Benzodiazepine, combinatorial

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. 

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

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. 

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. 

A Versatile Synthetic Strategy Enabling Solid-Phase Syntheses of 1,5-Ben-zothiazepines, 1,5-Benzodiazepines and Related Structures, Schwarz, M. K., Lecture presented at the 2nd Canadian Conference of Combinatorial Chemistry, Montreal, Canada, Oct. 6-7, 1997. 

PHC(16)431, 2005PHC(17)389, 2007PHC(18)402> combinatorial approaches to benzodiazepine derivatives <1996ACR132, 2006RMC53> 1,5-benzodiazepines and 1,5-benzodiazepinium salts <1998AHC2>. 

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],... 

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. 

A particularly important route to l,4-benzodiazepine-2,5-diones 361 is based on ring-closure of precursors 360 prepared from anthranilic acids 359 using the Ugi reaction, a 4-component process that allows considerable structural diversity to be introduced in a combinatorial fashion (Scheme 198) <1996JA2574, 1996JOC8935, CHEC-III(13.06.9.1)202>. The convenience of this procedure is further enhanced by using resin-bound isocyanides <20020L1167, 2002TL4083>. 

Fast binary filtering methods can also be used for scaffold ranking, i.e., the prioritization of combinatorial scaffolds based on predicted properties. Privileged scaffolds were selected to demonstrate this idea [82], Piperazines SI, benzodiazepines S2, and spiroindolines S3 have been described as GPCR-privileged scaffolds [83], Scaffold S4 represents a SPIKET motif for tubulin binding which is effective for inhibiting cellular proliferation [84], Dysidiolide-derived compounds... 

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