Scaffold substrate-based approach

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]. 

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... 

A second example of protease inhibitor design that properly illustrates the peptide scaffold-based approach is that of thrombin inhibitors. Work with these compounds led to the identification of highly potent, selective, and in vivo-effective lead compounds. A member of the serine protease family, thrombin cleaves a number of substrates (e.g., fibrinogen) and activates its platelet receptor (a G-protein-coupled receptor) by proteolysis of the extracellular N-terminal domain which results in self-activation (for a review see Reference 66). Initial lead inhibitors of thrombin were substrate-based, including the fibrinogen P3-Pi Phe-Pro-Arg sequence [67] and simple Arg derivatives such as Tos-Arg-OMe [68]. 

An example of the signal-transduction protein-targeted inhibitor design which illustrates both peptide scaffold- and nonpeptide template-based approaches is that for the Ras famesyl transferase inhibitor discovery. Such compounds show potential as new therapeutic agents for Ras-related carcinogenesis [81]. Substrate sequences for famesyl transferase have the consensus Cy s-A A, - A A2-Met motif (AA refers to Val or lie). Both substrate-based... 

Remarkably, Schreiber was able to use every single functionality of 46. Seven different highly selective pairing reactions were performed, to obtain seven different scaffolds (A-G), which is quite remarkable since they are all obtained from one single substrate. To come back to a term earlier introduced, this is an example of a reagent-based approach since a single substrate is converted by different reaction conditions, producing a diversity of scaffolds [42]. 

The reagent-based approach or branching pathways in diversity synthesis exploits different functional or reactive sites of a common substrate to yield diverse scaffold... 

A combinatorial natural-product-like and diversity-orientated library of 10 000 benzopyran-based small molecules was constructed by Nicolaou and coworkers [74, 75]. They chose a solid-phase approach and an anchoring strategy that does not limit complexity building operations (Scheme 14.11). They used a polystyrene-based selenyl bromide resin (43) on which substrates can be immobilized by electrophilic cyclization reactions. Here, ortho-prenylated phenol 44 was reacted with the selenyl bromide (43) to form the benzopyran scaffold (45) via a 6-endo-trig cyclization. 

Another approach followed by Wang et al. led to an inhibitor of Tritrichomonas foetus hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT). The X-ray structure of this enzyme is available and it was used in a search for novel scaffolds. The Available Chemicals Directory (ACD) was screened with the program DOCK. Isatin and phthalic anhydride were capable of mimicking the substrate purine base and acting as competitive inhibitors. A virtual library of substituted... 

---