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 analog1(Fig. 1 ) was modeled after the potent HIV protease inhibitor2, which together with a series of related derivatives was developed at Abbott Laboratories ( 11 ). This pseudopeptide contains a symmetrical diamino diol motif8(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 analog1was designed to restrict the orientation of the valine residues and to mimic this “extended” backbone conformation. Comparison of enzyme inhibition constants for both compound1and the parent inhibitor2will then elucidate the efficacy of the cyclopropane as a conformationally restrictive subunit. Fig. 1. HIV protease inhibitors. Fig. 2. Synthesis of the cyclopropane containing inhibitor 1.
