2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 2-methoxyestradiol analogs as dual selective estrogen receptor modulators (SERMs) and antiangiogenic agents

Design, synthesis and biological evaluation of novel 2-methoxyestradiol analogs as dual selective estrogen receptor modulators (SERMs) and antiangiogenic agents

  • Eur J Med Chem. 2017 Oct 20:139:390-400. doi: 10.1016/j.ejmech.2017.08.016.
Kejing Lao 1,  Yejun Wang 2,  Mingqi Chen 3,  Jingjing Zhang 4,  Qidong You 2,  Hua Xiang 5
Affiliations

Affiliations

  • 1 Institute of Basic and Translational Medicine, and School of Basic Medical Science, Xi'an Medical University, No.1 Xinwang Road, Xi'an, 710021, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 2 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.
  • 3 Laboratory of Biology, School of Higher Vocational Education, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 4 Jiangning Hospital Affiliated to Nanjing Medical University, Gushan Road 168, Nanjing, 211100, PR China.
  • 5 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: 28810190 DOI: 10.1016/j.ejmech.2017.08.016
Abstract

2-methoxyestradiol is a novel agent showing both anti-angiogenic and vascular disrupting properties. In this study, a series of 11α-substituted 2-methoxyestradiol analogs have been designed and synthesized targeting dual ERα and microtubulin. Biological evaluation was performed on their anti-proliferative activities against 5 different cell lines. The results indicated that most compounds exhibited good activities, in which compound 24c and 30c showed the best activity with low micromolar IC50 (2.73 μM -7.75 μM) in all cell lines. The investigation of ER affinity showed that the majority of the compounds displayed good activity at the concentration of 50 μM. In further mechanism study, it was observed that 24c and 30c could induce G2/M cell cycle arrest as well as significant anti-estrogenic activity. In CAM assay, compound 24c and 30c presented significantly anti-angiogenesis activity comparable with 2-methoxyestradiol. Overall, based on biological activities data, 24c and 30c can be identified as a potential lead molecule which might be of therapeutic importance for Cancer treatment.

Keywords

2-Methoxyestradiol; Antiangiogenesis; Estrogen receptor; Steroids.

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