ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

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

View Author Information
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
Copyright © 2012 American Chemical Society

    Article Views





    Other access options
    Supporting Info (1)»


    Abstract Image

    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.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    Jump To

    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

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 13 publications.

    1. Yangguang Gao, Zhou Cao, Qiang Zhang, Rui Guo, Fei Ding, Qingliang You, Jingjing Bi, Yongmin Zhang. Total Synthesis of the Proposed Structure of Penasulfate A: l-Arabinose as a Source of Chirality. Journal of Natural Products 2019, 82 (7) , 1908-1916.
    2. Mengdi Yuan, Rongwei Han, Li Bai, Yinping Dong, Qian Xi, Qijing Du, Yongxin Yang, Fereidoun Forghani, Qingli Yang, Juhee Ahn, Jun Wang. Recent Advances in the Characterization of Burkholderia Gladioli Pv. Cocovenenans and Its Toxin Production. Food Reviews International 2024, 40 (3) , 867-882.
    3. Mitsuru Shindo, Takayuki Iwata, Arihiro Kano, Yasuo Shinohara. Synthesis and Conversion of Bongkrekic Acid and its Bioactivity. Journal of Synthetic Organic Chemistry, Japan 2022, 80 (12) , 1136-1148.
    4. Vladimir F. Mironov, Andrey V. Nemtarev, Olga V. Tsepaeva, Mudaris N. Dimukhametov, Igor A. Litvinov, Alexandra D. Voloshina, Tatiana N. Pashirova, Eugenii A. Titov, Anna P. Lyubina, Syumbelya K. Amerhanova, Aidar T. Gubaidullin, Daut R. Islamov. Rational Design 2-Hydroxypropylphosphonium Salts as Cancer Cell Mitochondria-Targeted Vectors: Synthesis, Structure, and Biological Properties. Molecules 2021, 26 (21) , 6350.
    5. Masayo Hirao-Suzuki, Shuso Takeda, Mitsuru Shindo. Exposure to (–)-Xanthatin during the Haploid Formation of Mouse Spermatocyte GC-2spd(ts) Cells, an in vitro Male Germ Cell Model. BPB Reports 2021, 4 (6) , 202-205.
    6. Hanna Chen, Zhilong Bian, Vinothkannan Ravichandran, Ruijuan Li, Yi Sun, Liujie Huo, Jun Fu, Xiaoying Bian, Liqiu Xia, Qiang Tu, Youming Zhang. Biosynthesis of polyketides by trans -AT polyketide synthases in Burkholderiales. Critical Reviews in Microbiology 2019, 45 (2) , 162-181.
    7. Christos Chinopoulos. Mitochondrial permeability transition pore: Back to the drawing board. Neurochemistry International 2018, 117 , 49-54.
    8. Satoshi Fujita, Masaki Suyama, Kenji Matsumoto, Atsushi Yamamoto, Takenori Yamamoto, Yuka Hiroshima, Takayuki Iwata, Arihiro Kano, Yasuo Shinohara, Mitsuru Shindo. Synthesis and evaluation of simplified functionalized bongkrekic acid analogs. Tetrahedron 2018, 74 (9) , 962-969.
    9. Hiroyuki Okazaki, Shuso Takeda, Hiroyuki Ishii, Yukimi Takemoto, Satoshi Fujita, Masaki Suyama, Kenji Matsumoto, Mitsuru Shindo, Hironori Aramaki. A Novel Bongkrekic Acid Analog-Mediated Modulation of the Size of Lipid Droplets: Evidence for the Appearance of Smaller Adipocytes. Biological & Pharmaceutical Bulletin 2017, 40 (8) , 1192-1198.
    10. Atsushi Yamamoto, Keisuke Hasui, Hiroshi Matsuo, Katsuhiro Okuda, Masato Abe, Kenji Matsumoto, Kazuki Harada, Yuya Yoshimura, Takenori Yamamoto, Kazuto Ohkura, Mitsuru Shindo, Yasuo Shinohara. Bongkrekic Acid Analogue, Lacking One of the Carboxylic Groups of its Parent Compound, Shows Moderate but pH ‐insensitive Inhibitory Effects on the Mitochondrial ADP / ATP Carrier. Chemical Biology & Drug Design 2015, 86 (5) , 1304-1322.
    11. Kenji Matsumoto, Masaki Suyama, Satoshi Fujita, Takuya Moriwaki, Yukiko Sato, Yoshifumi Aso, Satoshi Muroshita, Hiroshi Matsuo, Keishi Monda, Katsuhiro Okuda, Masato Abe, Hiroyuki Fukunaga, Arihiro Kano, Mitsuru Shindo. Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues. Chemistry – A European Journal 2015, 21 (32) , 11590-11602.
    12. V.A. Chistyakov, P.V. Zolotukhin, E.V. Prazdnova, I. Alperovich, A.V. Soldatov. Physical consequences of the mitochondrial targeting of single-walled carbon nanotubes probed computationally. Physica E: Low-dimensional Systems and Nanostructures 2015, 70 , 198-202.
    13. Hiroyuki Okazaki, Shuso Takeda, Eriko Ikeda, Yoshifumi Fukunishi, Hiroyuki Ishii, Aya Taniguchi, Miki Tokuyasu, Taichi Himeno, Kazuhiro Kakizoe, Kenji Matsumoto, Mitsuru Shindo, Hironori Aramaki. Bongkrekic acid as a selective activator of the peroxisome proliferator-activated receptor γ (PPARγ) isoform. The Journal of Toxicological Sciences 2015, 40 (2) , 223-233.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect