Synthesis, structures and anticancer potentials of five platinum(II) complexes with benzothiazole-benzopyran targeting mitochondria

Abstract

Mitochondria were potential therapeutic targets for Pt-based anticancer drugs. Thus, five mitochondrion-targeted novel Pt(II) complexes, [Pt(FB1)Cl2] (FB1-Pt), [Pt(OHB)Cl2] (OHB-Pt), [Pt(FB2)Cl2] (FB2-Pt), [Pt(MB)Cl2]⋅CH3OH (MB-Pt) and [Pt(ClB)Cl2] (ClB-Pt) containing 3-(benzo[d]thiazol-2-yl)-8-fluoro-2H-chromen-2-imine (FB1), 3-(benzo[d]thiazol-2-yl)-2-imino-2H-chromen-8-ol (OHB), 3-(benzo[d]thiazol-2-yl)-7-fluoro-2H-chromen-2-imine (FB2), 3-(benzo[d]thiazol-2-yl)-N,N-diethyl-2-imino-2H-chromen-7-amine (MB) and 3-(benzo[d]thiazol-2-yl)-6-chloro-2H-chromen-2-imine (ClB), has been synthesized and characterized by single-crystal X-ray diffraction and elemental analysis. All of them benzothiazole-benzopyran Pt(II) derivatives were more cytotoxic to the cisplatin-resistant A549/DDP cells, with complex FB1-Pt displaying 525.5-fold higher activity than cisplatin, which should be certainly correlated with the key roles of different substituted groups in the benzothiazole-benzopyran derivatives. Strikingly, complex FB1-Pt, featuring 8-fluoro-benzothiazole-benzopyran, was the most efficacious, with nanomole IC50 concentrations. Interestingly, the benzothiazole-benzopyran Pt(II) derivatives displayed low toxicity against normal HL-7702 cells. Cellular distribution studies suggested that FB1-Pt accumulate more preferentially in mitochondria than in nuclei fraction. As a result, FB1-Pt causes a remarkable decrease in the membrane of mitochondria in the A549/DDP cancer cells, leading to more radical mitochondrial dysfunctions than that of OHB-Pt. The results indicated that mitochondrion-targeted benzothiazole-benzopyran Pt(II) derivatives may have potential to overcome the drug resistance of traditional cisplatin-based antitumor drugs.