DNA interactions of new antitumor aminophosphine platinum(II) complexes

Mechanistic studies are presented of a novel class of aminophosphine platin um(II) complexes as potential anticancer agents. These new agents, which ha ve demonstrated activity against murine and human tumor cells including tho se resistant to cisplatin are cis-[PtCl2(Me2N(CH2)(3)PPh2-P)(2)] (Com1) and cis-[PtCl(C6H11NH(CH2)(2)PPh2-N,P)(C6H11NH(CH2)(2)PPh2-P)] (Com2). We stud ied modifications of natural and synthetic DNAs in cell-free media by Com1 and Com2 by various biomedical and biophysical methods and compared the res ults with those obtained when DNA was modified by cisplatin. The results in dicated that Com1 and Com2 coordinated to DNA faster than cisplatin. Bifunc tional Com1 formed DNA adducts coordinating to single adenine or guanine re sidues or by forming cross-links between these residues. In comparison with cisplatin, Com1 formed the adducts more frequently at adenine residues and also formed fewer bidentate lesions. The monofunctional Com2 only formed D NA monodentate adducts at guanine residues. In addition, Com1 terminated DN A synthesis in vitro more efficiently than cisplatin whereas Com2 blocked D NA synthesis only slightly. DNA unwinding studies, measurements of circular dichroism spectra, immunochemical analysis, and studies of the B-Z transit ion in DNA revealed conformational alterations induced by the adducts of Co m1, which were distinctly different from those induced by cisplatin; Com2 h ad little influence on DNA conformation. It is suggested that the activity profile of aminophosphine platinum(II) complexes, which is different from t hat of cisplatin and related analogs, might be associated with the specific DNA binding properties of this new class of platinum(II) compounds.