Synthesis, characterization and in vitro cytotoxicity studies of platinum(IV) complexes with thiouracil ligands

Abstract

Reactions of [PtMe3(bpy)(Me2CO)][BF4] (2) with the thionucleobases 2-thiouracil (s2Ura), 4-thiouracil (s 4Ura) and 2,4-dithiouracil (s2s4Ura) resulted in the formation of complexes of the type [PtMe3 (bPy)(L-κS)] [BF4] (L= s2Ura, 3; s4Ura, 4; s 2s4Ura, 5). The complexes were characterized by NMR spectroscopy (1H, 13C, 195Pt), IR spectroscopy as well as microanalyses. The coordination through the C4=S groups (4, 5) was additionally confirmed by DFT calculations, where it was shown that these complexes [PtMe3(bpy)(L-κS4)]+ (L=s 4Ura, s2s4Ura) are about 5.8 (4b) and 3.3 kcal/mol (5b), respectively, more stable than the respective complexes, having thiouracil ligands bound through the C2=X groups (X=O, 4a; S, 5a). For [PtMe3(bpy)(s2Ura-κS2)][BF4] (3) no preferred coordination mode could be assigned solely based on DFT calculations. Analysis of NMR spectra showed the κS2 coordination. In vitro cytotoxic studies of complexes 3-5 on nine different cell lines (8505C, A253, FaDu, A431, A549, A2780, DLD-1, HCT-8, HT-29) revealed in most cases moderate activities. However, 3 and 5 showed significant activity towards A549 and A2780, respectively, possessing IC50 values comparable to those of cisplatin. Cell cycle perturbations and trypan blue exclusion test on cancer cell line A431 using [PtMe3(bpy)(s 2s4Ura-κS4)][BF4] (5) showed induction of apoptotic cell death. Furthermore, the reaction of [PtMe 3(OAc-κ2O,O′)(Me2CO)] (6) with 4-thiouracil yielded the dinuclear complex [(PtMe3)2(μ-s 4Ura-H)2] (7), which has been characterized by microanalysis, NMR (1H, 13C, 195Pt) and IR spectroscopy as well as ESI mass spectrometry. X-ray diffraction analysis of crystals yielded in an isolated case exhibited the presence of a hexanuclear thiouracilato platinum(IV) complex, possessing each three different kinds of methyl platinum(IV) moieties and 4-thiouracilato ligands. This exhibited the ability of 4-thiouracil platinum(IV) complexes to form multinuclear complexes.