Scaffold-based libraries

In addition to libraries derived from carbohydrates (see Chapter 7), a scaffold-based library approach using amino acids and alkaloids was implemented at Discovery Partners International. Quinine... 

Fig. 21 Synthetic scheme of benzimidazolium scaffold-based combinatorial library and their general structures and photophysical properties of the representative examples. All the photophysical properties were measured in methanol...

The integration of combinatorial chemistry, structure-based library design and virtual screening [268, 269] also resulted in successful applications [270, 271]. It ultimately should result in broader SAR information about directionality and physicochemical requirements of acceptable building blocks. This concept is based on feasible scaffolds for exploring protein subsites using parallel or combinatorial synthesis. 

The discovery of novel dihydrofolate reductase inhibitors by structure-based library design based on a 5-(dialkylamino)-2,4-diaminopyrimidine scaffold was reported by Wyss et al. [279] (cf Figure 4.5g). On the basis of a diaminopyrimidine core, a virtual... 

Nielsen, M. C. Ulven, T. Selective extraction of G-quadruplex ligands from a rationally designed scaffold-based dynamic combinatorial library. Chem. Ear. J. 2008,14, 9487-9490. 

Fig. 8.3. (Bottom) Thiomethylketone D of (88) is used as an example of a caspase 3 inhibitor designed via a docking-based library generation protocol. S1 and S2 denote the interaction sites within the binding pocket of caspase 3. (Top right) The thiomethylketone scaffold that is used as the starting point for library design. (Top left) The eight R-groups used to attach to the R attachment point of the scaffold.

Stahura, F. L., Xue, L., Godden, J. W., Bajorath, J. (1999) Molecular scaffold-based design and comparison of combinatorial libraries focused on the ATP-binding site of protein kinases. /Mol Graph Model 17, 1-9, 51-52. 

A library of cyclic peptides was obtained by the cyclooligomerization of mixtures of azole-based amino acids. This synthetic approach was applied to the synthesis of bistratamide H and didmolamide A, cyclic peptides containing oxazole rings <07OBC1541>. Other cyclic scaffolds based on oxazole peptides were published <07EJO1779 07T9862 07NAR3272>. 

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. 

Quinic acid was decorated on the Ci-carboxylic acid and on the C3, C4, Cs-hydroxyls by Phoon and Abell (53) as in Fig. 4.16, producing two small arrays L24 (ten monoester-monoamide compounds) and L25 (six triester-monoamide compounds). The reliability and the robustness of both the scaffold and of the acylation/esterifica-tions ensure an expansion of quinate-based libraries, which has already been reported for shikimate-based libraries (54). 

The extreme flexibility of these scaffolds would definitely allow the preparation of other large, primary libraries using chemistry-friendly synthetic schemes. The epoxide could be touched, as could the N-O function, which could be reductively cleaved and eventually used to obtain two new handles on constrained, stereo-determined novel scaffolds. The potential of such an integrated approach, where all the steps toward a large bead-based library are carefully assessed, is clearly enormous, especially if any library prepared would contain embedded biological information (starting from nam-... 

Figure 9.14 Patents regarding scaffold-based combinatorial libraries main features and claims.

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