An in vivo highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex largely circumvents in vitro cisplatin resistance: two linkage isomers yield the same product upon reaction with 9-ethylguanine but exhibit different cytotoxic profiles

Cytotoxicity assays of azolato-bridged dinuclear Pt(II) complexes, [{cis-Pt(NH3)(2)}(2)(mu-OH)(mu-azolato)](2+), where the azolato was pyrazolato (1), 1,2,3- triazolato-N1,N2 (2), tetrazolato-N1,N2 (3), or tetrazolato-N2,N3 (4), were performed in cisplatin-sensitive and -resistant human non-small-cell lung cancer cell lines (PC-9 and PC-14). These complexes largely circumvented the cisplatin resistance in both cell lines, with resistance factors for 1-4 in the range of 0.5-0.8 and 0.9-2.0 for PC-9 and PC-14 cells, respectively. Complex 4 exhibited approximately 10 times the cytotoxicity of 3. When 3 and 4 were reacted with 2 molar equiv. of 9-ethylguanine (9EtG), they yielded an identical product, [{cis-Pt(NH3)(2)(9EtG-N7)}(2)(mu-tetrazolato-N1,N3)](3+), that had N1,N3 platinum coordination through a Pt(II) migration process on the tetrazolate ring. The second-order rate kinetics of these isomers were almost the same as each other and faster than those of 1 and 2. The cytotoxicity of azolato-bridged complexes, except for 3, increases as their kinetic rates in the 9EtG reaction increase.