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

Molecules. 2020 Feb 15;25(4):859. doi: 10.3390/molecules25040859.

Abstract

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.

Keywords: apoptosis; crystal structure; in vitro anticancer activity; metallodrugs; organotin(IV); triazolopyrimidine.

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cytotoxins / chemical synthesis
  • Cytotoxins / pharmacology*
  • Drug Design
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • G1 Phase Cell Cycle Checkpoints / genetics
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • G2 Phase Cell Cycle Checkpoints / genetics
  • Gene Expression Regulation, Neoplastic*
  • HCT116 Cells
  • Hep G2 Cells
  • Humans
  • Inhibitory Concentration 50
  • MCF-7 Cells
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondrial Membranes / drug effects
  • Organotin Compounds / chemical synthesis
  • Organotin Compounds / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacology*
  • Reactive Oxygen Species / agonists
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / pharmacology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Cytotoxins
  • Organotin Compounds
  • Pyrimidines
  • Reactive Oxygen Species
  • Triazoles
  • Tumor Suppressor Protein p53