Scaffold selectivity

A whole set of related powerful isocyanide-based MCRs has been developed by Zhu s research group. By varying the structures of the starting materials and slightly changing the reaction conditions, the group was able to produce different hetereocyclic scaffolds selectively. For example, heating a methanolic mixture of an aldehyde, an amine and an isocyanoacetamide 9-80 allowed the clean formation of 5-amino-oxazoles 9-82 (Scheme 9.16) [56]. It can be assumed that, in the formation of the products 9-82, the imines 9-79 as well as the adducts 9-81 act as intermediates. 

Peptidomimetic approaches are heavily used to build protease inhibitor scaffolds. Selective protease inhibitors are quite straightforward to be obtained because of the substrate variety and specificity of the proteases. However, the concept of privileged scaffolds does not carry far for proteases. The unifying element in protease substrates is the extended beta-strand conformation that allows interactions with four to six subpockets in the protease active site (69). Mimics for this conformation have been developed but they still lack universal applicability for the transfer into clinical application (70). 

For a practical review of scaffold hopping, see Zhao, H. Scaffold selection and scaffold hopping in lead generation A medicinal chemistry perspective. Drug Discovery Today 2007, 12, 149-155. 

Fig. 2.19 Select red atoms for Replace Scaffold (Select Scaffold)...

Using Replace Scaffold (Select Scaffold) and selecting the atoms indicated in red results in two connection points (indicated by anows). The R-groups are indicated in black (Figs. 2.19 and 2.20). 

The availability of strains and an appropriate technical infrastructure are the prerequisites for the production of natural scaffolds in amounts necessary for library synthesis. For our in-house scaffold selection, we screen subfractions and compounds that originate from our own highly diverse microbial strain collection, containing more than 45,000 actinomycetes and 8,(X)0 fungi. If scaffolds are identified from literature or database mining, it may be difficult to acquire the producing strain. 

PRO-SELECT [77] fragment-based, scaffold-linker approach ... 

EMPl, selected by phage display from random peptide libraries, demonstrates that a dimer of a 20-residue peptide can mimic the function of a monomeric 166-residue protein. In contrast to the minimized Z domain, this selected peptide shares neither the sequence nor the structure of the natural hormone. Thus, there can be a number of ways to solve a molecular recognition problem, and combinatorial methods such as phage display allow us to sort through a multitude of structural scaffolds to discover novel solutions. 

In the frame of a medicinal project at J J Pharmaceutical Research and Development aimed at designing new potent and selective glycogen synthase kinase-3/i (GSK-3/3) inhibitors, the C-3 derivatization of the 1-methyl-4-[l-alkyl-lff-indol-3-yl]-lff-pyrrole-2,5-dione scaffold was explored [31]. Microwave-assisted Stille reaction of 3-chloro-l-methyl-4-[l-alkyl-lff-indol-3-yl]-lH-pyrrole-2,5-diones with (2,4-dimethoxy-5-pyrimidinyl)(tributyl) stannane at 200 °C yielded in 6 min the desired 3,4-diaryl-lff-pyrrole-2,5-diones in moderate yields (Scheme 12). 

There has been a plethora of recent hterature regarding the synthetic manipulations of the 2(lH)-pyrazinone skeleton. Even though the addition-elimination reactions at the C-3 position to decorate the pyrazinone scaffold are well documented [24], the versatihty of such approaches can be found somewhat limited. Selective attack of nucleophiles on the chloroimine group of the pyrazinone system can generate 3-alkoxy- and 3-amino-pyrazinones (Scheme 9) [27,28]. The 3-CN group was introduced via a Rosemund-von Braun reaction with copper(I)cyanide under harsh conditions (heating in NMP at 150 °C) [27] (Scheme 9). 

Here, two different sequences from transth3Tetin were successfully combined into mixed fibrils [54], This is not always the case, however. For amyloidogenic proteins, the ability of other fibrils to act as cross-seeds for growth is known to depend on sequence similarity [55]. Seeding hen lysozyme solutions with seeds formed from closely related sequences (e.g. hen and other lysozymes) led to the largest increases in the rate of formation of fibrils. Consequently, there may be some restrictions on the selection of distinct peptide sequences to produce scaffolds. 

Mewshaw RE, Edsall RJ, Yang C, Manas ES, Xu ZB, Henderson RA. et al. ERbeta ligands. 3. Exploiting two binding orientations of the 2-phenylnaphtha-lene scaffold to achieve ERbeta selectivity. J Med Chem 2005 48 3953-79. 

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