Synthesis, structures and in vitro cytotoxicity studies of platinum(IV) complexes with N,S and S,S heterocyclic ligands

Reactions of [(PtMe3I)4] (2) with the sodium salts of the N,S and S,S   heterocycles SDSDH (pyridine-2-thione, pytH; pyrimidine-2-thione, pymtH; thiazoline-2-thione, tztH; thiophene-2-thiol, tptH) resulted in the formation of the dinuclear complexes [(PtMe3)2(μ-SDSD)2] (SDSD = pyt, 3; pymt, 4; tzt, 5) and the tetranuclear complex [(PtMe3)4(μ3-tpt)4] (6), respectively. Single crystal X-ray diffraction analyses of 3 and 4 exhibited dinuclear complexes having a central [Pt2(μ-S)2] core. The platinum atoms are octahedrally coordinated by three methyl ligands and the bridging 1κN,1:2κ2S heterocyclic ligands. The two heterocyclic rings are face-to-face (cis) arranged, indicating stabilization through π–π stacking. The X-ray diffraction analysis of 6 confirmed a tetranuclear [Pt4S4] heterocubane structure. Each platinum atom is distorted octahedrally coordinated by three methyl ligands in facial arrangement and three μ3-bridging sulfur atoms. DFT calculations exhibited that the formation of the tetranuclear complex 6 can be mainly attributed to the weak coordination tendency of the thiophene S atoms of the tpt ligands to the trimethylplatinum(IV) unit. In vitro cytotoxic studies of the complexes 3–5 using five different tumor cell lines (8505C, A253, A549, A2780, DLD-1) revealed moderate to high cytotoxic activities. The most active compound is [(PtMe3)2(μ-tzt)2] (5) with IC50 values of 0.5–1.2 μM on investigated cell lines, which is comparable to cisplatin or even better.

Graphical abstractReactions of [(PtMe3I)4] with the sodium salts Na(SDSD) (D = N, S) of N,S and S,S heterocycles (pyridine-2-thione, pytH; pyrimidine-2-thione, pymtH; thiazoline-2-thione, tztH; thiophene-2-thiol, tptH) resulted in the formation of the dinuclear complexes [(PtMe3)2(μ-SDSD)2] (SDSD = pyt, pymt, tzt) having chelating S,N ligands and of the tetranuclear complex [(PtMe3)4(μ3-tpt)4], respectively. Single crystal X-ray diffraction analyses revealed the constitution of the complexes, while DFT calculations gave further insight into the dinuclear versus tetranuclear complex formation. Cytotoxic studies of the dinuclear complexes exhibited significant activities.Figure optionsDownload full-size imageDownload as PowerPoint slideFigure optionsDownload full-size imageDownload as PowerPoint slideFigure optionsDownload full-size imageDownload as PowerPoint slideFigure optionsDownload full-size imageDownload as PowerPoint slide