2. Academic Validation
  3. 1-Phenyl-dihydrobenzoindazoles as novel colchicine site inhibitors: Structural basis and antitumor efficacy

1-Phenyl-dihydrobenzoindazoles as novel colchicine site inhibitors: Structural basis and antitumor efficacy

  • Eur J Med Chem. 2019 Sep 1:177:448-456. doi: 10.1016/j.ejmech.2019.04.040.
Junhang Jiang 1,  Hao Zhang 2,  Chongqing Wang 1,  Qingsen Zhang 1,  Shaoyu Fang 1,  Ruolan Zhou 1,  Jian Hu 1,  Ju Zhu 1,  Youjun Zhou 3,  Cheng Luo 4,  Canhui Zheng 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
  • 2 State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Material Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 3 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: zhuoyoujun@smmu.edu.cn.
  • 4 State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Material Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: cluo@simm.ac.cn.
  • 5 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: canhuizheng@smmu.edu.cn.
PMID: 31174062 DOI: 10.1016/j.ejmech.2019.04.040
Abstract

The colchicine site inhibitors (CSIs) showed promising prospects as antitumor agents due to their vascular disrupting activities besides antimitotic activities. 1-Phenyl-dihydrobenzoindazole was found as a novel scaffold of CSI without the cis-trans isomerization problem. The X-ray co-crystal structure of the lead compound with tubulin was determined, which revealed the binding mode including special water-bridged hydrogen bonds. The structure also provided guidance for the structural optimization of this type of CSI, which led to the discovery of the most potent inhibitor A3, with growth IC50 lower than 1 nM against human colon Cancer cell lines and tubulin polymerization IC50 of 1.6 μM. In addition, its water-soluble prodrug B1 showed good in vivo antitumor activity on two human colon Cancer xenograft nude mice models, encouraging further study of this type of antitumor compound.

Keywords

Cis-trans photoisomerization; Colchicine site inhibitors; Microtubule-targeting agents; Water-soluble prodrug; X-ray co-crystal structure.

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