Combinatorial natural-product-derived

A list of privileged scaffolds - several of which are natural-product derived - for target-family-biased combinatorial libraries was recently presented by Muller [94], These scaffolds were proven to produce biologically active compounds for more than one member of a given target family. A rough-and-ready in-silico evaluation... 

As a source of novel chemical structures, natural products are now rivaled by the revolution that is combinatorial chemistry by which a vast number of compounds may be made from a relatively small number of starting compounds, or monomers (87). An alliance of natural products chemistry with combinatorial chemistry has resulted m the development of several libraries of natural product derivatives, using natural products as templates (88) and as targets for total synthesis on solid phase (89). Whereas natural products have often been the target or the starting point for synthetic chemists, the use of natural products as combinatorial chemistry monomers is likely to increase enormously the numbers of natural product-denved structures available for testing. 

Handcrafted by medicinal chemists Combinatorial chemistry Automated (parallel) synthesis Natural-product derivatives... 

Ciobanu, L.C. and Poirier, D., Solid-phase parallel synthesis of 17-substituted estradiol sulfamate and phenol libraries using the multidetachable sulfamate linker, J. Comb. Chem., 5, 429, 2003. Niggemann, J. et al.. Natural product-derived building bloeks for combinatorial synthesis. Part 1. Fragmentation of natural products from myxobacteria, J. Chem. Soc., Perkin Trans. 1, 2490, 2002. Bourel, L. et al.. Solid-phase total synthesis of kahalalide A and related analogues, J. Med. Chem., 48, 1530, 2005. 

Pharmacophore 15,590 compounds from the Ana-lytiCon Discovery collection of natural-product-derived combinatorial compounds (vOl/2007) Full 8 2 [96]... 

Since the introduction of solid-phase peptide synthesis by Merrifield (1) nearly forty years ago, solid-phase techniques have been applied to the construction of a variety of biopolymers and extended into the field of small molecule synthesis. The last decade has seen the emergenee of solid-phase synthesis as the leading technique in the development and production of combinatorial libraries of diverse compounds of varying sizes and properties. Combinatorial libraries can be classified as biopolymer based (e.g., peptides, peptidomimetics, polyureas, and others [2,3]) or small moleeule based (e.g., heterocycles [4], natural product derivatives [5], and inorganie eomplexes [6,7]). Libraries synthesized by solid-phase techniques mainly use polystyrene-divinylbenzene (PS) derived solid supports. Owing to physieal and ehemical limitations of PS-derived resins, other resins have been developed (8,9). Most of these resins are prepared from PS by functionalizing the resin beads with oligomers to improve solvent compatibility and physical stability (8,9). 

Niggemann J, Michaehs K, Frank R, Zander N, Hoefle G (2002) Natural product-derived building blocks for combinatorial synthesis. Part 1. Fragmentation of natural products from myxohacteria. J Chem Soc. Perkin Trans 1, pp 2490-2503... 

The term "structural genomics" is used to describe how the primary sequence of amino acids in a protein relates to the function of that protein. Currently, the core of structural genomics is protein structure determination, primarily by X-ray crystallography, and the design of computer programs to predict protein fold structures for new proteins based on their amino acid sequences and structural principles derived from those proteins whose 3-dimensional structures have been determined. Plant natural product pathways are a unique source of information for the structural biologist in view of the almost endless catalytic diversity encountered in the various pathway enzymes, but based on a finite number of reaction types. Plants are combinatorial chemists par excellence, and understanding the principles that relate enzyme structure to function will open up unlimited possibilities for the... 

The results of an antitumor screen are summarized in Table 8.1. The attrition table summarizes the results from 338,072 samples tested against tumor cells derived from soft tissue sarcomas. Given that the samples included one combinatorial collection with approximately 1.5 million compounds and that each natural product extract most likely contained 100 or more, the total number of compounds tested in this screen exceeded 5 million. As shown in the first column of Table 8.1, the samples were from 11 collections composed of single synthetics, compounds synthesized by combinatorial chemistries, and purified natural products and extracts. The natural products were derived from microorganisms (actinomyces and fungi), plants, and marine invertebrates. 

Scheme 3.30 Derivatives of natural product skeletons and combinatorial semi-synthesis products.

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...

Various N-alkylated derivatives of amino acids are natural products [e.g., H-D-(Me)Tyr-OH (D-surinamine) and H-(Me)Trp-OH (abrin) were found in cabbage tree bark1691] and many of them are used as enzyme inhibitors, receptor agonists and antagonists, building blocks for heterocyclic scaffolds in combinatorial chemistry, etc. In this section the preparation of N-alkyl amino acids in solution for their use in peptide synthesis is described. This implies that the synthetic procedures described in this section will ultimately result in V-alkyl amino acids appropriately protected for peptide synthesis. 

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