Combinatorial mixtures

Bressanelli S, Tomei L, Rey FA, De Francesco R (2002) Stmctural analysis of the hepatitis C vims RNA polymerase in complex with ribonucleotides. J Virol 76 3482-3492 Burton G, Ku TW, Carr TJ, Kiesow T, Sarisky RT, Lin-Goerke J, Baker A, Eamshaw DL, Hofmann GA, Keenan RM, Dhanak D (2005) Identification of small molecule inhibitors of the hepatitis C vims RNA-dependent RNA polymerase from a pyrrolidine combinatorial mixture. Bioorg Med Chem Lett 15 1553-1556... 

An additional complication of the bioassay of mixtures, be they natural extracts or combinatorial in nature, is that any activity present in a pool of compounds must still be assigned to the individual components to render the screening exercise useful for Drug Discovery. This is more straightforward with respect to combinatorial mixtures due to the fact that, by definition, the structural type is known, and what is not known is just the specifics of the attachment of monomer. Nonetheless, structure elucidation of active components must be made and this has traditionally been done through what is referred to as "deconvolution."... 

Lead optimization Combinatorial/medicinal chemistry support Open access Purification Combinatorial mixtures Combinatorial libraries-quality control Taylor et al., 1995 Pullen et al., 1995 Zeng and Kassel, 1998 Zeng et al., 1998 Richmond et al., 1999 Yates et al., 2001 Dunayevskiy et al., 1995 Fang et al., 1998 Fitch 1998-1999 FIsu et al., 1999 Dulery et al., 1999 Ventura et al., 2000 Shah et al., 2000... 

Combinatorial Mixture Screening The increased popularity of LC/MS-based methods combined with limited resources resulted in advances that effectively matched combinatorial chemistry samples (i.e., complexity) with instrument time. Richmond, Yates, and coworkers (Richmond et al, 1999 Yates et al.,2001) demonstrated the use of flow injection analysis (FIA)-LC/MS systems for rapid purity assessment and combinatorial mixture screening, respectively. These LC/MS-based applications addressed two critical bottlenecks HPLC... 

Yates, N. Wislocki, D. Roberts, A. Berk, S. Klatt, T. Shen, D.-M. Willoughby, C. Rosauer, K. Chapman, K. Griffin, P. 2001. Mass spectrometry screening of combinatorial mixtures, correlation of measured and predicted electrospray ionization spectra. Anal. Chem, 73, 2941-2951. 

For all of the above good reasons, few publications have come out on combinatorial mixture analysis in this review period. Mixture analysis of peptides by MS and MS/MS has continued as an active field [2,59,64], Nanospray (very low flow electrospray) has become the method of choice for studies of mixtures of peptides by MS/MS [65,66], 2D NMR has been used to assure that unusual amino acids were correctly incorporated in a mixed synthesis [59]. 

Eliseev AV, Emerging approaches to target assisted screening of combinatorial mixtures, Curr. Opin. Drug Discovery Dev., 1 106-115, 1998. 

Figure 3-11 four-component Ugi reaction reported by Keating and Armstrong. A combinatorial mixture of the intermediate cyclohexenyl amide can be split into several portions, and each can be further reacted to give a variety of products, all of which will be combinatorial. (Reaction redrawn from description from Keating. T. A., and Armstrong. R. W Molecular diversity via a convertible isocyanide in the Ugi four-component condensation J. Am. Chem. Soc. 117 7842-7843. 1995.)... 

KF Blom. Strategies and data precision requirments for the mass spectrometric determination of structures form combinatorial mixtures. Anal Chem 69(21) 4354-4362, 1997. 

From the point of view of synthetic effort, preparation of combinatorial mixtures is by far the most economical approach. It can be done with ordinary laboratory equipment and does not take more time than the synthesis of any one of the individual components of the library. This simplicity, however, has its price firstly, the more components a mixture contains the more difficult it becomes to follow the reaction analytically and to determine the actual composition of the reaction product. Secondly, if hits are found in a biological assay, deconvolution is required. In most cases this is done via resynthesis either of the individual components or of subsets of the mixture. If the composition of the initial mixtures was carefully planned it may be possible to identify the active component(s) by simply comparing the composition of the active mixtures with those of the inactive ones. Corresponding procedures have been reported in the literature (e.g., the techniques of indexed [1,2] and orthogonal [3] chemical libraries have been used in solution-phase synthesis). However, the biological effect of a mixture may also be due to a combined action of several weakly active members, with the result that deconvolution does not identify a significantly active compound. Finally, the problem of impurities multiplies with the complexity of the mixtures. 

R. A. Hoaghten, Linear Arrays and Combinatorial Mixtures of Quinazolinones, conference Exploiting Molecular Diversity Small Molecule Libraries For Drug Discovery, San Diego, CA, 1996. 

The traditional one-pot , three-component synthesis was adapted successfully for combinatorial mixture synthesis of dihydrophenyl triazines, which are nonclassical, dihydrofolate reductase (DHFR) inhibitors. The products precipitated out of the reaction mixture and could be collected easily and cleansed by washing. The reactions were monitored by TLC <1999BMC1255>. 

C. A. S. Barnes and D. E. Clemmer, Ion mobility/time-of-flight analysis of combinatorial mixtures, High-Throughput Analysis, 187-216 (2003). 

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