Design, synthesis and evaluation of 6-aryl-indenoisoquinolone derivatives dual targeting ERα and VEGFR-2 as anti-breast cancer agents

The estrogen receptors have played important roles in breast cancer development and progression. Selective estrogen receptor modulators, such as Tamoxifen, have showed great benefits in the treatment and prevention of breast cancer. But the disadvantages of induction of endometrial cancer and drug resistance have limited their use. Multiple ligand which act at multiple biomolecular targets may exert favorable advantages of improved efficacy with lower incidence of side effects. In this work, we described the synthesis and evaluation of a series of 6-aryl-indenoisoquinolone derivatives as dual ER alpha. and VEGFR-2 inhibitors. These compounds presented good ER alpha binding affinity and ER alpha antagonistic activity, as well as potent VEGFR-2 inhibitory potency. They also possessed excellent anti-proliferative activities against MCF-7, MDA-MB-231, Ishikawa and HUVEC cell lines. Further investigation of selective compound 21c showed that it was able to inhibit the activation of VEGFR-2 and the signaling transduction of Raf-11 MAPKJERK pathway in MCF-7 cells. (C) 2016 Elsevier Masson SAS. All rights reserved.