title: Synthesis and biological evaluation of N-alkyl-N-(4-methoxyphenyl)pyridin-2-amines as a new class of tubulin polymerization inhibitors.
abstract: Based on our prior antitumor hits, 32 novel N-alkyl-N-substituted phenylpyridin-2-amine derivatives were designed, synthesized and evaluated for cytotoxic activity against A549, KB, KB(VIN), and DU145 human tumor cell lines (HTCL). Subsequently, three new leads (6a, 7g, and 8c) with submicromolar GI(50) values of 0.19-0.41 μM in the cellular assays were discovered, and these compounds also significantly inhibited tubulin assembly (IC(50) 1.4-1.7 μM) and competitively inhibited colchicine binding to tubulin with effects similar to those of the clinical candidate CA-4 in the same assays. These promising results indicate that these tertiary diarylamine derivatives represent a novel class of tubulin polymerization inhibitors targeting the colchicine binding site and showing significant anti-proliferative activity.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, PR China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Wang
authors.forename: Emika
authors.initials: E
authors.lastname: Ohkoshi
authors.forename: Sheng-Biao
authors.initials: SB
authors.lastname: Wang
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D058105:Polymerization / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000588:Amines; D011725:Pyridines; D014404:Tubulin; D050257:Tubulin Modulators