The synthesis of trifluoromethyl (Tfm) analogs of known nanomolar matrix metalloproteinases (MMPs) inhibitors has been performed. The synthetic protocol is based on a moderately stereoselective aldol reaction of trifluoropyruvate with an N-acyl-oxazolidin-2-thione for the construction of the core alpha-Tfm-malic unit. Both the diastereomeric forms of the target alpha-Tfm-malic hydroxamates showed micromolar inhibitory potency toward MMP-2 and 9, according to zymographic tests, with a substantial drop with respect to the parent unfluorinated compounds. We also report some molecular modeling results, which provide a rationale for the experimental findings
Stereochemically pure alpha-trifluoromethyl-malic hydroxamates: synthesis and evaluation as inhibitors of matrix metalloproteinases / M. MORENO, M. SANI, G. RAOS, S.V. MEILLE, D. BELOTTI, R. GIAVAZZI, S. BELLOSTA, A. VOLONTERIO, M. ZANDA. - In: TETRAHEDRON. - ISSN 0040-4020. - 62:43(2006), pp. 10171-10181.
Stereochemically pure alpha-trifluoromethyl-malic hydroxamates: synthesis and evaluation as inhibitors of matrix metalloproteinases
S. BELLOSTA;
2006
Abstract
The synthesis of trifluoromethyl (Tfm) analogs of known nanomolar matrix metalloproteinases (MMPs) inhibitors has been performed. The synthetic protocol is based on a moderately stereoselective aldol reaction of trifluoropyruvate with an N-acyl-oxazolidin-2-thione for the construction of the core alpha-Tfm-malic unit. Both the diastereomeric forms of the target alpha-Tfm-malic hydroxamates showed micromolar inhibitory potency toward MMP-2 and 9, according to zymographic tests, with a substantial drop with respect to the parent unfluorinated compounds. We also report some molecular modeling results, which provide a rationale for the experimental findingsPubblicazioni consigliate
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