Modified carbazoles destabilize microtubules and kill glioblastoma multiform cells

被引：21

作者：

Diaz, Philippe ^{[1
,2
]}

Horne, Eric ^{[3
]}

Xu, Cong ^{[4
]}

Hamel, Ernest ^{[7
]}

Wagenbach, Michael ^{[5
]}

Petrov, Ravil R. ^{[1
]}

Uhlenbruck, Benjamin ^{[1
]}

Haas, Brian ^{[4
]}

Hothi, Parvinder ^{[9
]}

Wordeman, Linda ^{[5
]}

Gussio, Rick ^{[8
]}

Stella, Nephi ^{[3
,4
,6
]}

机构：

[1] Univ Montana, Dept Biomed & Pharmaceut Sci, 32 Campus Dr, Missoula, MT 59812 USA

[2] DermaXon LLC, 32 Campus Dr, Missoula, MT 59812 USA

[3] Stella Therapeut Inc, Pacific Northwest Res Inst, 720 Broadway, Seattle, WA 98122 USA

[4] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA

[5] Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA

[6] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

[7] NCI, Screening Technol Branch, NIH, Frederick, MD 21702 USA

[8] NCI, Computat Drug Dev Grp, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA

[9] Swedish Neurosci Inst, Ivy Ctr Adv Brain Tumor Treatment, 550 17th Ave, Seattle, WA 98122 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 159卷

关键词：

Microtubules; Colchicine; Carbazole; Gliomas; ANTIMITOTIC AGENTS; STEM-CELLS; TUBULIN; GLIOMA; HETEROGENEITY; COLCHICINE; INHIBITORS; PATHWAYS; SCREENS; CANCER;

D O I：

10.1016/j.ejmech.2018.09.026

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Small molecules that target microtubules (MTs) represent promising therapeutics to treat certain types of cancer, including glioblastoma multiform (GBM). We synthesized modified carbazoles and evaluated their antitumor activity in GBM cells in culture. Modified carbazoles with an ethyl moiety linked to the nitrogen of the carbazole and a carbonyl moiety linked to distinct biaromatic rings exhibited remarkably different killing activities in human GBM cell lines and patient-derived GBM cells, with IC50 values from 67 to > 10,000 nM. Measures of the activity of modified carbazoles with tubulin and microtubules coupled to molecular docking studies show that these compounds bind to the colchicine site of tubulin in a unique low interaction space that inhibits tubulin assembly. The modified carbazoles reported here represent novel chemical tools to better understand how small molecules disrupt MT functions and kill devastating cancers such as GBM. (C) 2018 Elsevier Masson SAS. All rights reserved.

引用

页码：74 / 89

页数：16

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