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Molecular modelling, synthesis, cytotoxicity and anti‐tumour mechanisms of 2‐aryl‐6‐substituted quinazolinones as dual‐targeted anti‐cancer agents
Author(s) -
Hour M J,
Lee K H,
Chen T L,
Lee K T,
Zhao Yu,
Lee H Z
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12233
Subject(s) - cytotoxicity , cell cycle , trypan blue , lung cancer , cancer cell , cell cycle checkpoint , cancer research , western blot , chemistry , cancer , mitosis , microbiology and biotechnology , biology , cell , biochemistry , medicine , pathology , in vitro , genetics , gene
Background and Purpose Our previous study demonstrated that 6‐(pyrrolidin‐1‐yl)‐2‐(3‐methoxyphenyl)quinazolin‐4‐one ( HMJ 38) was a potent anti‐tubulin agent. Here, HMJ 38 was used as a lead compound to develop more potent anti‐cancer agents and to examine the anti‐cancer mechanisms. Experimental Approach 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 HMJ 38. 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. Key Results Compounds MJ 65–70 exhibited strong anti‐proliferative effects towards melanoma M 21, lung squamous carcinoma CH 27, lung non‐small carcinoma H 460, hepatoma Hep3B and oral cancer HSC ‐3 cells, with one compund MJ 66 (6‐(pyrrolidin‐1‐yl)‐2‐(naphthalen‐1‐yl)quinazolin‐4‐one) highly active against M 21 cells ( IC 50 about 0.033 μM). Treatment of CH 27 or HSC ‐3 cells with MJ 65–70 resulted in significant mitotic arrest accompanied by increasing multiple asters of microtubules. JNK protein expression was involved in the MJ 65–70‐induced CH 27 and M 21 cell death. Consistent with the cell cycle arrest at G2/M phase, marked increases in cyclin B 1 and B cl‐2 phosphorylation were also observed, after treatment with MJ65–70. Conclusions and Implication MJ 65–70 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.