Design, Synthesis and Evaluation of New Bioactive Oxadiazole Derivatives as Anticancer Agents Targeting Bcl-2
A series of 2-(1<i>H</i>-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, <b>4a–m,</b> 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-oxadia...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-11-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/23/8980 |
| Summary: | A series of 2-(1<i>H</i>-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, <b>4a–m,</b> 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 <b>2</b> with substituted carboxylic acid derivatives <b>3a–m</b> in the presence of phosphorus oxychloride. New compounds <b>4a–m</b> showed a range of IC<sub>50</sub> values concentrated in the low micromolar range selectively in Bcl-2 positive human cancer cell lines. The most potent candidate 4-trifluoromethyl substituted analogue <b>4j</b> showed selective IC<sub>50</sub> 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, <b>4j</b> 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 <b>4j</b> as a candidate with drug-like properties for further investigation as a selective Bcl-2 inhibitory anticancer agent. |
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| ISSN: | 1661-6596 1422-0067 |