Benzodiazepine, combinatorial library

Figure 4 Four examples of large (>100 member) benzodiazepine combinatorial libraries prepared in academia or industry, by solid- or solution-phase parallel synthesis...

To speed the process of drug discovery, combinatorial chemistry> has been developed to prepare what are called combinatorial libraries, in which anywhere from a few dozen to several hundred thousand substances are prepared simultaneously. Among the early successes of combinatorial chemistry is the development of a benzodiazepine library, a class of aromatic compounds much used as antianxiety agents. 

Nedved, M. L. Habibi-Goudarzi, S. Ganem, B. Henion, J. D. 1996. Characterization of benzodiazepine combinatorial chemical libraries by on-line immunoaffinity extraction, coupled column HPLC-ion spray mass spectrometry-tandem mass spectrometry. Anal. Chem., 68, 4228-4236. 

Using the Multipin SPOC systems, researchers at Chiron have demonstrated the automated solid-phase synthesis of peptoids 1 (Scheme 1) [12], while Ellman and co-workers have completed the synthesis of a combinatorial library of 11 200 spatially dispersed benzodiazepines 2 (Scheme 2) [13],... 

M.L. Nedved, S. Habibi-Goudarzi, B. Ganem, J.D. Henion, Characterization of benzodiazepine combinatorial" chemical libraries by on-line lAC, coupled column LC-ESI-MS-MS, Anal. Chem., 68 (1996) 4228. 

Examples of this technique are described for artificial receptors for the alkaloid yohimbine binding peptides obtained from a phage display library [57], for the steroid libraries related to lla-hydroxyprogesterone [58], corticosterone [58] (reported in Fig. 12), and cortisol [59]. A molecularly imprinted polymer working as a synthetic receptor for a series of chiral benzodiazepines [47], artificial receptors for the tricyclic antidepressant drug nortriptyline—obtained by covalent and noncovalent molecular imprinting and studied by capillary liquid chromatography with a simulated combinatorial library [60,61]—were also examined. 

Figure 1 Combinatorial libraries built around a benzodiazepine scaffold (left) and a diketopiperazine scaffold (right).

Until 1992, combinatorial libraries were almost entirely restricted to peptides and oligonucleotides, but peptides are not ideal as drugs because they have poor oral bioavail-ablity and a short half-life, so the pharmaceutical industry needed more useful libraries. Chiron experimented with N-substituted glycine peptoids (Figure 2), where the side chains are attached to the amide nitrogen,but the real breakthrough in what is usually called small-molecule chemistry came when Bunin and Ellman reported the solid-phase synthesis of a 1,4-benzodiazepine library (Figure 3). Very soon afterwards DeWitt et al. reported a similar synthesis of benzodiazepines... 

Early reported applications of this technique were the preparation of a 24-member peptide library [83], of a 125-member tripeptide-substituted cinnamic acid library tested for inhibition of tyrosine phosphatase PTP1B [83], of a 64-member peptide-like library [83] and of libraries based on a natural product, epothilone, using also new polystyrene grafted solid supports [84], Other applications, ranging from l,5-benzodiazepin-2-one library synthesis [85] to chalcone library synthesis [86], were also recently reported. Commercialization of the basic components for this technique [87] (reaction supports and vessels, tags, software, sorters, reaction stations, and so on) will ensure its quick and effective use in combinatorial chemistry and also the implementation of new technical features and possibilities for more complex and demanding applications in future. 

Bunin BA, Plunkett MJ, Ellman JA, The combinatorial synthesis and chemical and biological evaluation of a 1,4-benzodiazepine library, Proc. Natl. Acad. Sci. USA, 91 4708-4712, 1994. 

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