Design, synthesis and evaluation of new bioactive oxadiazole derivatives as anticancer agents targeting Bcl-2

Hamdy, Rania, Elseginy, Samia A., Ziedan, Noha I., El-Sadek, Mohamed, Lashin, Elsaid, Jones, Arwyn T. ORCID: https://orcid.org/0000-0003-2781-8905 and Westwell, Andrew D. ORCID: https://orcid.org/0000-0002-5166-9236 2020. Design, synthesis and evaluation of new bioactive oxadiazole derivatives as anticancer agents targeting Bcl-2. International Journal of Molecular Sciences 21 (23) , 8980. 10.3390/ijms21238980

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Abstract

A series of 2-(1H-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, 4a–m, were designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2 inhibitory anticancer agents based on our previously reported hit compounds. Synthesis of the target 1,3,4-oxadiazoles was readily accomplished through a cyclization reaction of indole carboxylic acid hydrazide 2 with substituted carboxylic acid derivatives 3a–m in the presence of phosphorus oxychloride. New compounds 4a–m showed a range of IC50 values concentrated in the low micromolar range selectively in Bcl-2 positive human cancer cell lines. The most potent candidate 4-trifluoromethyl substituted analogue 4j showed selective IC50 values of 0.52–0.88 μM against Bcl-2 expressing cell lines with no inhibitory effects in the Bcl-2 negative cell line. Moreover, 4j showed binding that was two-fold more potent than the positive control gossypol in the Bcl-2 ELISA binding affinity assay. Molecular modeling studies helped to further rationalize anti-apoptotic Bcl-2 binding and identified compound 4j as a candidate with drug-like properties for further investigation as a selective Bcl-2 inhibitory anticancer agent.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Additional Information:	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Publisher:	MDPI
ISSN:	1422-0067
Date of First Compliant Deposit:	7 December 2020
Date of Acceptance:	21 November 2020
Last Modified:	05 May 2023 07:20
URI:	https://orca.cardiff.ac.uk/id/eprint/136849

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