Antimitotic and antivascular activity of heteroaroyl-2-hydroxy-3,4,5-trimethoxybenzenes

Hsueh-Yun Lee; Chih-Yi Chang; Mei-Jung Lai; Hsun-Yueh Chuang; Ching-Chuan Kuo; Chi-Yen Chang; Jang-Yang Chang; Jing-Ping Liou

doi:10.1016/j.bmc.2015.06.043

Antimitotic and antivascular activity of heteroaroyl-2-hydroxy-3,4,5-trimethoxybenzenes

Bioorg Med Chem. 2015 Aug 1;23(15):4230-4236. doi: 10.1016/j.bmc.2015.06.043. Epub 2015 Jun 25.

Authors

Hsueh-Yun Lee¹, Chih-Yi Chang¹, Mei-Jung Lai², Hsun-Yueh Chuang¹, Ching-Chuan Kuo³, Chi-Yen Chang⁴, Jang-Yang Chang⁵, Jing-Ping Liou⁶

Affiliations

¹ School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
² Center for Translational Medicine, Taipei Medical University, Taiwan.
³ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan.
⁴ National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan.
⁵ National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan; Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: jychang@nhri.org.tw.
⁶ School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; School of Pharmacy, National Defense Medical Center, 161 Minchuan East Road, Section 6, Taipei 114, Taiwan. Electronic address: jpl@tmu.edu.tw.

PMID: 26160020
DOI: 10.1016/j.bmc.2015.06.043

Abstract

This study reports the synthesis of a series of heteroaroyl-2-hydroxy-3,4,5-trimethoxybenzenes, which are potent antitubulin agents. Compound 13, (2-hydroxy-3,4,5-trimethoxyphenyl)-(6-methoxy-1H-indol-3-yl)-methanone exhibits marked antiproliferative activity against KB and MKN45 cells with IC50 values of 8.8 and 10.5 nM, respectively, binds strongly to the colchicine binding site and leads to inhibition of tubulin polymerization. It also behaves as a vascular disrupting agent which suppresses the formation of capillaries. The C2-OH group in the A-ring of this compound not only retains the biological activity but has valuable physicochemical properties.

Keywords: Antiproliferative; CA-4; Vascular-disrupting agents.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology
Antimitotic Agents / chemistry*
Antimitotic Agents / metabolism
Antimitotic Agents / pharmacology*
Benzene / chemistry
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Chemistry Techniques, Synthetic
Colchicine / metabolism
Drug Evaluation, Preclinical / methods*
Drug Resistance, Neoplasm / drug effects
HT29 Cells / drug effects
Human Umbilical Vein Endothelial Cells / drug effects
Humans
Inhibitory Concentration 50
Structure-Activity Relationship
Tubulin Modulators / chemistry
Tubulin Modulators / metabolism
Tubulin Modulators / pharmacology

Substances

Angiogenesis Inhibitors
Antimitotic Agents
Tubulin Modulators
Benzene
Colchicine