title: Discovery of 4-Aryl-2-benzoyl-imidazoles as tubulin polymerization inhibitor with potent antiproliferative properties.
abstract: A series of 4-aryl-2-benzoyl-imidazoles were designed and synthesized based on our previously reported 2-aryl-4-benzoyl-imidazole (ABI) derivatives. The new structures reversed the aryl group and the benzoyl group of previous ABI structures and were named as reverse ABI (RABI) analogues. RABIs were evaluated for biological activity against eight cancer cell lines including multidrug-resistant cancer cell lines. In vitro assays indicated that several RABI compounds had excellent antiproliferative properties, with IC50 values in the low nanomolar range. The average IC50 of the most active compound 12a is 14 nM. In addition, the mechanism of action of these new analogues was investigated by cell cycle analysis, tubulin polymerization assay, competitive mass spectrometry binding assay, and molecular docking studies. These studies confirmed that these new RABI analogues maintain their mechanisms of action by disrupting tubulin polymerization, similar to their parental ABI analogues.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xiao
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Ahn
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D014404:Tubulin; D050257:Tubulin Modulators
references.citation: J Med Chem. 2012 Aug 23;55(16):7285-9
references.pmid: 22783954
references.citation: Br J Cancer. 1996 Jan;73(2):154-61
references.pmid: 8546900
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: J Med Chem. 2010 Oct 28;53(20):7414-27
references.pmid: 20919720
references.citation: Pharm Res. 2012 Nov;29(11):3053-63
references.pmid: 22760659
references.citation: Pharm Res. 2012 Nov;29(11):3040-52
references.pmid: 22410804
references.citation: Bioorg Med Chem. 2011 Aug 15;19(16):4782-95
references.pmid: 21775150
references.citation: J Biol Chem. 2010 Oct 8;285(41):31672-81
references.pmid: 20675373
references.citation: J Med Chem. 2009 Mar 26;52(6):1701-11
references.pmid: 19243174
references.citation: J Pharmacol Exp Ther. 2003 Mar;304(3):1258-67
references.pmid: 12604704
references.citation: Cancer Res. 2009 May 1;69(9):3918-26
references.pmid: 19383919
references.citation: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references.pmid: 22237781
references.citation: Bioorg Med Chem. 2011 Aug 15;19(16):4868-75
references.pmid: 21782453
references.citation: Drug Metab Dispos. 2011 Oct;39(10):1833-9
references.pmid: 21742898
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13775-9
references.pmid: 19666559
references.citation: J Med Chem. 2007 Mar 8;50(5):940-50
references.pmid: 17269758
references.citation: Bioorg Med Chem. 2011 Aug 1;19(15):4635-43
references.pmid: 21733699
references.citation: J Natl Cancer Inst. 2001 Aug 15;93(16):1234-45
references.pmid: 11504769