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

• Published in: Dalton transactions : an international journal of inorganic chemistry 2010-06, Vol.39 (23), p.5556-5563
• Main Authors: Casini, Angela, Edafe, Fabio, Erlandsson, Mikael, Gonsalvi, Luca, Ciancetta, Antonella, Re, Nazzareno, Ienco, Andrea, Messori, Luigi, Peruzzini, Maurizio, Dyson, Paul J
• Format: Article
• Language: English
• Subjects: Acetylcysteine - analogs & derivatives; Acetylcysteine - chemistry; Cathepsin B - antagonists & inhibitors; Cathepsin B - metabolism; Cell Line, Tumor; Coordination Complexes - chemistry; Coordination Complexes - toxicity; Crystallography, X-Ray; Dimethyl Sulfoxide - analogs & derivatives; Dimethyl Sulfoxide - chemistry; Drug Screening Assays, Antitumor; Humans; Metals - chemistry; Molecular Conformation; Organometallic Compounds - chemistry; Organometallic Compounds - toxicity; Structure-Activity Relationship
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c003218b

A series of organometallic compounds of general formula [(arene)M(PTA)(n)X(m)]Y (arene = eta(6)-C(10)H(14), eta-C(5)Me(5)); M = Ru(ii), Os(ii), Rh(iii) and Ir(iii); X = Cl, mPTA; Y = OTf, PF(6)) 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 IC(50) values in the low muM 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.