Cytotoxic Activity of Organotin(IV) Derivatives with Triazolopyrimidine Containing Exocyclic Oxygen Atoms
| Autor: | Rosalia Busà, Piera Sabatino, Alessandro Attanzio, Simone d'Agostino, Anna Frazzitta, Luisa Tesoriere, Simona Rubino, Maria Assunta Girasolo |
|---|---|
| Přispěvatelé: | Alessandro Attanzio , Simone D’Agostino, Rosalia Busà, Anna Frazzitta, Simona Rubino, Maria Assunta Girasolo, Piera Sabatino *, Luisa Tesoriere, Attanzio A., D'Agostino S., Busa R., Frazzitta A., Rubino S., Girasolo M.A., Sabatino P., Tesoriere L. |
| Rok vydání: | 2020 |
| Předmět: |
Denticity
Cell Pharmaceutical Science 01 natural sciences Analytical Chemistry chemistry.chemical_compound Drug Discovery Organotin Compounds triazolopyrimidine Cytotoxicity Membrane Potential Mitochondrial Cytotoxins apoptosis Biological activity Hep G2 Cells G2 Phase Cell Cycle Checkpoints Gene Expression Regulation Neoplastic medicine.anatomical_structure Chemistry (miscellaneous) Mitochondrial Membranes MCF-7 Cells Molecular Medicine Cyclin-Dependent Kinase Inhibitor p21 crystal structure in vitro anticancer activity Pyrimidine Cell Survival Stereochemistry organotin(iv) 010402 general chemistry Article lcsh:QD241-441 Inhibitory Concentration 50 Structure-Activity Relationship lcsh:Organic chemistry medicine Humans Physical and Theoretical Chemistry Metallodrug 010405 organic chemistry Ligand Organic Chemistry Triazoles HCT116 Cells apoptosi G1 Phase Cell Cycle Checkpoints 0104 chemical sciences Pyrimidines chemistry metallodrugs Cell culture Apoptosis Drug Design Tumor Suppressor Protein p53 Reactive Oxygen Species |
| Zdroj: | Molecules, Vol 25, Iss 4, p 859 (2020) Molecules Volume 25 Issue 4 |
| ISSN: | 1420-3049 |
| Popis: | 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&minus ligands belonging to adjacent chains were also detected that resemble the &ldquo base-pairing&rdquo 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. |
| Databáze: | OpenAIRE |
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