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

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.

Synthesis and cytotoxic activity of organotin(IV) diallyldithiocarbamate compounds as anticancer agent towards colon adenocarcinoma cells (HT-29)

“…The SI can indicate the differentiation activity of compounds, where the higher the SI value, the more selective the compound against cancer cells ( Badisa et al, 2009 ). Therefore, this selective cytotoxicity is very important to identify the effectiveness of anticancer drugs ( Attanzio et al, 2019 ).…”

Cellular Basis of Organotin(IV) Derivatives as Anticancer Metallodrugs: A Review

“…Based on the wide range of organic moieties and donor ligands that are attached to the metal, several diorganotin(IV) and triorganotin(IV) compounds with in vitro antitumor properties against various solid and hematologic cancers have been studied (Gielen and Tiekink, 2005;Alama et al, 2009;Hadjikakou and Hadjiliadis, 2009). These compounds show lower toxic effects, higher antiproliferative activity, better excretion properties, and fewer side effects than other platinum-based drugs, even when used at low concentrations (Florea and Busselberg, 2011;Deo et al, 2018;Rubino et al, 2018;Attanzio et al, 2020). Additionally, novel organotin(IV) compounds have been shown to have high selectivity toward various cancer cell lines, regardless of ligand diversity (Awang et al, 2014;Girasolo et al, 2017;Attanzio et al, 2020).…”

“…These compounds show lower toxic effects, higher antiproliferative activity, better excretion properties, and fewer side effects than other platinum-based drugs, even when used at low concentrations (Florea and Busselberg, 2011;Deo et al, 2018;Rubino et al, 2018;Attanzio et al, 2020). Additionally, novel organotin(IV) compounds have been shown to have high selectivity toward various cancer cell lines, regardless of ligand diversity (Awang et al, 2014;Girasolo et al, 2017;Attanzio et al, 2020). Niu et al (2014), Sirajuddin et al (2014) and Hadi et al (2019a) stated that organotin(IV) derivatives are likely to show cytotoxic effects with the following trend: RSn 3+ < R 2 Sn 2+ < R 3 Sn + , with triorganotin(IV) substituents demonstrating the strongest effects.…”

“…Driven by the clinical achievements of cisplatin, the first platinum-based chemotherapeutic drug, researchers have focused much attention on nonplatinumbased chemotherapeutics in order to improve therapeutic efficacy and prevent severe side effects related to platinumbased drugs. Among all reported nonplatinum-based drugs, organotin(IV) compounds may be the most promising metallodrugs, as, in some cases, they portray better effects than cisplatin (Hadjikakou and Hadjiliadis, 2009;Attanzio et al, 2020) and have been shown to have substantial anticancer effects (Jan et al, 2002;Samuel et al, 2002;Shuaibu et al, 2003;Tabassum and Pettinari, 2006). Accordingly, in this review, we discuss the antiproliferative activities and mechanisms of organotin(IV) compounds to rationalize the potential of organotin(IV) compounds to be developed as effective and reliable anticancer agents in the future.…”

Mononuclear Perfluoroalkyl-Heterocyclic Complexes of Pd(II): Synthesis, Structural Characterization and Antimicrobial Activity

“…Because of the severe side effects of complexes, such as cisplatin [ 6 ], in the treatment of several carcinomas, and of the cancer resistance mechanisms against the clinically utilized drug doses, in recent years, the research has been moving toward the tentative toxicity reduction of Pt(II). In order to overcome the limitations of cisplatin and its analogues [ 6 ], the application of drug delivery systems depressing toxicity and negative side effects [ 7 ], or the synthesis of new complexes with different metal ions, such as Ni(II), Pd(II), Cu(II), Ru(II), Co(II), Zn(II), and Sn(IV) [ 8 , 9 , 10 , 11 , 12 ], are some of the proposed solutions. An interesting review of the mechanistic insight on different mononuclear Pt(II) and Pt(IV) complexes and dinuclear Pt(II) complexes through spectroscopic, kinetic, and DFT measurements described the chemistry of antitumor platinum complexes, highlighting their interaction with biomolecules containing nitrogen and sulfur as donor atoms.…”