New (arene)ruthenium(II) complexes of 4‑aryl‑4H‑naphthopyrans with anticancer and anti-vascular activities

A series of four 2‑amino‑3‑cyano‑4‑(3/4‑pyridyl)‑4H‑benzo[h]chromenes 2a–d and their dichlorido(p‑cymene)ruthenium(II) complexes 3a–d were tested for antiproliferative, vascular-disruptive, anti-angiogenic and DNA-binding activity. The coordination of the 4‑pyridyl‑4H‑naphthopyrans 2 to ruthenium led to complexes with pleiotropic effects. Unlike the free ligands 2a–d, their ruthenium complexes 3a–d showed a significant affinity for DNA as demonstrated by electrophoretic mobility shift assays (EMSA) and ethidium bromide assays. Binding of 3a–d to calf thymus DNA proceeded about 10-times faster compared with cisplatin. Treatment of HT-29 colon carcinoma, 518A2 melanoma and MCF-7Topo breast cancer cells with 3a and 3b caused an accumulation of cells in the G2/M phase and an increase of the fraction of mitotic cells in the case of HT-29, due to alterations of the microtubule cytoskeleton as shown by immunofluorescence staining. Complexes 3b–c showed a dual effect on the vascular system. They suppressed angiogenesis in zebrafish embryos and they destroyed the vasculature of the chorioallantoic membrane (CAM) in fertilized chicken eggs. They also inhibited the vasculogenic mimicry, typical of U-87 glioblastoma cells in tube formation assays. The new complexes 3a–d combine anti-cancer effects of naphthopyrans and a Ru(II) fragment. They bind to DNA 10 times faster and differently than cisplatin, and target the microtubular cytoskeleton causing mitotic arrest and antivascular effects. While active against cancer cells at nanomolar IC50 concentrations they do not affect non-malignant fibroblasts. [Display omitted] •Ru(II) complexes of 4‑aryl‑4H‑naphthopyrans 3 show selectivity for cancer cells.•3a–d bind to calf-thymus DNA ca. 10-times faster than cisplatin.•Complexes 3a–c lead to alterations of the microtubule cytoskeleton.•Complexes 3b and c are strong vascular-disrupting agents (VDA).•3b and 3c suppress angiogenesis in zebrafish embryos.