Synthesis, characterization, biological studies and in vitro cytotoxicity on human cancer cell lines of titanium(IV) and tin(IV) derivatives with the α,α′‐dimercapto‐o‐xylene ligand

Abstract

The reaction of α,α′‐dimercapto‐o‐xylene (H2dmox) with different precursors such as SnMe2Cl2, [Ti(η5‐C5H5)2Cl2] and [Ti(η5‐C5H4Me)2Cl2] (1:1) in the presence of two equivalents of NEt3 yielded the complexes [SnMe2(dmox)] (1), [Ti(η5‐C5H5)2(dmox)] (2) and [Ti(η5‐C5H4Me)2(dmox)] (3), respectively. 1–3 have been characterized by spectroscopic methods; in addition, complex 3 has been determined by X‐ray diffraction studies. Furthermore, structural studies based on density functional theory calculations of 1 and 2 have been carried out. The cytotoxic activity of 1–3 was tested against the tumour cell lines human adenocarcinoma HeLa, human myelogenous leukaemia K562 and human malignant melanoma Fem‐x. The results of this study show a higher cytotoxicity of the tin(IV) complex (1) in comparison to their titanium(IV) counterparts (2 and 3) as well as an improvement in the cytotoxic activity of compounds 2 and 3 compared to their titanocene(IV) dichloride analogues [Ti(η5‐C5H5)2Cl2] and [Ti(η5‐C5H4Me)2Cl2]. In view of the relatively high cytotoxicity of compound 1, a detailed study on the effects of the in vitro treatment of cancer cell lines using this compound was carried out. Thus cell cycle experiments on all the studied cell lines treated with 1 show that this complex seems to cause disturbances in the G1 phase of HeLa, and in the G1 and G2/M phases of Fem‐x cell line, while almost no disturbances were observed in the cycle of K562 cells treated with 1. Finally, DNA laddering method showed that treatment of the HeLa and Fem‐x cell lines with IC90 doses of 1 resulted in the induction of apoptosis. Copyright © 2012 John Wiley & Sons, Ltd.

Anticancer Applications and Recent Investigations of Metallodrugs Based on Gallium, Tin and Titanium

“…This result was expected as compound 21 presents two SnPh3 units which are normally associated with increase of cytotoxic activity due to the interaction of SnPh3 + moieties with protein kinases DNA. The cytotoxic activity of 20 and 21 was lower than that reported for carboxylate tin(IV) complexes (12)(13)(14)(15)(16)(17)(18)(19) [36]. However, a more in depth study of compound 21 against HeLa and Fem-x cell showed the induction of an apoptotic cell death [37].…”

“…In addition, the DNA binding studies carried out in simulated body fluid showed the weak interaction of the titanocene compounds with DNA [68]. Our group also synthesized titanocene compounds containing the α,α'-dimercapto-o-xylene as a thiolato ligand (71 and 72, Figure 13) and tested their efficacy against human tumor cell lines HeLa, Fem-x, K562 (Table 4) [36]. When the biological activity was analyzed, an improvement of the cytotoxic activity was observed compared with [Ti(η 5 -C5H5)2Cl2] and [Ti(η 5 -C5H4Me)2Cl2] against the cell lines tested K562, HeLa, and Fem-x with a higher cytotoxicity of 72 and a slight preference against K562 (Table 4) [36].…”

“…When the biological activity was analyzed, an improvement of the cytotoxic activity was observed compared with [Ti(η 5 -C5H5)2Cl2] and [Ti(η 5 -C5H4Me)2Cl2] against the cell lines tested K562, HeLa, and Fem-x with a higher cytotoxicity of 72 and a slight preference against K562 (Table 4) [36]. Our group also synthesized titanocene compounds containing the α,α'-dimercapto-o-xylene as a thiolato ligand (71 and 72, Figure 13) and tested their efficacy against human tumor cell lines HeLa, Fem-x, K562 (Table 4) [36]. When the biological activity was analyzed, an improvement of the cytotoxic activity was observed compared with [Ti(η 5 -C 5 H 5 ) 2 Cl 2 ] and [Ti(η 5 -C 5 H 4 Me) 2 Cl 2 ] against the cell lines tested K562, HeLa, and Fem-x with a higher cytotoxicity of 72 and a slight preference against K562 (Table 4) [36].…”

“…Our group also synthesized titanocene compounds containing the α,α'-dimercapto-o-xylene as a thiolato ligand (71 and 72, Figure 13) and tested their efficacy against human tumor cell lines HeLa, Fem-x, K562 (Table 4) [36]. When the biological activity was analyzed, an improvement of the cytotoxic activity was observed compared with [Ti(η 5 -C 5 H 5 ) 2 Cl 2 ] and [Ti(η 5 -C 5 H 4 Me) 2 Cl 2 ] against the cell lines tested K562, HeLa, and Fem-x with a higher cytotoxicity of 72 and a slight preference against K562 (Table 4) [36]. Our group also synthesized two titanium(IV) complexes anchored by a tripodal diamine bis(phenolate) ligands (73 and 74) which showed hydrolytic stability and a high cytotoxic activity against HeLa, K562, Fem-x and MDA-MB-453 with IC50 values between 22.4 ± 1.2 and 48.9 ± 0.8 µM [69].…”

Preparation and in vitro investigations of triphenyl[ω‐(tetrahydro‐2H‐pyran‐2‐yloxy)alkyl]tin(IV) compounds

“…Various mono‐ and polynuclear organotin(IV) compounds comprised of di‐ or triorganyltin(IV) (organyl = methyl, phenyl, etc.) and carboxylato or thiolato ligands showed high in vitro anticancer activity . Generally, the most active are found to be triphenyltin(IV) compounds (mostly in nM concentration), much more active than cisplatin.…”