Synthesis and biological evaluation of N-alkyl-N-(4-methoxyphenyl) pyridin-2-amines as a new class of tubulin polymerization inhibitors

被引：25

作者：

Wang, Xiao-Feng ^{[1
]}

Ohkoshi, Emika ^{[2
]}

Wang, Sheng-Biao ^{[1
]}

Hamel, Ernest ^{[3
]}

Bastow, Kenneth F. ^{[4
]}

Morris-Natschke, Susan L. ^{[2
]}

Lee, Kuo-Hsiung ^{[2
,5
]}

Xie, Lan ^{[1
]}

机构：

[1] Beijing Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China

[2] Univ N Carolina, Nat Prod Res Labs, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 USA

[3] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA

[4] Univ N Carolina, Div Chem Biol & Med Chem, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 USA

[5] China Med Univ & Hosp, Chinese Med Res & Dev Ctr, Taichung, Taiwan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 03期

关键词：

N-Alkyl-N-phenylpyridin-2-amines; Cytotoxicity; Tubulin polymerization inhibitors; Colchicine binding site; TUMOR-CELL LINES; DIVERSE PANEL; DERIVATIVES; BINDING; DESIGN; AGENTS; COLCHICINE; ASSAY;

D O I：

10.1016/j.bmc.2012.11.047

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Based on our prior antitumor hits, 32 novel N-alkyl-N-substituted phenylpyridin-2-amine derivatives were designed, synthesized and evaluated for cytotoxic activity against A549, KB, KBVIN, and DU145 human tumor cell lines (HTCL). Subsequently, three new leads (6a, 7g, and 8c) with submicromolar GI(50) values of 0.19-0.41 mu M in the cellular assays were discovered, and these compounds also significantly inhibited tubulin assembly (IC50 1.4-1.7 mu M) and competitively inhibited colchicine binding to tubulin with effects similar to those of the clinical candidate CA-4 in the same assays. These promising results indicate that these tertiary diarylamine derivatives represent a novel class of tubulin polymerization inhibitors targeting the colchicine binding site and showing significant anti-proliferative activity. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：632 / 642

页数：11

共 21 条

[1] Stathmin and Interfacial Microtubule Inhibitors Recognize a Naturally Curved Conformation of Tubulin Dimers [J].

Barbier, Pascale ;

Dorleans, Audrey ;

Devred, Francois ;

Sanz, Laura ;

Allegro, Diane ;

Alfonso, Carlos ;

Knossow, Marcel ;

Peyrot, Vincent ;

Andreu, Jose M. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (41) :31672-31681

[2]

BOYD MR, 1989, CANC PRINCIPLES PRAC, P1

[3] Synthesis of new 2-arylamino-6-trifluoromethylpyridine-3-carboxylic acid derivatives and investigation of their analgesic activity [J].

Cocco, MT ;

Congiu, C ;

Onnis, V ;

Morelli, M ;

Felipo, V ;

Cauli, O .

BIOORGANIC & MEDICINAL CHEMISTRY, 2004, 12 (15) :4169-4177

[4] Variations in the colchicine-binding domain provide insight into the structural switch of tubulin [J].

Dorleans, Audrey ;

Gigant, Benoit ;

Ravelli, Raimond B. G. ;

Mailliet, Patrick ;

Mikol, Vincent ;

Knossow, Marcel .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (33) :13775-13779

[5] Microtubule-binding agents: a dynamic field of cancer therapeutics [J].

Dumontet, Charles ;

Jordan, Mary Ann .

NATURE REVIEWS DRUG DISCOVERY, 2010, 9 (10) :790-803

[6] Discovery of 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a Tubulin Polymerization Inhibitor with Potent Antiproliferative and Tumor Vascular Disrupting Properties [J].

Flynn, Bernard L. ;

Gill, Gurmit S. ;

Grobelny, Damian W. ;

Chaplin, Jason H. ;

Paul, Dharam ;

Leske, Annabell F. ;

Lavranos, Tina C. ;

Chalmers, David K. ;

Charman, Susan A. ;

Kostewicz, Edmund ;

Shackleford, David M. ;

Morizzi, Julia ;

Hamel, Ernest ;

Jung, M. Katherine ;

Kremmidiotis, Gabriel .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (17) :6014-6027

[7] Recent progress in diaryl ether synthesis [J].

Frlan, Rok ;

Kikelj, Danijel .

SYNTHESIS-STUTTGART, 2006, (14) :2271-2285

[8] Evaluation of antimitotic agents by quantitative comparisons of their effects on the polymerization of purified tubulin [J].

Hamel, E .

CELL BIOCHEMISTRY AND BIOPHYSICS, 2003, 38 (01) :1-21

[9] Design, synthesis and biological evaluation of 3-substituted 2,5-dimethyl-N-(3-(1H-tetrazol-5-yl)phenyl)pyrroles as novel potential HIV-1 gp41 inhibitors [J].

He, Xiao-Yang ;

Zou, Peng ;

Qiu, Jiayin ;

Hou, Ling ;

Jiang, Shibo ;

Liu, Shuwen ;

Xie, Lan .

BIOORGANIC & MEDICINAL CHEMISTRY, 2011, 19 (22) :6726-6734

[10] The sulphorhodamine (SRB) assay and other approaches to testing plant extracts and derived compounds for activities related to reputed anticancer activity [J].

Houghton, Peter ;

Fang, Rui ;

Techatanawat, Isariya ;

Steventon, Glyn ;

Hylands, Peter J. ;

Lee, C. C. .

METHODS, 2007, 42 (04) :377-387

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