title: Synthesis and biological evaluation of 2,4,5-substituted pyrimidines as a new class of tubulin polymerization inhibitors.
abstract: Members of a series of 2,4,5-substituted pyrimidine derivatives were synthesized, and their interactions with tubulin and their antiproliferative activities against the human hepatocellular carcinoma cells of liver (BEL-7402) were evaluated. One member of this family, the indole-pyrimidine 4k, having an indole-aryl-substituted aminopyrimidine structure, was observed to be an excellent inhibitor of tubulin polymerization (IC(50) = 0.79 μM) and to display significantly high antiproliferative activities against several cancer cell lines with IC(50) values ranging from 16 to 62 nM. This substance displayed a high propensity to arrests cells at the G(2)/M phase of the cell cycle (EC(50) = 20 nM). In addition, 4k was found to competitively inhibit colchicine binding to tubulin, indicating that it binds to the colchicine-binding site of tubulin. The observations made in this investigation demonstrate that 2,4,5-substituted pyrimidines represent a new class of tubulin polymerization inhibitors with significant antiproliferative activity.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Fuchun
authors.initials: F
authors.lastname: Xie
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhao
authors.forename: Dewen
authors.initials: D
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Haitian
authors.initials: H
authors.lastname: Quan
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Shi
authors.forename: Liguang
authors.initials: L
authors.lastname: Lou
authors.forename: Youhong
authors.initials: Y
authors.lastname: Hu
mesh_terms: D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003078:Colchicine / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D007211:Indoles; D011743:Pyrimidines; D014404:Tubulin; D050257:Tubulin Modulators; D014747:Vinblastine; D017239:Paclitaxel; D000077235:Vinorelbine; D003078:Colchicine