Scaffold diversity approach

In practice, an HTS collection of microclusters around diverse scaffolds provides a certain redundancy in noisy primary HTS data and facilitates the data analysis methods described above to identify active series. Recent library design efforts have shifted away from the optimal diversity approach and focus more on scaffold representation, high quality lead-like (Hann and Oprea, 2004) compounds, synthetic feasibility, and smart focused libraries to provide the best starting points for medicinal chemistry (Davies, Glick, and Jenkins 2006 Schnur, 2008). 

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. 

Abstract In the past decade, it has been extensively demonstrated that multicomponent chemistry is an ideal tool to create molecular complexity. Furthermore, combination of these complexity-generating reactions with follow-up cyclization reactions led to scaffold diversity, which is one of the most important features of diversity oriented synthesis. Scaffold diversity has also been created by the development of novel multicomponent strategies. Four different approaches will be discussed [single reactant replacement, modular reaction sequences, condition based divergence, and union of multicomponent reactions (MCRs)], which all led to the development of new MCRs and higher order MCRs, thereby addressing both molecular diversity and complexity. 

Finally, scaffold diversity (Fig. 2c), probably the most important element of diversity, is the generation of a collection of products with different molecular skeletons (scaffolds). This can, for example, be realized by changing the reagents added to a common substrate (reagent-based approach) or by transforming a collection of substrates having suitable preencoded skeletal information with similar reaction conditions (substrate-based approach) [2, 10]. 

From the previous examples it is clear that scaffold diversity can be achieved using MCRs and post condensation cyclizations. However, during the last decade much work has also been devoted to obtain scaffold diversity by using MCR strategies exclusively. Besides scaffold diversity, this has also lead to the development of a number of novel MCRs. These new multicomponent design strategies, to achieve scaffold diversity, can be divided into four main approaches ... 

In conclusion, the CBD approach makes it possible to obtain scaffold diversity starting from the same reaction inputs by adapting the temperature, reaction promoter or solvent. 

Figure 26.1 Examples of strategies for generating scaffold diversity in DOS. (a) An example of the "branching" approach. Here, the exposure of a given starting material to different reagents results in the generation of different molecular scaffolds, (b) An example of the "folding" approach. Here,...

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... 

Substituted pyridines and pyridazines represent privileged scaffolds and are present in various therapeutic agents and in multiple classes of natural products (08CHEC(7)1, 08CHEC(8)1). Diverse approaches for the synthesis of pyridines, pyridones, and pyridazines using RCM as the key step are described below. 

Reagent-based and substrate-based approaches can also be combined in a single two-directional synthesis in which different symmetrical substrates can be used under different reaction conditions to achieve predictable scaffold diversity [23]. In an example by Spring et al, two domino reactions were used to synthesize polycyclic alkaloids from a common substrate 147. A Boc-removal/bicyclization process using AlClj as Lewis acid from 147 was used to produce 5-5, 5-6, and 6-6 bicyclic compounds (148-153), and a domino Michael addition/Dieckmann process/Michael addition reaction yielded 6-6-6, 6-6-5 tricyclic compounds (154-156). The 6-5-5 tricyclic scaffold 156 could not be synthesized by means of the same domino... 

The build-couple-pair is an extremely powerful and flexible approach for preparing small molecule libraries based on a diverse range of scaffolds. The approach is highly general, and many different reactions have been used to connect ( couple ) building blocks. Variants of the Ugi multi-component reaction are, however, still over-represented amongst the reactions that have been used to connect building blocks. 

Designing new multicomponent approaches in a less haphazard and more rational manner is vital for increasing the limited scaffold diversity obtained by the MCRs reported... 

Havonoids have a benzopyranone-ring system at their core, and a number of solid-phase and combinatorial approaches have been explored to synthesize and introduce diversity to this scaffold (such approaches have been reviewed ) with the aim of discovering novel biologically active flavonoids, flavones, and other related compounds. As with other natural products discussed herein, stmetures can be built up on resin, or preformed scaffolds can be loaded and modified... 

A limitation of this approach was the fact that the cyclization could not be accomplished on the resin. This would preclude further functionalization of the core. Therefore an alternate approach was to link the resin to the core via an aminoalcohol spacer as in 93. Furthermore, since linkage was conducted through the P-ketoester component rather than through the nitrogen atom, dihydropyridines 94 could now be formed on the solid support. When the 4-aryl substituent of 94 was nitro, on-resin reduction to the corresponding amine was possible. This allowed for further addition of diversity elements to the core scaffold before cleavage from the resin. 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

Hence there are multiple solutions for the final set of 10000 compounds. The final selection can be diversity driven using for example cluster analysis based on multiple fingerprints [63], hole filling strategies by using scaffold/ring analysis (LeadScope [66], SARVision [66]) or pharmacophore analysis [67, 68]. For a review of computational approaches to diversity and similarity-based selections, see the paper of Mason and Hermsmeier [69] and the references therein. 

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