The relevance of chirality to the study of biological activity

Crossley, Roger

doi:10.1016/s0040-4020(01)80486-5

Cited by 134 publications

(57 citation statements)

References 57 publications

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“…1 Enantiomers of drugs often display different activities 2 and at the early discovery stages of drug development three reasons favor the use of a rugged, generally applicable enantioselective HPLC method. First, if the compound is derived from a conventional synthesis that affords a racemic mixture it is important to obtain complete HPLC separation with adequate resolution as a powerful alternative to enantioselective synthesis.…”

Section: Introductionmentioning

confidence: 99%

Direct high‐performance liquid chromatographic separation of the enantiomers of an aromatic amine and four aminoalcohols using polysaccharide chiral stationary phases and acidic additive

2007

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The HPLC enantiomeric separation of N-benzyl-alpha-methyl-benzylamine, phenylalaninol, tryptophanol, 2 (diphenylhydroxymethyl)pyrrolidine, and isoproterenol was accomplished in the normal-phase mode using two polysaccharide-derived chiral stationary phases (CSPs) and various n-hexane/2-propanol mobile phases with acidic (TFA) or basic (DEA) additive. The compounds were separated without any derivatization and separation factor range between 2.09 and 1.09 with resolution factor 3.4 and 0.4, respectively. The best separation of the enantiomers of the amine was achieved on amylose tris (3, 5-dimethylphenylcarbamate) CSP with TFA additive in the mobile phase; in acidic conditions, instead, the best enantioseparation of the aminoalcohols was achieved on cellulose tris (3, 5-dimethylphenilcarbamate). A long equilibration time of the CSP when switching from an undoped mobile phase to a doped one is required to obtain reproducible results.

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Section: Introductionmentioning

confidence: 99%

Direct high‐performance liquid chromatographic separation of the enantiomers of an aromatic amine and four aminoalcohols using polysaccharide chiral stationary phases and acidic additive

2007

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“…The principle of chirality and the natural predisposition for shape and handedness in molecular binding by receptors, pumps, and enzymes have been recognized as essential principles for effective drug design (6). In turn, asymmetric enzymatic catalysis, unlike scalar chemical methods, is the optimal tool for synthesis of these enantiopure, pharmaceutically optimal molecules (24).…”

mentioning

confidence: 99%

Exploring Nitrilase Sequence Space for Enantioselective Catalysis

Robertson

Chaplin

DeSantis

et al. 2004

Appl Environ Microbiol

210

116

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Nitrilases are important in the biosphere as participants in synthesis and degradation pathways for naturally occurring, as well as xenobiotically derived, nitriles. Because of their inherent enantioselectivity, nitrilases are also attractive as mild, selective catalysts for setting chiral centers in fine chemical synthesis. Unfortunately, <20 nitrilases have been reported in the scientific and patent literature, and because of stability or specificity shortcomings, their utility has been largely unrealized. In this study, 137 unique nitrilases, discovered from screening of >600 biotope-specific environmental DNA (eDNA) libraries, were characterized. Using culture-independent means, phylogenetically diverse genomes were captured from entire biotopes, and their genes were expressed heterologously in a common cloning host. Nitrilase genes were targeted in a selection-based expression assay of clonal populations numbering 10 6 to 10 10 members per eDNA library. A phylogenetic analysis of the novel sequences discovered revealed the presence of at least five major sequence clades within the nitrilase subfamily. Using three nitrile substrates targeted for their potential in chiral pharmaceutical synthesis, the enzymes were characterized for substrate specificity and stereospecificity. A number of important correlations were found between sequence clades and the selective properties of these nitrilases. These enzymes, discovered using a high-throughput, culture-independent method, provide a catalytic toolbox for enantiospecific synthesis of a variety of carboxylic acid derivatives, as well as an intriguing library for evolutionary and structural analyses.An inherent macromolecular asymmetry, determined by the primordial choice of L-amino acids as protein structural determinants, results in a bias in the populations of chiral molecular moieties produced by stereoselective enzymatic catalysis and in the specificities of those enantiomers in their subsequent interactions with proteins in complex natural systems (16). The principle of chirality and the natural predisposition for shape and handedness in molecular binding by receptors, pumps, and enzymes have been recognized as essential principles for effective drug design (6). In turn, asymmetric enzymatic catalysis, unlike scalar chemical methods, is the optimal tool for synthesis of these enantiopure, pharmaceutically optimal molecules (24). However, the synthetic potential of biocatalysts has yet to be fully realized due to the paucity of available enzymes.The protein sequence space parsed by modern science represents a small fraction of the genetic information available in the biosphere. This has become apparent from recent microbiological efforts targeting a spectrum of physical and chemical environments. These studies have shown that biotopes at extremes of temperature, pressure, pH, salinity, etc., are rich in microbial biodiversity. It is also clear that the physical properties and chemical specificities of the associated gene products reflect the extrinsic and int...

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“…8,9 However, the relevance of the stereochemistry at the C-2 stereogenic center has not been considered, although it is well known that interactions of an enzymatic system leading to the functionalization of a substrate are stereospecific. 10 An example of stereospecificity is shown by the differential inhibition of Cinchona alkaloids quinine and quinidine (enantiomers at C-8 and C-9) on a human isoform of cytochrome P450. 11 Direct separation of diastereomers at C-2 of flavanone glycosides in Citrus juice was accomplished by reversephase HPLC using a b-cyclodextrin-bonded stationary phase 12 and normal-phase gradient elution of a mixture of authentic samples using a cellulose triacetate diol stationary phase.…”

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confidence: 99%

Chiral HPLC separation and CD spectra of the C‐2 diastereomers of naringin in grapefruit during maturation

2003

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Naringin is the chief flavanone glycoside of grapefruit (Citrus paradisi). It is responsible for part of the bitter taste of the fruit and can cause the inhibition of some cytochrome P450s. The direct separation of (2R)-and (2S)-naringin in the albedo of grapefruits was obtained in normal phase HPLC mode using Chiralcel OD as chiral stationary phase and n-hexane/ethanol with 0.1% of TFA as mobile phase. Chiralpak AD was almost ineffective in the separation. This procedure was used to evaluate the stereochemistry at C-2 during maturation of the grapefruit. The CD curves of (2R)-and (2S)-naringin isolated by semipreparative chiral HPLC were determined and the elution order of the chromatographic peaks was related to the absolute C-2 configuration. Partial resolution of the C-2 diastereomers of narirutin was obtained on Chiralpak AD. Chirality 15:661 -667,

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The relevance of chirality to the study of biological activity

Cited by 134 publications

References 57 publications

Direct high‐performance liquid chromatographic separation of the enantiomers of an aromatic amine and four aminoalcohols using polysaccharide chiral stationary phases and acidic additive

Direct high‐performance liquid chromatographic separation of the enantiomers of an aromatic amine and four aminoalcohols using polysaccharide chiral stationary phases and acidic additive

Exploring Nitrilase Sequence Space for Enantioselective Catalysis

Chiral HPLC separation and CD spectra of the C‐2 diastereomers of naringin in grapefruit during maturation

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