title: Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl-thiazoles analogues as potent and orally bioavailable anticancer agents.
abstract: In a continued effort to improve upon the previously published 4-substituted methoxybenzoyl-aryl-thiazole (SMART) template, we explored chemodiverse "B" rings and "B" to "C" ring linkage. Further, to overcome the poor aqueous solubility of this series of agents, we introduced polar and ionizable hydrophilic groups to obtain water-soluble compounds. For instance, based on in vivo pharmacokinetic (PK) studies, an orally bioavailable phenyl-amino-thiazole (PAT) template was designed and synthesized in which an amino linkage was inserted between "A" and "B" rings of compound 1. The PAT template maintained nanomolar (nM) range potency against cancer cell lines via inhibiting tubulin polymerization and was not susceptible to P-glycoprotein mediated multidrug resistance in vitro, and markedly improved solubility and bioavailability compared with the SMART template (45a-c (PAT) vs 1 (SMART)).
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee, Health Science Center, Memphis, Tennessee 38163, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Li
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.forename: Michael L
authors.initials: ML
authors.lastname: Mohler
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002417:Cattle; D045744:Cell Line, Tumor; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D013844:Thiazoles; D014404:Tubulin; D050257:Tubulin Modulators