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

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

  • Eur J Med Chem. 2016 Aug 8:118:328-39. doi: 10.1016/j.ejmech.2016.04.029.
Zhichao Tang 1,  Chengzhe Wu 1,  Tianlin Wang 1,  Kejing Lao 1,  Yejun Wang 1,  Linyi Liu 1,  Moses Muyaba 1,  Pei Xu 1,  Conghui He 1,  Guoshun Luo 1,  Zhouyang Qian 1,  Shaoxiong Niu 1,  Lijun Wang 2,  Ying Wang 2,  Hong Xiao 2,  Qidong You 1,  Hua Xiang 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 2 Nanjing Brain Hospital Affiliated to Nanjing Medical University, 264 Guangzhou Road, Nanjing 210029, PR China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: xianghua@cpu.edu.cn.
PMID: 27176944 DOI: 10.1016/j.ejmech.2016.04.029
Abstract

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.

Keywords

Breast cancer; Dual inhibitor; Estrogen receptor; VEGFR-2.

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