Combinatorial natural product libraries

Mass spectrometry (MS) is playing an increasingly visible role in the molecular characterization of combinatorial libraries, natural products, drug metabolism and pharmacokinetics, toxicology and forensic investigations, and proteomics. Toward this end, electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure photo-ionization (APPI) have proven valuable for both qualitative and quantitative screening of small molecules (e.g., pharmaceutical products) [9-14]. 

Natural products have been identified as the active principle of herbs and extracts used in folk medicine [1], The importance of natural products in the pharmaceutical industry has continued to the present day and is reflected by the fact that close to half of the best selling pharmaceuticals are either natural products (e.g. cyclosporine, Taxol, FK 506) or derivatives thereof [3]. In high throughput screening processes performed by the pharmaceutical industry natural product extracts exhibit a hit rate which is estimated to be substantially higher than the hit rate of random libraries from combinatorial chemistry. Natural products such as epothilones, discodermolide or ecteinascidin are promising clinical candidates for future cancer treatment. 

The four major sources of starting material for drug screens are chemical libraries, natural products, specifically designed medicinal chemistry-derived drugs often modified and synthesized using directed combinatorial chemistry—and computationally designed drugs. 

Abstract In the continuous drive to increase screening throughput and reduce sample requirement, microarray-based technologies have risen to the occasion. In the past 7 years, a number of new methodologies have been developed for preparing small molecule microarrays from combinatorial and natural product libraries with the goal of identifying new interactions or enzymatic activities. Recent advances and applications of small molecule microarrays are reviewed. 

The feasibility of multistep natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first demonstrated by Nicolaou and coworkers in epothilone synthesis and in the generation of an epothilone library [152]. The traceless release of TBS-protected epoC 361 by RCM of resin-bound precursor 360 (Scheme 69) is an early and most prominent example for the strategy outlined in Fig. 11a. 

Lee, M.L. Schneider, G. (2001) Scaffold Architecture and Pharmacophoric Properties of Natural Products and Trade Drugs Application in the Design of Natural Product-Based Combinatorial Libraries. Journal of Combinatorial Chemistry, 3, 284-289. 

P. A. Keifer 1998, (New methods for obtaining high resolution NMR spectra of solid-phase-synthesis resins, natural products, and solution-state combinatorial chemistry libraries), Drugs Future 23, 301-307. 

A collection of samples (e.g., chemical compounds, natural products, overexpression library of a microbe) available for screening (2) a set of compounds produced through combinatorial chemistry. 

We still need much better medicines to cure cancer, heart disease, stroke, and Alzheimer s disease. We need better drugs to deal with obesity, diabetes, arthritis, and schizophrenia. The treatments of diabetes, arthritis, and mental defects such as schizophrenia or manic depression are not yet cures, just ways to keep the symptoms under control. Cures are needed. Insights from genetics may help guide us toward elegant and rational cures, but we will also make use of screens to identify natural products and libraries of randomly generated synthetic compounds (combinatorial chemistry). A semi-empirical approach may be the best hope over the next two decades to yield drugs to alleviate these diseases. 

Ley S V, Baxendale IR, Myers RM (2006) The use of polymer supported reagents and scavengers in the synthesis of natural products. In Boldi AM (ed) Combinatorial synthesis of natural product-based libraries. CRC Press Boca-Raton, pp 131-163... 

Combinatorial Synthesis of Natural Product-Based Libraries... 

While this may in fact be the case for natural product mixtures, it is rarely the case when dealing with synthesized mixtures. Despite our attempts to create real molecular diversity in the test tube, our efforts have not even begun to anticipate the true diversity of atomic connectivity within "drug space" (estimated to be of the order of 1063 unique compounds, theory, famously in this case, greatly outpacing the amount of matter in the universe). Thus, combinatorial chemistry was never practically able to produce true chemical diversity and compounds produced in such library format ended up looking very much like one another, with the attendant similarities in biological activity profiles. 

Fig. 10.6 Concept of multitarget affinity specificity screening (MASS). Macromolecular targets (typically structured RNA constructs or proteins) in nondenaturing buffers are mixed in solution with a collection of potential ligands derived from natural product fractions, combinatorial libraries, or other diverse compound collections. The...

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