Abstract
The use of cyclopropanes as a conformationally restricted subunits in biological systems has been the subject of intense study by our group and others (1–10). Our recent efforts have focused on the use of 1, 2, 3-trisubstituted cyclopropanes as novel [-NH-Cα-] or [-CO-Cα-] bond replacements in pseudopeptides to restrict both side-chain orientation and enforce backbone secondary structures. To test these assumptions, the cyclopropane containing analog 1 (Fig. 1) was modeled after the potent HIV protease inhibitor 2, which together with a series of related derivatives was developed at Abbott Laboratories (11). This pseudopeptide contains a symmetrical diamino diol motif 8 (Fig. 2) flanked by Cbz-protected valine residues and is known to bind in a β-strand fashion at the enzyme-active site (12). Our analog 1 was designed to restrict the orientation of the valine residues and to mimic this “extended” backbone conformation. Comparison of enzyme inhibition constants for both compound 1 and the parent inhibitor 2 will then elucidate the efficacy of the cyclopropane as a conformationally restrictive subunit.
HIV protease inhibitors.
Synthesis of the cyclopropane containing inhibitor 1.
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Hillier, M.C., Martin, S.F. (1999). A Conformationally Restricted β-Strand HIV Protease Inhibitor. In: Kazmierski, W.M. (eds) Peptidomimetics Protocols. Methods in Molecular Medicine™, vol 23. Humana Press. https://doi.org/10.1385/0-89603-517-4:397
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DOI: https://doi.org/10.1385/0-89603-517-4:397
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