Cytotoxic Activity of Organotin(IV) Derivatives with Triazolopyrimidine Containing Exocyclic Oxygen Atoms

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-02, Vol.25 (4), p.859
• Main Authors: Attanzio, Alessandro, D'Agostino, Simone, Busà, Rosalia, Frazzitta, Anna, Rubino, Simona, Girasolo, Maria Assunta, Sabatino, Piera, Tesoriere, Luisa
• Format: Article
• Language: English
• Subjects: apoptosis; crystal structure; in vitro anticancer activity; metallodrugs; organotin(iv); triazolopyrimidine
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25040859

In this study cytotoxicity of organotin(IV) compounds with 1,2,4-triazolo[1,5- ]pyrimidines, Me Sn(5tpO) ( ), n-Bu Sn(5tpO) ( ), Me Sn(mtpO) ( ), n-Bu Sn(mtpO) ( ), n-Bu Sn(HtpO ) ( ), Ph Sn(HtpO ) ( ) where = 4,5-dihydro-5-oxo-[1,2,4]triazolo-[1,5- ]pyrimidine, = 4,7-dihydro-5-methyl-7-oxo-[1,2,4]triazolo-[1,5- ]pyrimidine, and = 4,5,6,7-tetrahydro-5,7- dioxo-[1,2,4]triazolo-[1,5- ]-pyrimidine, was assessed on three different human tumor cell lines: HCT-116 (colorectal carcinoma), HepG2 (hepatocarcinoma) and MCF-7 (breast cancer). While and were inactive, compounds , , and inhibited the growth of the three tumor cell lines with IC 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 arrested the cell progression in the G2/M cell cycle phase and increased p53 and p21 levels, compounds , and blocked cell duplication in the G1 phase without affecting the expression of either of the two tumor suppressor proteins. Compounds and 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-Bu Sn(5tpO)( ) 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 . In addition, they are the first example of bidentate N(3), O coordination for the 5HtpO ligand on two adjacent metal atoms.