Organotin derivatives of cholic acid induce apoptosis into breast cancer cells and interfere with mitochondrion; Synthesis, characterization and biological evaluation

Steroids play an important role in hormone depended human breast cancer and they posse’s low toxicity on normal ones. Organotins, on the other hand, interfere with DNA, mitochondria, cell membranes, activating apoptotic pathways. Therefore the combination of tri- or di- organotin(ΙV) ions with cholic acid, results in novel selective chemotherapeutics for the breast cancer. Thus the compounds with the formulae R3Sn(CA) (R= Ph- (1), n-Bu- (2)) and R2Sn(CA)2 (R= Ph- (3), n-Bu- (4) and Me- (5) have been synthesized, characterized and tested against breast cancer cells positive and negative to hormone receptors. The mechanism of action of 1–4 against MCF-7 was clarified in vitro by the means of cell morphology studies, cell cycle arrest, Acridine Orange/Ethidium Bromide (AO/EB) Staining to Detect Apoptosis, permeabilization of the mitochondrial membrane test and by their binding affinity toward the calf thymus (CT) DNA. [Display omitted] •Organotin(I) Metallotherapeutic compounds.•Human breast adenocarcinoma cells, positive (MCF-7) and negative (MD-MB-231) to hormones receptors.•The mitochondrion apoptotic pathway activation.•cell cycle arrest and permeabilization of the mitochondrial membrane tests.•Binding affinity towards CT-DNA. Organotin(IV) derivatives of cholic acid (CAH) with the formulae R3Sn(CA) (R = Ph- (1), n-Bu- (2)) and R2Sn(CA)2 (R = Ph- (3), n-Bu- (4) and Me- (5)) were synthesized. The compounds were characterized in solid state by melting point, FT-IR, 119Sn Mössbauer, X-ray fluorescence (XRF) spectroscopy and in solution by 1H NMR, UV–Vis spectral data and by Electrospray Ionisation Mass spectrometry (ESI-MS), High Resolution Mass spectrometry (HRMS), and atomic absorption analysis. The in vitro bioactivity of 1–5 against human breast adenocarcinoma cancer cells MCF-7 (positive to hormone receptors) and MDA-MB-231 (negative to hormone receptors) reveal that triorganotin derivatives 1–2 exhibit significantly stronger activity than the corresponding diorganotin ones. Compound 5 is inactive against both cell lines at the concentrations tested. Triorganotins 1–2 inhibit selectively MCF-7 than MDA-MB-231 cells, suggesting hormone mimetic behavior of them. Organotins 1–4 inhibit both cancerous cell lines, stronger than cisplatin which rise up to 55-fold against MCF-7 and 170-fold against MDA-MB-231. The in vitro toxicity of 1–4 was evaluated on normal human fetal lung fibroblast cells (MRC-5), while their genotoxicity in vitro by micronucleus assay