title: Optimization of 4-(N-cycloamino)phenylquinazolines as a novel class of tubulin-polymerization inhibitors targeting the colchicine site.
abstract: 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 (GI50 1.9-3.2 nM), significant potency against tubulin assembly (IC50 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.
authors: Beijing Institute of Pharmacology and Toxicology , 27 Tai-Ping Road, Beijing 100850, China.
authors: Xiao-Feng
authors: XF
authors: Wang
authors: Fang
authors: F
authors: Guan
authors: Emika
authors: E
authors: Ohkoshi
authors: Wanjun
authors: W
authors: Guo
authors: Lili
authors: L
authors: Wang
authors: Dong-Qing
authors: DQ
authors: Zhu
authors: Sheng-Biao
authors: SB
authors: Wang
authors: Li-Ting
authors: LT
authors: Wang
authors: Ernest
authors: E
authors: Hamel
authors: Dexuan
authors: D
authors: Yang
authors: Linna
authors: L
authors: Li
authors: Keduo
authors: K
authors: Qian
authors: Susan L
authors: SL
authors: Morris-Natschke
authors: Shoujun
authors: S
authors: Yuan
authors: Kuo-Hsiung
authors: KH
authors: Lee
authors: Lan
authors: L
authors: Xie
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry*; D005260:Female; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011799:Quinazolines; D050257:Tubulin Modulators; D003078:Colchicine