title: Molecular modelling, synthesis, cytotoxicity and anti-tumour mechanisms of 2-aryl-6-substituted quinazolinones as dual-targeted anti-cancer agents.
abstract: OBJECTIVE
  Our previous study demonstrated that 6-(pyrrolidin-1-yl)-2-(3-methoxyphenyl)quinazolin-4-one (HMJ38) was a potent anti-tubulin agent. Here, HMJ38 was used as a lead compound to develop more potent anti-cancer agents and to examine the anti-cancer mechanisms.
  
  
  METHODS
  Using computer-aided drug design, 2-aryl-6-substituted quinazolinones (MJ compounds) were designed and synthesized by introducing substituents at C-2 and C-6 positions of HMJ38. The cytotoxicity of MJ compounds towards human cancer cells was examined by Trypan blue exclusion assay. Microtubule distribution was visualized using TubulinTracker(TM) Green reagent. Protein expression of cell cycle regulators and JNK was assessed by Western blot analysis.
  
  
  RESULTS
  Compounds MJ65-70 exhibited strong anti-proliferative effects towards melanoma M21, lung squamous carcinoma CH27, lung non-small carcinoma H460, hepatoma Hep3B and oral cancer HSC-3 cells, with one compund MJ66 (6-(pyrrolidin-1-yl)-2-(naphthalen-1-yl)quinazolin-4-one) highly active against M21 cells (IC50 about 0.033 μM). Treatment of CH27 or HSC-3 cells with MJ65-70 resulted in significant mitotic arrest accompanied by increasing multiple asters of microtubules. JNK protein expression was involved in the MJ65-70-induced CH27 and M21 cell death. Consistent with the cell cycle arrest at G2/M phase, marked increases in cyclin B1 and Bcl-2 phosphorylation were also observed, after treatment with MJ65-70.
  
  
  CONCLUSIONS
  MJ65-70 are dual-targeted, tubulin- and JNK-binding, anti-cancer agents and induce cancer cell death through up-regulation of JNK and interfering in the dynamics of tubulin. Our work provides a new strategy and mechanism for developing dual-targeted anti-cancer drugs, contributing to clinical anti-cancer drug discovery and application.
authors: School of Pharmacy, China Medical University, Taichung, Taiwan. mjhou@mail.cmu.edu.tw
authors: M J
authors: MJ
authors: Hour
authors: K H
authors: KH
authors: Lee
authors: T L
authors: TL
authors: Chen
authors: K T
authors: KT
authors: Lee
authors: Yu
authors: Y
authors: Zhao
authors: H Z
authors: HZ
authors: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D056744:Cyclin B1; D019253:Proto-Oncogene Proteins c-bcl-2; D052999:Quinazolinones; D014404:Tubulin
keywords: 2-aryl-6-substituted quinazolinones; c-Jun N-terminal kinase; computer-aided drug design; dual-targeted anti-cancer agents; tubulin
references: J Med Chem. 2000 Nov 16;43(23):4479-87
references: 11087572
references: Nat Rev Cancer. 2003 Jul;3(7):502-16
references: 12835670
references: Oncogene. 2004 Apr 12;23(16):2825-37
references: 15077146
references: Mol Cell. 2002 May;9(5):931-43
references: 12049731
references: Oncogene. 2003 Oct 20;22(47):7340-58
references: 14576842
references: J Biol Chem. 1998 Jul 24;273(30):18984-91
references: 9668078
references: Nat Rev Drug Discov. 2002 Nov;1(11):882-94
references: 12415248
references: PLoS One. 2011;6(8):e24312
references: 21918689
references: Oral Oncol. 2009 Dec;45(12):1037-43
references: 19692293
references: J Pharmacol Exp Ther. 2011 Sep;338(3):942-51
references: 21652781
references: J Chem Inf Model. 2006 Jan-Feb;46(1):401-15
references: 16426074
references: Mol Cancer Ther. 2009 Nov;8(11):3036-45
references: 19887548
references: Nat Rev Cancer. 2002 Jan;2(1):48-58
references: 11902585
references: Nat Rev Drug Discov. 2004 May;3(5):451-6
references: 15136792
references: Drug Resist Updat. 2001 Oct;4(5):303-13
references: 11991684
references: Anticancer Res. 2004 May-Jun;24(3a):1769-78
references: 15274354
references: J Biol Chem. 2000 Jul 14;275(28):21661-7
references: 10766756
references: Prog Cell Cycle Res. 2003;5:309-25
references: 14593726
references: J Cell Biol. 1982 Sep;94(3):688-96
references: 6127342
references: Mutat Res. 2001 Jul 1;478(1-2):23-43
references: 11406167
references: Eur J Pharmacol. 2010 Dec 1;648(1-3):50-8
references: 20840846
references: Cancer Res. 1997 Jan 15;57(2):229-33
references: 9000560
references: Arch Toxicol. 2013 May;87(5):835-46
references: 23212307
references: Oncogene. 1998 Jan 29;16(4):533-40
references: 9484843