Silicon diol

Silicon Diols, Effective Inhibitors of Human Leucocyte Elastase... 

Keywords human elastase, protease inhibitors, silicon diol, privileged structure. 

A stable structure that mimics this tetrahedral Intermediate would be a transition state analog inhibitor. A silicon diol structure, in which the C(OH)2NH group of the transition state is replaced by an Si(OH)2CH2 moiety, mimics that tetrahedral transition state, and it has recently been shown that incorporating silicon diol moieties into peptide mimetics results in potent and selective inhibitors for metallo and aspartyl proteases [1 - 3] (1 and 2, Fig. 2). 

Fig. 2. Silicon diol proteases inhibitors, 1 (angiotensin-converting enzyme (metallo) inhibitor) and 2 (HIV protease (aspartyl) inhibitor).

Employing this strategy, a silicon diol warhead moiety was incorporated into the Val-Pro-Val motif however, also realizing that this provided a relatively rigid inhibitor, more flexible analogs were designed around an isoleucine-isobutyl peptide template wherein the isobutyl group would... 

Table 1. Inhibitoiy activity at human ieucoc elastase for the silicon diol inhibitors 8 and 9.

The results presented have demonstrated the ability of silicon diols to have serine protease inhibitory activity. The silicon diol 9 is a potent human leucocyte elastase inhibitor. The fact that the silicon diol moiety can be used across the aspartyl, metaJlo, and serine gene mily of proteases shows the power of such a simple privileged structure within the drug design process. 

Molecular modeling studies were performed using the crystal structure of human elastase (pdb code IHNE), Sybyl molecular modeling software and a Tripos forcefield. An assumption was made that the silicon diol forms a covalent bond with the catalytic serine residue, Serl95. 

Silicone acrylates also are usually prepared via an esterification reaction between a silicone diol and (meth)acrylic acid. 

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