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Molecular Design, Synthesis, and Evaluation of Novel Potent Apoptosis Inhibitors Inspired from Bongkrekic Acid

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Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasuga-koen, Kasuga, Fukuoka 816-8580, Japan
Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasuga-koen, Kasuga, Fukuoka 816-8580, Japan
*Tel: +81-92-583-7802. Fax: +81-92-583-7875. E-mail: [email protected]
Cite this: Chem. Res. Toxicol. 2012, 25, 10, 2253–2260
Publication Date (Web):September 21, 2012
https://doi.org/10.1021/tx300315h
Copyright © 2012 American Chemical Society

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    Abstract

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    Bongkrekic acid (BKA) is an inhibitor of adenine nucleotide translocase (ANT). Since inhibition of ANT is connected to the inhibition of cytochrome c release from mitochondria, which then results in the suppression of apoptosis, it has been used as a tool for the mechanistic investigation of apoptosis. BKA consists of a long carbon chain with two asymmetric centers, a nonconjugated olefin, two conjugated dienes, three methyl groups, a methoxyl group, and three carboxylic acids. This complicated chemical structure has caused difficulties in synthesis, supply, and biochemical mechanistic investigations. In this study, we designed and synthesized more simple tricarboxylic acids that were inspired by the molecular structure of BKA. Their cytotoxicity and apoptosis-preventing activity in HeLa cells and the effect on the mitochondrial inner membrane potential (ΔΨm) in HL-60 cells were then evaluated. All tested tricarboxylic acid derivatives including BKA showed little toxicity against HeLa cells. BKA and two of the synthesized derivatives significantly suppressed staurosporine (STS)-induced reductions in cell viability. Furthermore, STS-induced ΔΨm collapse was significantly restored by pretreatment with BKA and a tricarboxylic acid derivative. Other derivatives, in which one of three carboxylic acids was esterified, exhibited potent toxicity, especially a derivative bearing a carbon chain of the same length as that of BKA. In conclusion, we have developed a new lead compound as an apoptosis inhibitor bearing three carboxylic acids connected with the proper length of a long carbon chain.

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    Experimental procedures, DNA fragmentation caused by STS addition in HeLa cells, and apoptotic changes in morphology in HL-60 cells exposed with STS. This material is available free of charge via the Internet at http://pubs.acs.org.

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