Gagnon Véronique, St-Germain Marie-Eve, Descôteaux Caroline, Provencher-Mandeville Josée, Parent Sophie, Mandal Sanat K, Asselin Eric, Bérubé Gervais
Département de Chimie-Biologie, GRBCM, Université du Québec à Trois-Rivières, C.P. 500, Trois-Rivières, Québec, Canada G9A 5H7.
Bioorg Med Chem Lett. 2004 Dec 6;14(23):5919-24. doi: 10.1016/j.bmcl.2004.09.015.
We have recently reported the synthesis of a series of original 17beta-estradiol-linked platinum(II) hybrid molecules. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER(+) and ER(-)) human uterine and ovarian cancers. The hybrid molecules present higher affinity than that of 17beta-estradiol for the estrogen receptor alpha (ERalpha). The cytotoxicity and the affinity of the hybrid molecules are explained using molecular modeling analysis. This study further confirms that the derivatives made of a 2-(2'-aminoethyl)pyridine ligand displayed superior activity against the cell lines particularly when the connecting arm is 8-10 carbon atoms long. Molecular modeling shows that a long side chain can facilitate the access of the platinum(II) moiety to DNA. The novel compounds also prove to be moderately cytotoxic against platinum resistant endometrial and ovarian cancer cell lines.
我们最近报道了一系列原创的17β-雌二醇连接的铂（II）杂化分子的合成。这些化合物的生物活性在体外针对雌激素依赖性和非依赖性（ER(+)和ER(-)）人子宫癌和卵巢癌进行了评估。杂化分子对雌激素受体α（ERα）的亲和力高于17β-雌二醇。使用分子建模分析解释了杂化分子的细胞毒性和亲和力。这项研究进一步证实，由2-(2'-氨基乙基)吡啶配体构成的衍生物对细胞系表现出卓越的活性，尤其是当连接臂长为8至10个碳原子时。分子建模表明，长侧链可促进铂（II）部分接近DNA。这些新型化合物对铂耐药的子宫内膜癌和卵巢癌细胞系也显示出中等程度的细胞毒性。
