Synthesis, characterization and cytotoxicity studies of platinum(II) complexes with amino acid ligands in various coordination modes

Reactions of [Pt(CO3)(PPh3)(2)]center dot CH2Cl2 (1) with non-substituted and alkyl substituted amino acids, NH(R)CH(R')CO2H (R/R' = H/Me, L1; H/Pr-i, L2; H/CH2CHMe2, L3; Me/H, L4; Et/H, L5), in the presence of Tl[PF6] in methanol afforded with liberation of CO2 the formation of platinum(II) complexes of the type [Pt(PPh3)(2){NHR-CHR'-C(O)O-kappa N, kappa O}][PF6] (R/R' = H/Me, 2; H/Pr-i, 3; H/CH2CHMe2, 4; Me/H, 5; Et/H, 6). Single-crystal X-ray diffraction analysis of complex 4 exhibited a square-planar coordination of the platinum atom having coordinated two triphenylphosphane ligands and a deprotonated jN, jO-coordinated leucine ligand (L3 (H)). On varying the pK(a) value of the amino group, platinum(II) complexes with different coordination modes of amino acid ligands were obtained. Thus, treatment of complex 1 with N-acetyl L-alanine (L6), possessing a comparatively highly acidic NH proton, in 1: 1 ratio in methanol resulted in the formation of [Pt(PPh3)(2){N(COMe)-CHMe-C(O) O-kappa N, kappa O}] (7), while reacting N-phenyl glycine (L7) having a moderately acidic NH proton with complex 1 afforded a mixture of complexes [Pt(PPh3)(2){NPh-CH2-C(O) O-kappa N, kappa O}] (8) and [Pt(PPh3)(2){NHPh-CH2-C(O)O-kappa O}(2)] (10). Treatment of complex 1 with two equivalents of L6/L7 in dichloromethane resulted in the formation of [Pt(PPh3)(2){NHR-CHR'-C(O)O-kappa O}(2)] (R/R' = COMe/Me, 9; Ph/H, 10). An analogous reactivity was observed for L-lactic acid on treating with complex 1 in 1:1 and 2:1 ratio resulting in [Pt(PPh3)(2){O-CHMe-C(O)O-kappa O, kappa O'}] (11) and [Pt(PPh3)(2){HO-CHMe-C(O) O-kappa O}(2)] (12). The identities of all complexes have been proven by NMR (H-1, C-13, P-31) spectroscopic and high-resolution ESI mass-spectrometric investigations. In vitro cytotoxicity studies against human tumor cell lines (8505C, A2780, HeLa, SW480, and MCF-7) showed the highest activities for the neutral complex 7. Furthermore, complexes 7 and 9 against the A2780 cell line induced an apoptotic mode of cell death, which was further supported by morphological investigation and DNA laddering. Cell cycle perturbation studies showed that both complexes induced faster cell death than cisplatin. (C) 2012 Elsevier B.V. All rights reserved.