Design, Synthesis, and Biological Evaluation of (E)-N-aryl-2-arylethenesulfonamide Analogues As Potent and Orally Bioavailable Microtubule-targeted Anticancer Agents

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2013 Jun 12

PMID 23750455

Citations 5

Authors

M V Ramana Reddy

Muralidhar R Mallireddigari

Venkat R Pallela

Stephen C Cosenza

Vinay K Billa

Balaiah Akula

D R C Venkata Subbaiah

E Vijaya Bharathi

Amol Padgaonkar

Hua Lv

James M Gallo

E Premkumar Reddy

Affiliations

Soon will be listed here.

Abstract

A series of novel (E)-N-aryl-2-arylethenesulfonamides (6) were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC50 values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound (E)-N-(3-amino-4-methoxyphenyl)-2-(2',4',6'-trimethoxyphenyl)ethenesulfonamide (6t) showed dramatic reduction in tumor size, indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood-brain barrier permeability relative to many clinically used antimitotic agents. Mechanistic studies indicate that 6t and some other analogues disrupted microtubule formation, formation of mitotic spindles, and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin, indicating its binding site on tubulin.

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