Synthesis and evaluation of 5-(1H-indo1-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines as Bcl-2 inhibitory anticancer agents

被引：30

作者：

Hamdy, Rania ^{[1
,2
]}

Ziedan, Noha I. ^{[1
,2
]}

Ali, Samia ^{[1
,3
]}

Bordoni, Cinzia ^{[1
]}

El-Sadek, Mohamed ^{[2
]}

Lashin, Elsaid ^{[2
]}

Brancale, Andrea ^{[1
]}

Jones, Arwyn T. ^{[1
]}

Westwell, Andrew D. ^{[1
]}

机构：

[1] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Redwood Bldg,King Edward 7 Ave, Cardiff CF10 3NB, S Glam, Wales

[2] Zagazig Univ, Fac Pharm, Zagazig, Egypt

[3] Natl Res Ctr, Cairo, Egypt

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 04期

关键词：

Anti-apoptotic; Bcl-2; Indoles; Oxadiazoles; Anticancer; Drug discovery; PEPTIDE;

D O I：

10.1016/j.bmcl.2016.12.061

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 5-(1H-indol-3-y1)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a-j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin. Active compounds of the series 8a-j were found to have sub-micromolar IC50 values selectively in Bcl-2 expressing human cancer cell lines; notably the 2-nitrophenyl analogue 8a was found to exhibit potent activity, and compounds 8a and 8e possessed comparable Bcl-2 binding affinity (ELISA assay) to the established natural product-based Bcl-2 inhibitor, gossypol. Molecular modeling studies helped to further rationalise anti-apoptotic Bcl-2 binding, and identified compounds 8a and Se as candidates for further development as Bcl-2 inhibitory anticancer agents. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：1037 / 1040

页数：4

共 16 条

[1]

Begum A, 2009, INDIAN J CHEM B, V48, P1565

[2] ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development [J].

Cang, Shundong ;

Iragavarapu, Chaitanya ;

Savooji, John ;

Song, Yongping ;

Liu, Delong .

JOURNAL OF HEMATOLOGY & ONCOLOGY, 2015, 8

[3] The BCL-2 Family Reunion [J].

Chipuk, Jerry E. ;

Moldoveanu, Tudor ;

Llambi, Fabien ;

Parsons, Melissa J. ;

Green, Douglas R. .

MOLECULAR CELL, 2010, 37 (03) :299-310

[4] Synthesis and evaluation of 3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines as Bcl-2 inhibitory anticancer agents [J].

Hamdy, Rania ;

Ziedan, Noha ;

Ali, Samia ;

El-Sadek, Mohamed ;

Lashin, Elsaid ;

Brancale, Andrea ;

Jones, Arwyn T. ;

Westwell, Andrew D. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (08) :2391-2394

[5] Hallmarks of Cancer: The Next Generation [J].

Hanahan, Douglas ;

Weinberg, Robert A. .

CELL, 2011, 144 (05) :646-674

[6] A short Nur77-derived peptide converts Bcl-2 from a protector to a killer [J].

Kolluri, Siva Kumar ;

Zhu, Xiuwen ;

Zhou, Xin ;

Lin, Bingzhen ;

Chen, Ya ;

Sun, Kai ;

Tian, Xuefei ;

Town, James ;

Cao, Xihua ;

Lin, Feng ;

Zhai, Dayong ;

Kitada, Shinichi ;

Luciano, Frederick ;

O'Donnell, Edmond ;

Cao, Yu ;

He, Feng ;

Lin, Jialing ;

Reed, John C. ;

Satterthwait, Arnold C. ;

Zhang, Xiao-kun .

CANCER CELL, 2008, 14 (04) :285-298

[7] Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis [J].

Nguyen, Mai ;

Marcellus, Richard C. ;

Roulston, Anne ;

Watson, Mark ;

Serfass, Lucile ;

Madiraju, S. R. Murthy ;

Goulet, Daniel ;

Viallet, Jean ;

Belec, Laurent ;

Billot, Xavier ;

Acoca, Stephane ;

Purisima, Enrico ;

Wiegmans, Adrian ;

Cluse, Leonie ;

Johnstone, Ricky W. ;

Beauparlant, Pierre ;

Shore, Gordon C. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (49) :19512-19517

[8] Curcumin reduces expression of Bcl-2, leading to apoptosis in daunorubicin-insensitive CD34+ acute myeloid leukemia cell lines and primary sorted CD34+ acute myeloid leukemia cells [J].

Rao, Jia ;

Xu, Duo-Rong ;

Zheng, Fei-Meng ;

Long, Zi-Jie ;

Huang, Sheng-Shan ;

Wu, Xing ;

Zhou, Wei-Hua ;

Huang, Ren-Wei ;

Liu, Quentin .

JOURNAL OF TRANSLATIONAL MEDICINE, 2011, 9

[9] Synthesis of 2-amino-5-substituted-1,3,4-oxadiazoles using 1,3-dibromo-5,5-dimethylhydantoin as oxidant [J].

Rivera, Nelo R. ;

Balsells, Jaume ;

Hansen, Karl B. .

TETRAHEDRON LETTERS, 2006, 47 (28) :4889-4891

[10] Synthesis and evaluation of indole-containing 3,5-diarylisoxazoles as potential pro-apoptotic antitumour agents [J].

Tohid, Siti Farah Md ;

Ziedan, Noha I. ;

Stefanelli, Fabio ;

Fogli, Stefano ;

Westwell, Andrew D. .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2012, 56 :263-270

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