A series of organometallic compounds of general formula [(arene)M(PTA) nXm]Y (arene = η6-C10H 14, η-C5Me5); M = Ru(ii), Os(ii), Rh(iii) and Ir(iii); X = Cl, mPTA; Y = OTf, PF6) have been screened for their cytotoxicity and ability to inhibit cathepsin B in vitro, in comparison to the antimetastatic compound NAMI-A. The Ru and Os analogues and NAMI-A showed similar enzyme inhibition properties (with IC50 values in the low μM range), whereas the Rh(iii) and Ir(iii) compounds were inactive. In order to build up a rational for the observed differences, DFT calculations of the metal complexes adducts with N-acetyl-l-cysteine-N′-methylamide, a mimic for the Cys residue in the cathepsin B active site, were performed to provide insights into binding thermodynamics in solution. Initial structure-activity relationships have been defined with the calculated binding energies of the M-S bonds correlating well with the observed inhibition properties of the compounds. © 2010 The Royal Society of Chemistry.

Rationalization of the inhibition activity of structurally related organometallic compounds against the drug target cathepsin B by DFT

CIANCETTA, ANTONELLA;
2010

Abstract

A series of organometallic compounds of general formula [(arene)M(PTA) nXm]Y (arene = η6-C10H 14, η-C5Me5); M = Ru(ii), Os(ii), Rh(iii) and Ir(iii); X = Cl, mPTA; Y = OTf, PF6) have been screened for their cytotoxicity and ability to inhibit cathepsin B in vitro, in comparison to the antimetastatic compound NAMI-A. The Ru and Os analogues and NAMI-A showed similar enzyme inhibition properties (with IC50 values in the low μM range), whereas the Rh(iii) and Ir(iii) compounds were inactive. In order to build up a rational for the observed differences, DFT calculations of the metal complexes adducts with N-acetyl-l-cysteine-N′-methylamide, a mimic for the Cys residue in the cathepsin B active site, were performed to provide insights into binding thermodynamics in solution. Initial structure-activity relationships have been defined with the calculated binding energies of the M-S bonds correlating well with the observed inhibition properties of the compounds. © 2010 The Royal Society of Chemistry.
2010
Casini, A.; Edafe, F.; Erlandsson, M.; Gonsalvi, L.; Ciancetta, Antonella; Re, Nazzareno; Ienco, A.; Messori, L.; Peruzzini, M.; Dyson, P. J.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2466372
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