Library scaffold diversity

Grabowski, ., Baringhaus, . -H., Schneider, G. (2008) Scaffold diversity of natural products inspiration for combinatorial library design. Nat Prod Rep 25, 892-904. 

Krchnak Y, Weichseil AS, Issakova O, Lam KS, Lebl M, Bifunctional scaffolds as templates for synthetic combinatorial libraries, Molec. Diversity, 1 177-182, 1995. 

Viewing secondary metabolites from a chemical perspective, the scaffold diversity and polyfunctional features offer significant potential to generate random libraries for screening purposes. The structural status of a compound on this level is, therefore, a transition state with the goal to become a hit or a lead for further development (Table 7.2). Various automatic chromatographic separation techniques and modern spectroscopic methodologies can... 

Contributions by R. Joseph and P. Arya as well as M. A. Koch and H. Waldmann focus on synthetic aspects towards lead structures originating from natural product-derived scaffolds. R. Joseph and P. Arya refer to two complementary approaches, the synthetic access to focussed libraries around bioactive natural product cores, and diversity-oriented synthesis aiming at 3D scaffold diversity for hit generation, respectively. On the other hand, M. A. Koch and H. Waldmann emphasise the correlation of natural product-based library concepts with structural features of targeted protein domains, thus strengthening the privileged structure concept from a bioorganic viewpoint. 

W.H.B. Sauer and M.K. Schwarz, Size doesn t matter scaffold diversity, shape diversity and biological activity of combinatorial libraries, Chimia, 2003, 57(5), 276. 

Commercial screening libraries Range from low scaffold diversity (e.g., combinatorial libraries) to high diversity. 100s to > 100 K Used widely in academia. 21... 

Ubrary A collection of structures, cither a generic library (baiicd on some icalTold plus multiple residues) or a mixture library (containing diverse. scaffolds). The number of. specific structures in a library is either the product of the numbers of residues pos.sible at each variable position (for a generic library) or. simply the sum of the number of structures (for a mixture library). 

Our group recently reported the development of a coumarin library with diversity at the 6-position via Suzuki-Miyaura coupling.21 The reaction conditions were optimized for the reaction of the 6-bromocoumarin scaffold 9 with the unsubstituted phenyl boronic acid pinacol ester 10a (Figs. 18.6 and 18.7). 

Krier, M., Bret, G., and Rognan, D. (2006) Assessing the scaffold diversity of screening libraries. Journal of Chemical Information and Modeling, 46, 512—524. 

Ideally, a DOS should address all four of the principal types of structural diversity mentioned previously. However, the ideal synthesis of a structurally diverse small molecule collection is one in which the diversity is achieved in the most efficient manner possible [1]. As alluded to previously, it is the scaffold diversity of the library that is the key parameter in this regard. It is generally acknowledged... 

Scaffold diversity is an important parameter to characterize any compound collection. Organic synthesis is expected to provide efficient approaches to create three-dimensionally complex and structurally diverse small molecules. Branching pathways in DOS is an elegant approach to access scaffold diversity that could lead to small, yet diverse, focused compound libraries. Branching cascades strategy has successfully demonstrated the power and application of cascade or domino reactions in compound collection synthesis to build rapidly complex scaffolds for library synthesis. Further synthesis endeavors toward branching pathways... 

The diversity of chemical libraries may derive from the high substitutional, stereochemical and scaffold diversity of its members. Combinatorial chemistry is focused on the synthesis of chemical libraries with only high substitutional diversity. In general, combinatorial syntheses exploit a rather limited palette of chemical transformations to vary the substitution of library members. The synthesis of compound libraries with high substitutional diversity is described in Section 1.2.1. 

Synthesis of Compound Libraries with High Scaffold Diversity... 

In time, the vast libraries of combinatorial chemistry have given way to the smaller designed libraries of diversity-oriented synthesis (DOS). Rather than preparing multimillion compound libraries in the hope of finding new lead scaffolds, DOS concentrates on... 

There is a widespread consensus that in terms of producing functionally (biologically) diverse molecules, the most important type of diversity that can be incorporated into a library is scaffold diversity.The rationale behind this is that biomacromolecules are (on a molecular scale) large 3D environments with certain defined potential binding pockets and surfaces, and as such they will interact only with small molecules that have complementary 3D structure. Libraries that contain compounds based around distinct molecular scaffolds and so distinct 3D shape and stmcture should therefore cover a large range of potential binding partners. 

In SPOS, the choice of the linker that serves to attach the library scaffold to the polymer support is critical. As a result, a variety of elegant linking methods have been developed that enable the introduction of additional diversity into the products during the cleavage reactions. The sulfone linker is an example of a safety-catch linker that can be cleaved from resins by using nucleophilic substitution reactions with amines. 

Finally, in an example of the second approach (i.e., SPOS modification of preformed flavone scaffolds), Lam and colleagues prepared a library of diverse flavone-based... 

Moody and coworkers have also applied this methodology to the preparation of a library of functionalized pyridine scaffold 49 with two points of diversity by coupling ynone 47 with enamine 48. 

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