title: Biological activity of 4-substituted methoxybenzoyl-aryl-thiazole: an active microtubule inhibitor.
abstract: Formation of microtubules is a dynamic process that involves polymerization and depolymerization of αβ-tubulin heterodimers. Drugs that enhance or inhibit tubulin polymerization can destroy this dynamic process, arresting cells in the G(2)/M phase of the cell cycle. Although drugs that target tubulin generally demonstrate cytotoxic potency in the subnanomolar range, resistance due to drug efflux is a common phenomenon among the antitubulin agents. We recently reported a class of 4-substituted methoxybenzoyl-aryl-thiazoles (SMART) that exhibited great in vitro potency and broad spectrum cellular cytotoxicity. Evaluation of the in vitro and in vivo anticancer activities of 3 SMART compounds, SMART-H (H), SMART-F (F), and SMART-OH (OH), with varying substituents at the 4-position of aryl ring, demonstrated that they bind potently to the colchicine-binding site in tubulin, inhibit tubulin polymerization, arrest cancer cells in G(2)/M phase of the cell cycle, and induce their apoptosis. The SMART compounds also equipotently inhibit the growth of parental and MDR-overexpressing cells in vitro, indicating that they can overcome multidrug resistance. In vivo antitumor efficacy studies in human prostate (PC-3) and melanoma (A375) cancer xenograft models demonstrated that SMART-H and SMART-F treatments resulted in %T/C values ranging from 4% to 30%. In addition, in vivo SMART-H treatment for 21 days at the higher dose (15 mg/kg) failed to produce any apparent neurotoxicity. These studies provide the first in vivo evidence and proof-of-concept that SMART compounds are similarly efficacious to currently FDA approved antitubulin drugs for cancer treatment, but they can circumvent P-glycoprotein-mediated drug resistance.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Li
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Ahn
authors.forename: Ramesh
authors.initials: R
authors.lastname: Narayanan
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Kearbey
authors.forename: Deanna N
authors.initials: DN
authors.lastname: Parke
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008870:Microtubules / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D013844:Thiazoles