Mononuclear Platinum(II) Complex with 2-Phenylpyridine Ligands Showing High Cytotoxicity against Mouse Sarcoma 180 Cells Acquiring High Cisplatin Resistance

Mouse sarcoma 180 cell with a 25-fold higher cisplatin (CDDP) resistance, termed S-180cisR, is newly established. S-180cisR cells grow quite slowly in the presence of CDDP with high concentration. This may show that S-180cisR cells modulate the cell cycle to acquire CDDP resistance. P-Glycoprotein is selectively expressed on the surface of S-180cisR, which is not on CDDP-sensitive S-180 parent cells. In an experiment using an inhibitor (verapamil) of P-glycoprotein, cytotoxicity of CDDP against S-180cisR is significantly increased (viz., IC<INF>50</INF> value is decreased) and accumulation of CDDP in S-180cisR cells is also increased. These results indicate that enhanced pumping-out of CDDP by P-glycoprotein should be one of the reasons for the CDDP resistance of S-180cisR. A platinum(II) complex with a cyclometalated 2-phenylpyridine ligand and a nonchelated one (complex <BO>5</BO>) is synthesized, and its structure is determined by X-ray structural analysis. Complex <BO>5</BO> has a cyctotoxicity against S-180cisR higher than that of CDDP and its derivatives with 2- or 3-substituted pyridine ligands (complexes <BO>2</BO>−<BO>4</BO>, <BO>6</BO>, <BO>7</BO>). Complex <BO>5</BO> is incorporated in S-180cisR to an enormously greater extent than CDDP; that is, the ratio of accumulated platinum amount after 3 h is 61.9. In S-180 parent cells, on the other hand, the ratio remains 8.1. This high accumulation of complex <BO>5</BO> into S-180cisR must account for the higher activity of complex <BO>5</BO> against S-180cisR compared to CDDP.