Synthesis, characterization, structures and in vitro antitumor activity of platinum(II) complexes bearing adeninato or methylated adeninato ligands

Abstract

Reactions of the carbonato platinum(II) complexes [Pt(CO3)(PPh3)2]·CH2Cl2 (1) and [Pt(CO3)(dppe)] (dppe = 1,2-bis(diphenylphosphino)ethane; 2) with adenine (3a) and its N6-methylated derivatives (N6-MeAde, 3b; N6,N6-Me2Ade, 3c) resulted under splitting off carbon dioxide in formation of bis(adeninato)platinum complexes [Pt(N6,N6-RR’Ade–H-κN9)2(PPh3)2] (4a–4c) and [Pt(N6,N6-RR’Ade–H-κN9)2(dppe)] (5a–5c) R/R’ = H, Me, respectively. Analogous reactions with adenines methylated at the N9 or N3 position (9-MeAde, 3d; N6,9-Me2Ade, 3e; 3-MeAde, 3f) gave cationic complexes which could be isolated as hexafluorophosphate salts: [Pt(9-MeAde–H-κ2N6,N7)(PPh3)2][PF6] (6a), [Pt(N6,9-Me2Ade–H-κ2N6,N7)(dppe)][PF6] (6b), and [Pt(3-MeAde–H-κ2N6,N7)(PPh3)2][PF6] (7). The deprotonation of the less acidic exocyclic N6HR (R = H, Me) group and the chelating κ2N6,N7 coordination in complexes 6/7 could unambiguously clarified by 1H,15N HMBC NMR spectroscopy and additionally by DFT calculations. All complexes were fully characterized especially by NMR (1H, 13C, 31P) and single-crystal X-ray structural investigations (4b∙2i-PrOH, 4c, 5a∙MeOH, and 5c∙1.5 MeOH). In vitro antitumoral activity was investigated against five tumor cell lines (A549 lung, A2780 ovarian, DLD-1 colon, FaDu head and neck, and SW1736 anaplastic thyroid). The most active compound 4b was found more active than cisplatin against cisplatin resistant DLD-1 (IC50 = 4.1 ± 0.5 µM) and SW1736 cell lines (IC50 = 1.5 ± 0.4 µM).