Synthesis, Characterization and Anti-cancer Application of Platinum(Ii) Thiosemicarbazone Complexes

Abstract

Coordination compounds have great potential as drug molecules. However, their instability, poor water solubility, and multi-drug resistance limit their use. Unstable coordination compounds may undergo unnecessary ligand exchange reactions when introduced into biological systems. While literature reports that bulky ligands can help stabilize the metal center, their use with platinum metal centers has not been explored extensively. This work involved the synthesis of stable metal complexes to be used as anticancer agents. Four thiosemicarbazone ligands; 2-((5-ethylthiophen-2-yl)methylene-N-phenylhydrazine carbothiomide (L1), 2-((5-ethylthiophene-2-yl)methylene)-1-methylhydrazine carbothiomide (L2), N,N–dimethyl–2-((4-nitrophene-2-yl)methylene)hydrazine carbothiomide (L3), and 2-([2,2’-bithiophen]-5-ylmethylene-1-methylhydrazine carbothiomide (L4) were synthesized through condensation reactions of aldehydes and amines. Their respective platinum(II) complexes 2-((5-ethylthiophen-2-yl)methylene-N-phenylhydrazinecarbothiomide platinum(II) chloride (C1), 2-((5-ethylthiophene-2-yl) methylene)-1-methylhydrazine carbothiomide platinum(II) chloride (C2), N,N–dimethyl–2-((4-nitrophene-2-yl)methylene)hydrazinecarbothiomide platinum(II) chloride (C3), and 2-([2,2’-bithiophen]-5-ylmethylene-1-methylhydrazine carbothiomide platinum(II) (C4) were synthesized by reacting the ligands with K2PtCl4. The synthesis reactions were all performed under mild conditions, and refluxing was the preferred reaction technique. The yields of the thiosemicarbazone ligands ranged between 89% and 99% while the yields of the complexes were between 77% and 88%. The yields of the complexes were significantly lower than those of the ligands, which can be attributed to the steric shielding of the heavy ligands to the platinum metal center. The compounds exhibited sharp melting points. The characterization techniques employed were: FTIR, UV-Vis, 1H NMR, 13C NMR, elemental analysis, and XRD. The ligands were bidentate and coordinated via sulphur and nitrogen atoms. The mode of coordination was established by the disappearance of the thioamide proton and changes in chemical shifts observed in the NMR spectra of the complexes. The anti-cancer activities of the thiosemicarbazone ligands and complexes were performed in vitro on four human cell lines; three cancerous cell lines (HeLa, Caco-2 and HT-29) and the non-cancerous KMST-6, and cisplatin was used as the positive control. The results revealed that three ligands (L1, L2, and L4) had less anti-cancer activity compared to their complexes. L3 was lethal to Caco-2 (IC50 = 3.412 μg/mL), HT-29 (IC50 = 0.6886 μg/mL) and HeLa (IC50 = 0.107 μg/mL) cell lines at lower concentrations than cisplatin. However, L3 was also lethal to KMST-6 (IC50 = 2.1 μg/mL). Complexes exhibited varying anti-cancer activity on the different cell lines. C1 had a low inhibition value of (IC50 = 45.42 μg/mL) for the Caco-2 cell line. C2 showed inhibition values of; (IC50 = 31.63 μg/mL) for HT-29 and (IC50 = 41.82 μg/mL) for Caco-2 cell line, suggesting that it had better activity than cisplatin, which had inhibition values (IC50 = 35.5 μg/mL) for HT-29 and (IC50 = 48.83 μg/mL) for Caco-2 cell lines. C3 showed inhibition values of (IC50 = 0.0001973 μg/mL) for HeLa, suggesting better activity than cisplatin, whose inhibition was (IC50 = 0.1099 μg/mL). Altogether, this study shows that these some of these thiosemicarbazone (II) complexes offer a promising alternative to other platinum complexes in cancer therapy.