Anticancer activity of Pt-selenolate metallacycles

Abstract

A series of Pt metallacycles [(P^∩P)Pt(μ-py-E)]_n(X)_n (n = 2 or 4, E = S or Se, and X = OTf or BPh₄) were constructed from 4-pyridylthiolate/selenolate and the chelating phosphines dppe (diphenylphosphinoethane) and dppf (diphenylphosphinoferrocene) or from the neutral complexes [(P^∩P)Pt(4-Epy)₂]. ¹H and ³¹P NMR spectroscopy showed slow equilibria between dimers and tetramers and ESI mass spectrometry indicated the presence of dimers, trimers, tetramers and pentamers of metallacycles. The single-crystal X-ray structures of dimers [Pt(P^∩P)(4-Sepy)]₂(OTf)₂ (P^∩P = dppe and dppf) and tetramers [Pt(dppf)(4-Epy)]₄(OTf)₄ showed cis-N,E,(P^∩P) coordination around Pt. Stability tests using NMR showed that the oligomers were stable in cell culture medium for at least 24 h. Antiproliferative activity was tested for the new Pt complexes along with each of the two previously reported mononuclear and tetranuclear Pd analogues, and the tetranuclear Pt metallacycle of 4,4′-biphenylene dithiolate using MCF7, A549 and U2OS cancer cell lines, showing low activity for the neutral complexes but appreciable IC₅₀ values for the dimers and tetramers (lower than that of cisplatin). Sub-G1 assays showed high induction of apoptosis for the oligomers. Induction of DNA damage was assessed by γ-H2AX foci in MCF7 cells, and the cationic Pt macrocycles exhibited significantly improved induction compared to cisplatin and tetranuclear Pt compounds of dithiolate. A similar trend was observed in the case of induction of apoptosis by the compounds using the sub-G1 assay.