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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Hamdy, Rania^1,2  Ziedan, Noha I.^1,2  Ali, Samia^1,3  Bordoni, Cinzia¹  El-Sadek, Mohamed²  Lashin, Elsaid²  Brancale, Andrea¹  Jones, Arwyn T.¹  Westwell, Andrew D.¹ 

[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

关键词: Anti-apoptotic;    Bcl-2;    Indoles;    Oxadiazoles;    Anticancer;    Drug discovery;   

DOI  :  10.1016/j.bmcl.2016.12.061

来源: Elsevier

【 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.

【 授权许可】

Free