Abstract
The synthesis of novel triphenyltin(IV) compounds, Ph3SnLn (n = 1–3), with oxaprozin (3-(4,5-diphenyloxazol-2-yl)propanoic acid), HL1, and the new propanoic acid derivatives 3-(4,5-bis(4-methoxylphenyl)oxazol-2-yl)propanoic acid, HL2, and 3-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)propanoic acid, HL3, has been performed. The ligands represent commercial drugs or their derivatives and the tin complexes have been characterized by standard analytical methods. The in vitro antiproliferative activity of both ligands and organotin(IV) compounds has been evaluated on the following tumour cell lines: human prostate cancer (PC-3), human colorectal adenocarcinoma (HT-29), breast cancer (MCF-7), and hepatocellular cancer (HepG2), as well as on normal mouse embryonic fibroblast cells (NIH3T3) with the aid of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-12 diphenyltetrazolium bromide) and CV (crystal violet) assays. Contrary to the inactive ligand precursors, all organotin(IV) carboxylates showed very good activity with IC50 values ranging from 0.100 to 0.758 µM. According to the CV assay (IC50 = 0.218 ± 0.025 µM), complex Ph3SnL1 demonstrated the highest cytotoxicity against the caspase 3 deficient MCF-7 cell line. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated a two-fold lower concentration of tin in MCF-7 cells in comparison to platinum. To investigate the mechanism of action of the compound Ph3SnL1 on MCF-7 cells, morphological, autophagy and cell cycle analysis, as well as the activation of caspase and ROS/RNS and NO production, has been performed. Results suggest that Ph3SnL1 induces caspase-independent apoptosis in MCF-7 cells.
Highlights
Carcinogenic diseases represent a spectrum of related disorders, characterized by uncontrolled cell division in individual organs, with a tendency to invade other parts of the body
Triphenyltin(IV) compounds were synthesised as follows: a suspension of the ligand precursors, 0.5 mmol of HL1 (147 mg), HL2 (177 mg), and HL3 (162 mg), in 5 mL of distilled water was treated with a solution of 1 M LiOH (0.5 mL, 0.5 mmol) and a clear solution formed after 3 h of stirring at 40 ◦C
Three novel triphenyltin(IV) compounds based on commercial drugs and their derivatives have been synthesised, characterised and tested in vitro for antiproliferative activity on four different tumour cell lines
Summary
Carcinogenic diseases represent a spectrum of related disorders, characterized by uncontrolled cell division in individual organs, with a tendency to invade other parts of the body. The use of cisplatin and other platinum derivatives for the treatment of malignant tumours causes a series of side effects such as nausea, vomiting, neurotoxicity, nephrotoxicity, and ototoxicity [5,6] To reduce these side effects of metal-based cytotoxins, the focus of novel investigations shifted to non-platinum candidates [7]. Organotin(IV) compounds benefit from better water solubility, lower toxicity and reduced side effects [11] These types of complexes display a strong apoptotic effect on tumour cells, via p53 tumour suppression [11]. Organotin(IV) carboxylates, compared to organotin(IV) compounds with thiolato and ditiocarbamato ligands, usually display higher cytotoxic activity against human tumour cell lines [12]. The accumulations of tin and platinum in MCF-7 cells have been compared
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