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

• Published in: European journal of medicinal chemistry 2016-08, Vol.118, p.328-339
• Main Authors: Tang, Zhichao, Wu, Chengzhe, Wang, Tianlin, Lao, Kejing, Wang, Yejun, Liu, Linyi, Muyaba, Moses, Xu, Pei, He, Conghui, Luo, Guoshun, Qian, Zhouyang, Niu, Shaoxiong, Wang, Lijun, Wang, Ying, Xiao, Hong, You, Qidong, Xiang, Hua
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - metabolism; Angiogenesis Inhibitors - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Breast cancer; Chemistry Techniques, Synthetic; Drug Design; Dual inhibitor; Estrogen receptor; Estrogen Receptor alpha - chemistry; Estrogen Receptor alpha - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; MCF-7 Cells; Models, Molecular; Molecular Targeted Therapy; Protein Conformation; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - metabolism; Quinolones - pharmacology; Receptors, Progesterone - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR-2
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.04.029

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 ERα and VEGFR-2 inhibitors. These compounds presented good ERα binding affinity and ERα 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-1/MAPK/ERK pathway in MCF-7 cells. [Display omitted] •Designed multiple ligands may exert improved efficacy with lower incidence of side effects.•A series of 6-aryl-indenoisoquinolone derivatives were described as dual ERα and VEGFR-2 inhibitors.•Compound 21c turned out to be a promising dual targeting candidate for breast cancer.