands. But the n-dentate macrocyclic ligand gives more stable environment in the metal complexes as compared to open-chain ligands. This change is very favorable for entropy (ΔS) and enthalpy (ΔH) change.
There are so many parameters to determination of formation constants or stability constant in solution for all types of chelating agents. These numerous parameters or techniques are refractive index, conductance, temperature, distribution coefficients, refractive index, nuclear magnetic resonance volume changes, and optical activity.
Solubility products are helpful and used for the insoluble salt that metal ions formed and complexes which are also formed by metal ions and are more soluble. The formation constant is observed in presence of donor atoms by measuring increased solubility.
To determine the solubility constant, it involves the distribution of the ligands or any complex species; metal ions are present in two immiscible solvents like water and carbon tetrachloride, benzene, etc.
In this method metal ions or ligands are present in solution and on exchanger. A solid polymers containing with positive and negative ions are ion exchange resins. These are insoluble in nature. This technique is helpful to determine the metal ions in resin phase, liquid phase, or even in radioactive metal. This method is also helpful to determine the polarizing effect of metal ions on the stability of ligands like Cu(II) and Zn(II) with amino acid complex formation.
At the equilibrium free metal and ions are present in the solution, and using the different electrometric techniques as described determines its stability constant.
This method is based upon the titration method or follows its principle. A stranded acid-base solution used as titrate and which is titrated, it may be strong base or strong acid follows as potentiometrically. The concentration of solution using 103− M does not decomposed during the reaction process, and this method is useful for protonated and nonprotonated ligands.
This is the graphic method used to determine the stability constant in producing metal complex formation by plotting a polarograph between the absences of substances and the presence of substances. During the complex formation, the presence of metal ions produced a shift in the half-wave potential in the solution.
If a complex is relatively slow to form and also decomposes at measurable rate, it is possible, in favorable situations, to determine the equilibrium constant.
This involves the study of the equilibrium constant of slow complex formation reactions. The use of tracer technique is extremely useful for determining the concentrations of dissociation products of the coordination compound.
This method is based on the study of the effect of an equilibrium concentration of some ions on the function at a definite organ of a living organism. The equilibrium concentration of the ion studied may be determined by the action of this organ in systems with complex formation.
The solution of 25 ml is adopted by preparing at the 1.0 × 10−5 M ligand or 1.0 × 10−5 M concentration and 1.0 × 10−5 M for the metal ion:
The solutions containing the metal ions were considered both at a pH sufficiently high to give almost complete complexation and at a pH value selected in order to obtain an equilibrium system of ligand and complexes.
In order to avoid modification of the spectral behavior of the ligand due to pH variations, it has been verified that the range of pH considered in all cases does not affect absorbance values. Use the collected pH values adopted for the determinations as well as selected wavelengths. The ionic strengths calculated from the composition of solutions allowed activity coefficient corrections. Absorbance values were determined at wavelengths in the range 430–700 nm, every 2 nm.
For a successive metal complex formation, use this method. If ligand is protonate and the produced complex has maximum number of donate atoms of ligands, a selective light is absorbed by this complex, while for determination of stability constant, it is just known about the composition of formed species.
Bjerrum (1941) used the method stepwise addition of the ligands to coordination sphere for the formation of complex. So, complex metal–ligand-n forms as the following steps [22]. The equilibrium constants, K1, K2, K3, … Kn are called stepwise stability constants. The formation of the complex metal-ligandn may also be expressed by the following steps and equilibrium constants.
Where:
M = central metal cation
L = monodentate ligand
N = maximum coordination number for the metal ion M for the ligand
If a complex ion is slow to reach equilibrium, it is often possible to apply the method of isotopic dilution to determine the equilibrium concentration of one or more of the species. Most often radioactive isotopes are used.
This method was extensively used by Werner and others to study metal complexes. In the case of a series of complexes of Co(III) and Pt(IV), Werner assigned the correct formulae on the basis of their molar conductance values measured in freshly prepared dilute solutions. In some cases, the conductance of the solution increased with time due to a chemical change, e.g.,
It is concluded that the information presented is very important to determine the stability constant of the ligand metal complexes. Some methods like spectrophotometric method, Bjerrum’s method, distribution method, ion exchange method, electrometric techniques, and potentiometric method have a huge contribution in quantitative analysis by easily finding the stability constants of metal complexes in aqueous solutions.
All the authors thank the Library of University of Delhi for reference books, journals, etc. which helped us a lot in reviewing the chapter.
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\\n\\nWhen distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\\n\\nThe Author agrees to:
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\\n\\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\\n\\nThe Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
\\n\\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
\\n\\nThe Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\nAUTHOR'S WARRANTY
\\n\\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\\n\\nThe Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement purport to assign, any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\\n\\nThe Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\\n\\nNothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\nTERMINATION
\\n\\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
\\n\\nIn the event of termination, IntechOpen will notify the Author of the decision in writing.
\\n\\nIntechOpen’s DUTIES AND RIGHTS
\\n\\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\\n\\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
\\n\\nIntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\\n\\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\nIntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\nMISCELLANEOUS
\\n\\nFurther Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\nThird Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\\n\\nWaiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
\\n\\nSeverance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\nNo partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\\n\\nGoverning law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
\\n\\nPolicy last updated: 2018-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
\n\nCORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\nSubject to the following Article, the Author grants to IntechOpen, during the full term of copyright, and any extensions or renewals of that term, the following:
\n\nThe foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\n\nThe Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Author, and any Co-Author, confirms that they are, and will remain, a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Work and all versions of it created during IntechOpen's editing process, including all published versions, is retained by the Author and any Co-Authors.
\n\nSubject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\n\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\n\nThe Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\n\nAUTHOR'S DUTIES
\n\nWhen distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\n\nThe Author agrees to:
\n\nThe Author will be held responsible for the payment of the agreed Open Access Publishing Fee before the completion of the project (Monograph/Compacts publication).
\n\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\n\nThe Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
\n\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
\n\nThe Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\nAUTHOR'S WARRANTY
\n\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\n\nThe Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement purport to assign, any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\n\nThe Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\n\nNothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\nTERMINATION
\n\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
\n\nIn the event of termination, IntechOpen will notify the Author of the decision in writing.
\n\nIntechOpen’s DUTIES AND RIGHTS
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
\n\nIntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\n\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\nIntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
\n\nMISCELLANEOUS
\n\nFurther Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\nThird Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\n\nWaiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
\n\nSeverance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\nNo partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\n\nGoverning law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
\n\nPolicy last updated: 2018-09-11
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