Organotin(IV) derivatives with 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine and their cytotoxic activities: the importance of being conformers.

Abstract

The organotin(IV) compounds Me2SnCl2(dbtp)(1), Me2SnCl2(dbtp)2 (2), Et2SnCl2(dbtp) (3), Et2SnCl2(dbtp)2 (4), Et2SnCl2(dptp) (5), nBu2SnCl2(dbtp)2 (6), nBu2SnCl2(dptp) (7), Ph2SnCl2(dbtp) (8), Ph2SnCl2(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 towards their cytotoxic activity by MTT test 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 dose-dependent anti-proliferative effect toward the three cell lines. By calculated IC50 values, cytotoxicity of the complexes followed the order nBu > Ph > Et > Me for all the selected tumor cells. Organotin(IV) compounds (6-9)-induced cell death of HepG2 was considered to be apoptotic by measuring the exposure of phosphadytilserine to the outer membrane and observing the typical apoptotic morphological change by acridine orange/ethidium bromide staining. Flow cytometric analysis of propidium iodide-stained cells also demonstrated that organotin(IV) complexes caused apoptosis of HepG2 cells through cell arrest at G0-G1 phase. The crystal structure of 7 was investigated by X-ray diffraction analysis, exhibiting 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 cocrystallized 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 Hbonds and π···π stacking, facilitating its intracellular uptake.