In this study cytotoxicity of organotin(IV) compounds with 1,2,4-triazolo[1,5-a]pyrimidines, Me3Sn(5tpO) (1), n-Bu3Sn(5tpO) (2), Me3Sn(mtpO) (3), n-Bu3Sn(mtpO) (4), n-Bu3Sn(HtpO2) (5), Ph3Sn(HtpO2) (6) where 5HtpO = 4,5-dihydro-5-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, HmtpO = 4,7-dihydro-5-methyl-7-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, and H2tpO2 = 4,5,6,7-tetrahydro-5,7- dioxo-[1,2,4]triazolo-[1,5-a]-pyrimidine, was assessed on three different human tumor cell lines: HCT-116 (colorectal carcinoma), HepG2 (hepatocarcinoma) and MCF-7 (breast cancer). While 1 and 3 were inactive, compounds 2, 4, 5 and 6 inhibited the growth of the three tumor cell lines with IC50 values in the submicromolar range and showed high selectivity indexes towards the tumor cells (SI > 90). The mechanism of cell death triggered by the organotin(IV) derivatives, investigated on HCT-116 cells, was apoptotic, as evident from the externalization of phosphatidylserine to the cell surface, and occurred via the intrinsic pathway with fall of mitochondrial inner membrane potential and production of reactive oxygen species. While compound 6 arrested the cell progression in the G2/M cell cycle phase and increased p53 and p21 levels, compounds 2, 4 and 5 blocked cell duplication in the G1 phase without affecting the expression of either of the two tumor suppressor proteins. Compounds 1 and 2 were also investigated using single crystal X-ray diffraction and found to be, in both cases, coordination polymers forming 1 D chains based on metal-ligand interactions. Interestingly, for n-Bu3Sn(5tpO)(2) H-bonding interactions between 5tpO− ligands belonging to adjacent chains were also detected that resemble the “base-pairing” assembly and could be responsible for the higher biological activity compared to compound 1. In addition, they are the first example of bidentate N(3), O coordination for the 5HtpO ligand on two adjacent metal atoms.

a b s t r a c tThe organotin(IV) compounds Me 2 SnCl 2 (dbtp)(1), Me 2 SnCl 2 (dbtp) 2 (2), Et 2 SnCl 2 (dbtp) (3), Et 2 SnCl 2 (dbtp) 2 (4), Et 2 SnCl 2 (dptp) (5), n Bu 2 SnCl 2 (dbtp) 2 (6), n Bu 2 SnCl 2 (dptp) (7), Ph 2 SnCl 2 (dbtp) (8), Ph 2 SnCl 2 (EtOH) 2 (dptp) 2 (9), where dbtp = 5,7-di-tert-butyl-1,2,4-triazolo[1,5-a]pyrimidine and dptp = 5,7-diphenyl-1,2,4-triazolo [1,5-a]pyrimidine, have been tested by MTT for their cytotoxic activity on three tumor cell lines, HepG2 (human hepatocellular carcinoma), HeLa (human cervix adenocarcinoma) and MCF-7 (human breast cancer). Except for 1 and 2, which were ineffective, all compounds significantly showed a dosedependent anti-proliferative effect against the three cell lines. By calculated IC 50 values, the cytotoxicity of the complexes followed the order n Bu > Ph > Et > Me for all the selected tumor cells. The cell death of HepG2, induced by organotin(IV) compounds 6-9, was considered to be apoptotic by measuring the exposure of phosphatidylserine to the outer membrane and observing the typical apoptotic morphological change by acridine orange/ethidium bromide staining. Flow cytometric analysis of propidium iodidestained cells also demonstrated that organotin(IV) complexes caused apoptosis of HepG2 cells through cell arrest at G0-G1 phase. The crystal structure of 7, investigated by X-ray diffraction study, exhibited a distorted trigonal bipyramidal geometry with N, Cl as axial atoms and Cl and butyl groups in the equatorial plane. The triazolopyrimidine unit coordinates to the Sn atom through N(3) in a monodentate mode. Two conformational isomers (molecule A and B in the crystallographic independent unit) are co-crystallized in the solid state, a phenomenon that has been observed only occasionally. Conformational mobility of the cytotoxic complex 7 can sum up to the ligands ability to form H-bonds and pÁ Á Áp stacking, facilitating its intracellular uptake.

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