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.
Highlights
Organotin (IV) compounds have been receiving increasing attention over the past years [1,2,3,4,5,6]due to their possible use as biologically active non-platinum chemotherapeutic agents, that might have lower toxicity, better excretion properties and fewer side effects than platinum based drugs [7,8,9].These compounds, even at low doses, present high anti-proliferative activity which, in some cases, Molecules 2020, 25, 859; doi:10.3390/molecules25040859 www.mdpi.com/journal/moleculesMolecules 2020, 25, 859 is higher than that of cisplatin
As a continuation of our work, in this study we present the crystal structures of compounds Me3 Sn(5tpO) 1 and n-Bu3 Sn(5tpO) 2 and assess the cytotoxic activity of the compounds 1-6 on a number of human carcinoma cell lines to evaluate the influence of the substituents connected to the triazolopyrimidine ring on the antitumor activity
LC50 concentration, which is lethal to 50% of the normal cells, compared to untreated controls
Summary
Organotin (IV) compounds have been receiving increasing attention over the past years [1,2,3,4,5,6]due to their possible use as biologically active non-platinum chemotherapeutic agents, that might have lower toxicity, better excretion properties and fewer side effects than platinum based drugs [7,8,9].These compounds, even at low doses, present high anti-proliferative activity which, in some cases, Molecules 2020, 25, 859; doi:10.3390/molecules25040859 www.mdpi.com/journal/moleculesMolecules 2020, 25, 859 is higher than that of cisplatin. Due to their possible use as biologically active non-platinum chemotherapeutic agents, that might have lower toxicity, better excretion properties and fewer side effects than platinum based drugs [7,8,9] These compounds, even at low doses, present high anti-proliferative activity which, in some cases, Molecules 2020, 25, 859; doi:10.3390/molecules25040859 www.mdpi.com/journal/molecules. 1,2,4-triazolo[1,5-a] pyrimidine derivatives have been used as model systems to mimic the reactivity between purines and several metal ions [11] due to their ability to coordinate through different nitrogen atoms with accessible electron pairs in their basic skeleton Their versatility can be increased by changing the number of exocyclic substituents on the triazolopyrimidine rings. Such derivatives are interesting for their many biological effects such as antimicrobial [13,14], antitumor [15,16,17,18,19] and antiparasitic [20,21,22] activity
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