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

Abstract

The Pt(II) α-diimine complexes [PtCl₂{κ²N-(HCNR)₂}] (R = C₆H₁₁, 1; 4-C₆H₁₀OH, 2; 4-C₆H₄CH₃, 3; 4-C₆H₄OH, 4) and [PtCl₂{κ²N-(CH₃CNOH)₂}] (5) were prepared in 60–81% yields from the 1 : 1 molar reactions of cis-[PtCl₂(DMSO)₂] with the appropriate α-diimine, [HCN(R)]₂ (R = C₆H₁₁, L1; 4-C₆H₁₀OH, L2; 4-C₆H₄Me, L3; 4-C₆H₄OH, L4), or dimethylglyoxime (dmgH₂), in acetone at reflux. The reaction of cis-[PtCl₂(DMSO)₂] with two molar equivalents of dmgH₂ and NEt₃ in methanol at reflux afforded the bis-dimethylglyoximato compound [Pt{κ²N,N′-(ONC(CH₃)C(CH₃)NOH)}₂], [Pt(dmgH)₂], as an insoluble material, in 97% yield. The oxalato derivative [Pt(κ²O-C₂O₄){κ²N-(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 (aspCO₂H) led to [PtCl₂{κ²N-(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 4·THF 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 °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.