1494589-74-0Relevant academic research and scientific papers
Scaffold Hopping-Driven Optimization of 4-(Quinazolin-4-yl)-3,4-dihydroquinoxalin-2(1 H)-ones as Novel Tubulin Inhibitors
Cui, Mutian,Goto, Masuo,He, Xiaoyang,Hsu, Pei-Ling,Jiang, Li,Lee, Kuo-Hsiung,Li, Kang-Po,Morris-Natschke, Susan Lynne,Xie, Lan,Zhu, Dong-Qing
, p. 83 - 89 (2020)
Scaffold hopping-driven lead optimizations were performed based on our prior lead 7-methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (2a) by C-ring expansion and isometric replacement of the A/B-ring, successively, aimed at finding new potential alternative drug candidates with different scaffold(s), high antitumor activity, and other improved properties to replace prior, once promising drug candidates that failed in further studies. Two series of new compounds 7 (a-d) and 13 (a-j) were synthesized and evaluated for antitumor activity, leading to the discovery of three highly potent compounds 13c, 13d, and 13e with different scaffolds. They exhibited similar high antitumor activity with single digital low nanomolar GI50 values (4.6-9.6 nM) in cellular assays, comparable to lead 2a, clinical drug candidate CA-4, and paclitaxel in the same assays. Further biological evaluations identified new active compounds as tubulin polymerization inhibitors targeting the colchicine binding site. Moreover, 13d showed better aqueous solubility than 2a and a similar log P value.
N-Aryl Unsaturated Fused Ring Tertiary Amine Compounds, Preparation Method and Anti-Tumor Applications Thereof
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, (2015/05/26)
The present invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, its preparation method, a pharmaceutical composition comprising the compound, and its use in manufacture of a medicament for treatment of a disease or disorder, wherein R1, R2, R5, R6, X, Y, Q, W, n1 and n2 are defined as those stated in the description.
N-ARYL UNSATURATED FUSED RING TERTIARY AMINE COMPOUND, PREPARATION METHOD THEREOF AND ANTITUMOR APPLICATION THEREOF
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Paragraph 0107-0108, (2015/04/15)
The present invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, its preparation method, a pharmaceutical composition comprising the compound, and its use in manufacture of a medicament for treatment of a disease or disorder, wherein R1, R2, R5, R6, X, Y, Q, W, n1 and n2 are defined as those stated in the description.
Optimization of 4-(N-cycloamino)phenylquinazolines as a novel class of tubulin-polymerization inhibitors targeting the colchicine site
Wang, Xiao-Feng,Guan, Fang,Ohkoshi, Emika,Guo, Wanjun,Wang, Lili,Zhu, Dong-Qing,Wang, Sheng-Biao,Wang, Li-Ting,Hamel, Ernest,Yang, Dexuan,Li, Linna,Qian, Keduo,Morris-Natschke, Susan L.,Yuan, Shoujun,Lee, Kuo-Hsiung,Xie, Lan
, p. 1390 - 1402 (2014/03/21)
The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a-c and 5a-m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI 50 1.9-3.2 nM), significant potency against tubulin assembly (IC 50 0.77 μM), and substantial inhibition of colchicine binding (99% at 5 μM). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose.
