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

Hamdy, Rania, Ziedan, Noha, Ali, Samina, Bordoni, Cinzia, El-Sadek, Mohamed, Lashin, Elsaid, Brancale, Andrea, Jones, Arwyn Tomos and Westwell, Andrew D 2017. Synthesis and evaluation of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines as Bcl-2 inhibitory anticancer agents. Bioorganic & Medicinal Chemistry Letters 27 (4) , pp. 1037-1040. 10.1016/j.bmcl.2016.12.061

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A series of 5-(1H-indol-3-yl)-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 8e as candidates for further development as Bcl-2 inhibitory anticancer agents.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Anti-apoptotic Bcl-2; Indoles; Oxadiazoles; Anticancer; Drug discovery
Publisher: Elsevier
ISSN: 0960-894X
Date of First Compliant Deposit: 15 February 2017
Date of Acceptance: 24 December 2016
Last Modified: 19 Jan 2021 08:31

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