Solution/Solid-Phase Synthesis of Partially Modified Retro- and Retro-Inverso-ψ[NHCH(CF3)]-Peptidyl Hydroxamates and Their Evaluation as MMP-9 Inhibitors

The synthesis of a novel family of partially modified (PM) retro- and retro-inverso-peptidyl hydroxamates, each incorporating a [CH(CF3)CH2CO] unit as a surrogate for the conventional malonyl group, has been accomplished both in solution and in solid phase. The key step is the Michael-type N-addition of free or polymer-bound α-amino hydroxamates to 3-[(E)-enoyl]-1,3-oxazolidin-2-ones, which takes place in high yields, although with low stereocontrol. This method is suitable for the preparation of combinatorial libraries of PM retro-ψ[NHCH(CF3)]-peptidyl hydroxamates for screening as metalloprotease inhibitors. A number of tri- and tetrapeptidyl hydroxamates were indeed obtained either in diastereomerically pure form by solution-phase synthesis followed by chromatographic purification, or as mixtures of two epimers by solid-phase synthesis and release from the resin. X-ray diffraction of a Tfm-retropeptidyl hydroxamate showed an interesting turn-like conformation with an intramolecularly hydrogen-bonded nine-membered ring, and a nearly planar geometry of the NH group bound to the CH(CF3) group. Three retro-peptidyl hydroxamates were submitted to bioassays, and displayed the capacity to reduce MMP-9 (Gelatinase B) gelatinolytic activity.