Combinatorial mixture screening

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... 

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."... 

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. 

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

The second method for mixture analysis is the use of specialized software together with spectral databases. We have developed a mixture analysis program AMIX for one- and multidimensional spectra. The most important present applications are the field of combinatorial chemistry and toxicity screening of medical preparations in the pharmaceutical industry. An important medical application is screening of newborn infants for inborn metabolic errors. 

Combinatorial synthesis of multicomponent mixtures, among them mixtures of heterocycles, for screening of bioactive compounds 99JMC3743. 

Our group also demonstrated another combinatorial approach in which a CSP carrying a library of enantiomerically pure potential selectors was used directly to screen for enantioselectivity in the HPLC separation of target analytes [93, 94]. The best selector of the bound mixture for the desired separation was then identified in a few deconvolution steps. As a result of the parallelism advantage , the number of columns that had to be screened in this deconvolution process to identify the single most selective selector CSP was much smaller than the number of actual selectors in the library. 

Taylor, E.W., Giboons, J.A., and Baeck-man, R.A. Intestinal absorption screening of mixtures from combinatorial libraries in the Caco-2 model. Pharm. Res. 1997, 14, 572-577. 

A set of chemicals that has been labeled or annotated for easy storage and retrieval and that is available for screening. Consists of compounds synthesized by combinatorial or standard synthetic methods, purchased from commercial or academic sources, or samples of natural products either as pure samples or as mixtures. 

The disulfonamide library was tested in the TifO PrC-mcdiatcd addition of Et2Zn to aldehydes, a known process using the bis-trifluoromethylsulfonamide of 1,2-diaminocyclohexane.106 The tests were run in 30 different reaction vessels in parallel format. In order to increase throughput, each vessel was charged with four different aldehydes, and the enantioselectivities of the four reaction products were determined by conventional GC analysis of the crude mixtures. The idea of using a given catalyst to screen combinatorially the reactions of different substrates had previously been proposed but in a different context.45 In the present case each mixture required about one hour to be screened, which means that about 96 ee-determinations of products (52) (Scheme 11) could be performed per day.105 A total of 120 results were collected, the best ees being >90%. 

Classical Drug Discovery focused on the biological evaluation of individual purified compounds. But in light of HTS and combinatorial chemistry, it became widely accepted that the biological screening of mixtures of compounds should, in theory, provide much more biological data in the same amount of time used for bioassay of individual compounds,... 

The use of combinatorial chemistry to produce libraries of compounds is pivotal in drug discovery. Screen hits need to be analyzed to identify the structure of the individual active component. Large numbers of samples containing only small quantities of complex mixtures require... 

---