1. Design, synthesis, and biological evaluation of (E)-N-aryl-2-arylethenesulfonamide analogues as potent and orally bioavailable microtubule-targeted anticancer agents.
- Author
-
Reddy MV, Mallireddigari MR, Pallela VR, Cosenza SC, Billa VK, Akula B, Subbaiah DR, Bharathi EV, Padgaonkar A, Lv H, Gallo JM, and Reddy EP
- Subjects
- Administration, Oral, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacokinetics, Biological Availability, Blood-Brain Barrier metabolism, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Survival drug effects, Drug Resistance, Neoplasm drug effects, HCT116 Cells, Humans, K562 Cells, MCF-7 Cells, Mice, Mice, Nude, Microtubules metabolism, Neoplasms metabolism, Neoplasms pathology, Polymerization drug effects, Sulfonamides chemical synthesis, Sulfonamides pharmacokinetics, Tubulin metabolism, Tumor Burden drug effects, Antineoplastic Agents pharmacology, Drug Design, Microtubules drug effects, Neoplasms drug therapy, Sulfonamides pharmacology, Xenograft Model Antitumor Assays
- 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.
- Published
- 2013
- Full Text
- View/download PDF