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(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 dose-dependent anti-proliferative effect against the three cell lines. By calculated IC50 values, the cytotoxicity of the complexes followed the order nBu>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 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, 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 π⋯π stacking, facilitating its intracellular uptake.