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Stereochemically pure α-trifluoromethyl-malic hydroxamates: synthesis and evaluation as inhibitors of matrix metalloproteinases |
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| Authors: | Margherita Moreno Monica Sani Guido Raos Stefano V. Meille Raffaella Giavazzi Alessandro Volonterio |
| Affiliation: | a Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘G. Natta’ del Politecnico di Milano, via Mancinelli 7, I-20131 Milano, Italy b C.N.R.—Istituto di Chimica del Riconoscimento Molecolare, via Mancinelli 7, I-20131 Milano, Italy c Dipartimento di Oncologia, Istituto di Ricerche Farmacologiche Mario Negri, via Gavazzeni 11, 24125 Bergamo, Italy d Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, via Balzaretti 9, I-20133 Milano, Italy |
| 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 α-Tfm-malic unit. Both the diastereomeric forms of the target α-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. |
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