Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria.
Inorg Chem. 2012 Jul 2;51(13):7153-63. doi: 10.1021/ic300148e. Epub 2012 Jun 12.
Novel platinum complexes of trans geometry [PtCl(2){(Z)-R(H)C═NOH}(2)] [R = Me (1), Et (3)] and [PtCl(2){(E)-R(H)C═NOH}{(Z)-R(H)C═NOH}] [R = Me (2), Et (4)] as well as the classic trans-[PtCl(2)(R(2)C═NOH)(2)] [R = Me, Et] were reacted with an equivalent amount of silver acetate in acetone solution at ambient temperature, resulting in formation of unprecedented head-to-tail-oriented oximato-bridged dimers PtCl{μ-(Z)-R(H)C═NO}{(Z)-R(H)C═NOH} [R = Me (5), Et (7)], PtCl{μ-(Z)-R(H)C═NO}{(E)-R(H)C═NOH} [R = Me (6), Et (8)], and PtCl(μ-R(2)C═NO)(R(2)C═NOH) [R = Me (9), Et (10)], correspondingly. The dimeric species feature a unique six-membered diplatinacycle and represent the first example of oxime ligands coordinated to platinum via the oxygen atom. All complexes were characterized by elemental analyses, electrospray ionization mass spectrometry, IR and multinuclear ((1)H, (13)C, and (195)Pt) NMR spectroscopy, as well as X-ray diffraction in the cases of dimers 6 and 9. Furthermore, the crystal and molecular structures of a trimeric oximato-bridged complex 11 comprising three platinum units connected in a chain way were established. The cytotoxicity of both dimers and the respective monomers was comparatively evaluated in three human cancer cell lines: cisplatin-sensitive CH1 cells as well as cisplatin-resistant SW480 and A549 cells, whereupon structure-activity relationships were drawn. Thus, it was found that dimerization results in a substantial (up to 7-fold) improvement of IC(50) values of (aldoxime)Pt(II) compounds, whereas for the analogous complexes featuring ketoxime ligands the reverse trend was observed. Remarkably, the novel dimers yielded no cross-resistance with cisplatin in SW480 cells, exhibiting up to 2-fold enhanced cytotoxicity in comparison with the CH1 cell line and thereby possessing a promising potential to overcome resistance toward platinum anticancer drugs. The latter point was also confirmed by investigating the potency of apoptosis induction in the case of one monomer as well as one dimer; the investigated complexes proved to be strong apoptotic agents which could induce cell death even in the cisplatin-resistant SW480 cell line.
顺式几何的新型铂配合物[PtCl2{(Z)-R(H)C═NOH}(2)] [R = Me（1），Et（3）]和[PtCl2{(E)-R(H)C═NOH}{(Z)-R(H)C═NOH}] [R = Me（2），Et（4）]以及经典的反式-[PtCl2（R2C═NOH）2] [R = Me，Et]与等当量的醋酸银在丙酮溶液中于室温下反应，形成前所未有的头对头定向肟桥联二聚体PtCl{μ-(Z)-R(H)C═NO}{(Z)-R(H)C═NOH} [R = Me（5），Et（7）]，PtCl{μ-(Z)-R(H)C═NO}{(E)-R(H)C═NOH} [R = Me（6），Et（8）]和PtCl（μ-R2C═NO）（R2C═NOH） [R = Me（9），Et（10）]，相应地。二聚体特征为独特的六元二价铂环，代表肟配体通过氧原子配位到铂的首例。所有配合物均通过元素分析、电喷雾电离质谱、IR 和多核（1H、13C 和 195Pt）NMR 光谱以及二聚体 6 和 9 的 X 射线衍射进行了表征。此外，建立了由三个以链状方式连接的铂单元组成的三肟桥联配合物 11 的晶体和分子结构。在三种人癌细胞系中，比较了二聚体和各自单体的细胞毒性：顺铂敏感的 CH1 细胞以及顺铂耐药的 SW480 和 A549 细胞，由此得出结构-活性关系。因此，发现二聚化导致（aldoxime）Pt（II）化合物的 IC50 值显著提高（高达 7 倍），而对于具有酮肟配体的类似配合物，则观察到相反的趋势。值得注意的是，新型二聚体与 SW480 细胞中的顺铂没有交叉耐药性，与 CH1 细胞系相比，其细胞毒性提高了 2 倍，因此具有克服铂类抗癌药物耐药性的潜在可能性。通过研究一个单体和一个二聚体诱导细胞凋亡的能力，也证实了这一点；研究的配合物是强凋亡剂，甚至可以在顺铂耐药的 SW480 细胞系中诱导细胞死亡。
