Molecular design, synthesis, and evaluation of novel potent apoptosis inhibitors inspired from bongkrekic acid

Katsuhiro Okuda, Keisuke Hasui, Masato Abe, Kenji Matsumoto, Mitsuru Shindo

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2253-2260
Number of pages8
JournalChemical Research in Toxicology
Volume25
Issue number10
DOIs
Publication statusPublished - Oct 15 2012

Fingerprint

Bongkrekic Acid
Apoptosis
Tricarboxylic Acids
Derivatives
Bearings (structural)
Carboxylic Acids
ATP Translocases Mitochondrial ADP
Staurosporine
Carbon
HeLa Cells
Toxicity
Lead compounds
Mitochondria
Mitochondrial Membrane Potential
HL-60 Cells
Alkenes
Cytotoxicity
Cytochromes c
Molecular Structure
Molecular structure

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Molecular design, synthesis, and evaluation of novel potent apoptosis inhibitors inspired from bongkrekic acid. / Okuda, Katsuhiro; Hasui, Keisuke; Abe, Masato; Matsumoto, Kenji; Shindo, Mitsuru.

In: Chemical Research in Toxicology, Vol. 25, No. 10, 15.10.2012, p. 2253-2260.

Research output: Contribution to journalArticle

Okuda, Katsuhiro ; Hasui, Keisuke ; Abe, Masato ; Matsumoto, Kenji ; Shindo, Mitsuru. / Molecular design, synthesis, and evaluation of novel potent apoptosis inhibitors inspired from bongkrekic acid. In: Chemical Research in Toxicology. 2012 ; Vol. 25, No. 10. pp. 2253-2260.
@article{4adee45debf7441f893262c6d1922525,
title = "Molecular design, synthesis, and evaluation of novel potent apoptosis inhibitors inspired from bongkrekic acid",
abstract = "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.",
author = "Katsuhiro Okuda and Keisuke Hasui and Masato Abe and Kenji Matsumoto and Mitsuru Shindo",
year = "2012",
month = "10",
day = "15",
doi = "10.1021/tx300315h",
language = "English",
volume = "25",
pages = "2253--2260",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "10",

}

TY - JOUR

T1 - Molecular design, synthesis, and evaluation of novel potent apoptosis inhibitors inspired from bongkrekic acid

AU - Okuda, Katsuhiro

AU - Hasui, Keisuke

AU - Abe, Masato

AU - Matsumoto, Kenji

AU - Shindo, Mitsuru

PY - 2012/10/15

Y1 - 2012/10/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84867522055&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867522055&partnerID=8YFLogxK

U2 - 10.1021/tx300315h

DO - 10.1021/tx300315h

M3 - Article

C2 - 22998163

AN - SCOPUS:84867522055

VL - 25

SP - 2253

EP - 2260

JO - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

SN - 0893-228X

IS - 10

ER -