2. Academic Validation
  3. Design, synthesis and biological evaluation of vinyl selenone derivatives as novel microtubule polymerization inhibitors

Design, synthesis and biological evaluation of vinyl selenone derivatives as novel microtubule polymerization inhibitors

  • Eur J Med Chem. 2020 Dec 1;207:112716. doi: 10.1016/j.ejmech.2020.112716.
Huajian Zhu 1,  Honghao Sun 1,  Yang Liu 1,  Yiping Duan 2,  Jie Liu 3,  Xue Yang 2,  Wenlong Li 1,  Shuai Qin 1,  Shengtao Xu 1,  Zheying Zhu 4,  Jinyi Xu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
  • 2 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China; Department of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
  • 3 Department of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
  • 4 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham, NG7 2RD, UK.
  • 5 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: jinyixu@china.com.
PMID: 32853870 DOI: 10.1016/j.ejmech.2020.112716
Abstract

A series of novel vinyl selenone derivatives were designed, synthesized and evaluated as the tubulin polymerization inhibitors using a bioisosteric strategy. Among them, the representative compound 11k exhibited satisfactory anti-proliferative activities with IC50 values ranging from 0.287 to 0.621 μM against a panel of Cancer cell lines. Importantly, 11k displayed more potent in vivo antitumor activity than the positive control paclitaxel, CA-4 and parent compound 4 without apparent toxicity, which was presumably ascribed to the antiangiogenic, antiproliferative and selective effects of selenium, along with the unique physiological activity of indole skeleton, which were both introduced into the structure of target compounds. Further mechanism study demonstrated that compound 11k showed potent activity in tubulin polymerization inhibition with IC50 value of 1.82 μM. Moreover, cellular mechanism studies disclosed that 11k blocked cell cycle arrest at G2/M phase, induced cell Apoptosis and depolarized mitochondria of K562 cells. Meanwhile, 11k reduced the cell migration and had potent vascular disrupting activity. In summary, 11k could serve as a promising lead for the development of more efficient microtubule polymerization inhibitors for Cancer therapy.

Keywords

Antitumor; Bioisosteric strategy; Selenium; Tubulin inhibitors; Vinyl selenone.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z