Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
Dalton Trans. 2010 Jun 21;39(23):5556-63. doi: 10.1039/c003218b. Epub 2010 May 14.
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.
一系列通式为 [(arene)M(PTA)(n)X(m)]Y 的有机金属化合物（arene = eta(6)-C(10)H(14), eta-C(5)Me(5)）；M = Ru(ii), Os(ii), Rh(iii) 和 Ir(iii)；X = Cl, mPTA；Y = OTf, PF(6)）已被筛选用于体外细胞毒性和抑制组织蛋白酶 B 的能力，与抗肿瘤转移化合物 NAMI-A 进行比较。Ru 和 Os 类似物和 NAMI-A 表现出相似的酶抑制特性（IC(50) 值在低微摩尔范围内），而 Rh(iii) 和 Ir(iii) 化合物则没有活性。为了建立观察到的差异的合理依据，对金属配合物与 N-乙酰-l-半胱氨酸-N'-甲基酰胺的加合物进行了 DFT 计算，这是组织蛋白酶 B 活性部位 Cys 残基的模拟物，以提供对溶液中结合热力学的深入了解。已经定义了初步的结构-活性关系，计算出的 M-S 键的结合能与化合物的观察到的抑制特性很好地相关。
