Combinatorial libraries synthesis

Dolle RE (2002) Comprehensive survey of combinatorial library synthesis. J Comb Chem 4(5) 369-418... 

Armstrong, R.W., Combs, A.R, Tempest, P.A., Brown, S.D., Keating, T.A. (1996) Multiple-Component Condensation Strategies for Combinatorial Library Synthesis. Accounts of Chemical Research, 29, 123-131. 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

Dolle, R. E., Comprehensive survey of combinatorial library synthesis 2000, J. Comb. Chem. 2001, 3, 477-517. 

Kobayashi, S. Combinatorial Library Synthesis Using Polymer-supported Catalysts. In Combinatorial Chemistry, Fenniri, H., Ed., Oxford University Press Oxford, U.K., 2000 pp 421-432. 

The combinatorial library synthesis of a diverse set of trisubstituted ureas has been described [64]. The synthetic pathway involves the prehminary preparation of various nitrophenylcarbamates from commercially available nitrophenyl chlorofor-mate and a selection of amines allowing for wide scope in the divergence of the final urea products. In a further reaction of the nitrophenylcarbamates with a second amine, the urea was generated. Simultaneous addition of an electrophilic and basic scavenger resin removed all by-products, again allowing rapid isolation of the products in excellent yield and purity (Scheme 2.43). 

Scheme 2.43 Combinatorial library synthesis of trisubstituted ureas.

Dolle, R.E. Comprehensive survey of combinatorial library synthesis 2001. 

Kumaravel K, Vasuki G (2009) Four-component catalyst-free reaction in water combinatorial library synthesis of novel 2-amino-4-(5-hydroxy-3-methyl-lH-pyrazol-4-yl) H-chro-mene-3-carbonitrile derivatives. Green Chem 11 1945-1947... 

Key words Drug discovery, chem-informatics, molecular design, combinatorial chemistry, combinatorial library, synthesis protocol, PGVL, reactant, product, enumeration, filtering integration, workflow, streamline, desktop tool, software deployment. 

Cortese, R., ed. (1996) Combinatorial Libraries Synthesis, Screening and Application Potential, Walter de Gruyter Co., New York... 

The bioanalytical revolution continues in fact, the drug discovery revolution continues inexorably forward. Today, not only are humans benefiting from revolutionary new medicines that have dramatically improved the quality of life, but more is expected to come. Compound collections have ballooned through combinatorial library synthesis biological science has mapped the human genome, and society impatiently awaits the promise of genetically tailored medicines that will treat virtually every ailment. 

Cesareni, G., Minenkova, O., Dente, L., Iannolo, G., Zucconi, A., Citterich, M.H., Lanfrancotti, A., Castagnoli, L. and Vetriani, C., In Cortese, R. (Ed.) Combinatorial Libraries. Synthesis, Screening and Application Potential, Walter de Gruyter, Berlin, Germany, 1995, pp. 111-126. 

Armstrong RW, Combs AP, Tempest PA, Brown SD, Keating TA, Multiple-component condensation strategies for combinatorial library synthesis, Acc. Chem. Res., 29 123-131, 1996. 

This simple and versatile combinatorial one-pot method will surely provide, in future, many diverse libraries, and its use in combination with solution purification techniques (see the next sections) will help in automating the experimental procedures. A thorough search for new multicomponent condensations should even increase their applications in combinatorial library synthesis. 

Gaus HJ, Kung PP, Brooks D, Cook PD, Cummins LL, Monitoring solution-phase combinatorial library synthesis by capillary electrophoresis, Biotechnol. Bioeng, 61 169-177, 1999. 

A. Strategies of Combinatorial Libraries Synthesis and Analytical Challenges Associated with Them... 

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