alpha-Diimine homologues of cisplatin: synthesis, speciation in DMSO/water and cytotoxicity

The Pt(ii) -diimine complexes [PtCl2{N-2-(HCNR)(2)}] (R = C6H11, 1; 4-C6H10OH, 2; 4-C6H4CH3, 3; 4-C6H4OH, 4) and [PtCl2{N-2-(CH3CNOH)(2)}] (5) were prepared in 60-81% yields from the 1:1 molar reactions of cis-[PtCl2(DMSO)(2)] with the appropriate -diimine, HCN(R) (R = C6H11, L1; 4-C6H10OH, L2; 4-C6H4Me, L3; 4-C6H4OH, L4), or dimethylglyoxime (dmgH(2)), in acetone at reflux. The reaction of cis-[PtCl2(DMSO)(2)] with two molar equivalents of dmgH(2) and NEt3 in methanol at reflux afforded the bis-dimethylglyoximato compound [Pt{N-2,N-(ON?C(CH3)C(CH3)?NOH)}(2)], [Pt(dmgH)(2)], as an insoluble material, in 97% yield. The oxalato derivative [Pt(O-2-C2O4){N-2-(HCN(C6H11))(2)}], 6, was obtained from the sequential treatment of 1 with AgNO3 and Na2C2O4, in 61% yield. Attempts to functionalize 4via esterification of the hydroxyl groups with aspirin (aspCO(2)H) led to [PtCl2{N-2-(HCN(4-C6H4OCO-asp))(2)}], 7, in an admixture with 4. All the products were characterized by elemental analysis, and IR and multinuclear NMR spectroscopy, and the molecular structures of 4THF and 5 were elucidated by single crystal X-ray diffraction. NMR spectroscopic studies in DMSO or DMSO/water/NaCl evidenced the substantial stability of 1-2 at 37 degrees C over 72 hours, whereas 3-5 released their N,N-ligand. The cytotoxic activity of 1, 2 and 6 was assessed on cisplatin sensitive and cisplatin resistant human ovarian carcinomas (A2780 and A2780cisR) and non-tumorigenic human embryonic kidney (HEK-293) cells. Compound 1 is moderately cytotoxic, whereas 2 and 6 did not display appreciable antiproliferative activity.