2. Academic Validation
  3. (E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides as tubulin polymerization inhibitors: Structure-based bioisosterism design, synthesis, biological evaluation, molecular docking and in silico ADME prediction

(E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides as tubulin polymerization inhibitors: Structure-based bioisosterism design, synthesis, biological evaluation, molecular docking and in silico ADME prediction

  • Bioorg Med Chem Lett. 2018 Nov 1;28(20):3350-3355. doi: 10.1016/j.bmcl.2018.09.004.
Guangcheng Wang 1,  Zhiyun Peng 2,  Shanshan Peng 3,  Jie Qiu 3,  Yongjun Li 4,  Yanyu Lan 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China. Electronic address: wanggch123@163.com.
  • 2 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
  • 3 College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
  • 4 Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004, China. Electronic address: liyongjun_gmu@163.com.
  • 5 Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004, China.
PMID: 30197030 DOI: 10.1016/j.bmcl.2018.09.004
Abstract

A series of (E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides have been synthesized and evaluated for their Anticancer activity in human hepatocellular liver carcinoma HepG2 and breast adenocarcinoma MCF-7 cell lines. Among all the tested compounds, compound 3a, 3e and 3n displayed more activity than lead compound with IC50 value of 0.26-0.61 μM. Meanwhile, these compounds (3a, 3e and 3n) showed potent antiproliferative activity against a panel of Cancer cells and the HCT-8/T multidrug resistant cell line with IC50 values in the range of 0.077- 7.44 μM. Flow cytometric analyses revealed that compound 3n induced cell cycle arrest in G2/M phases in a dose dependent manner. The compound 3n also displayed potent tubulin polymerization inhibition with an IC50 value of 0.9 µM, with ten folds more active than colchicine (IC50 = 9 μM). Molecular docking studies revealed that compound 3n efficiently interacted with the colchicine binding site of tubulin through hydrophobic, cation-π and hydrogen bond interaction. Furthermore, in silico pharmacokinetic prediction shown that these compounds have a good ADME-related physicochemical parameters. These results demonstrate that 3n exhibits potent cytotoxicity in Cancer cells by targeting the colchicine binding site of tubulin and potentially acts as a therapeutic lead compound for the development of Anticancer drugs.

Keywords

ADME prediction; Acetohydrazonoyl cyanide; Anticancer activity; Bioisosterism; Tubulin.

Figures