Synthesis, structures, and anticancer potentials of four platinum (II) complexes with benzopyran derivatives targeting mitochondria

Four new benzopyranplatinum (Pt) complexes, [Pt(C1)Cl-2]center dot CH3OH (C1-Pt), [Pt(C2)Cl-2] (C2-Pt), [Pt(C3)Cl-2] (C3-Pt), and [Pt(C4)Cl-2] (C4-Pt) with 3-(1H-benzo[d]imidazol-2-yl)-2H-chromen-2-imine (C1), 6-bromo-3-(pyridin-2-yl)-2Hchromen-2-imine (C2), 6-chloro-3-(pyridin-2-yl)-2H-chromen-2-imine (C3), and 5,7-dichloro-3-(pyridin-2-yl)-2Hchromen-2-imine (C4), were first designed and synthesized as mitochondria-targeting antitumor agents. C1-Pt - C4-Pt showed cytotoxic activity against A549 and A549/DDP cancer cells, and most 6-chloro-substituted groups had stronger cytotoxicity than did the benzopyran Pt(II)-substituted ones. Significantly, C3-Pt was much more effective on cisplatinresistant A549/DDP tumor cells (IC50 = 0.15 +/- 0.03 mu M) than C1-Pt, C2-Pt and C4-Pt. Interestingly, C1-Pt - C4-Pt exhibited much lower cytotoxicity against normal cells (IC50 > 100 mu M) than against A549/DDP tumor cells. Additionally, mechanistic studies showed that C2-Pt and C3-Pt significantly inhibited cell growth in A549/DDP cells in S phase, accumulated more in mitochondria than in nuclei, and caused the loss of mitochondrial membrane potential, concurrently targeting mitochondria.