1 research outputs found
Molecular Design, Synthesis, and Evaluation of Novel Potent Apoptosis Inhibitors Inspired from Bongkrekic Acid
Bongkrekic acid (BKA) is an inhibitor of adenine nucleotide
translocase
(ANT). Since inhibition of ANT is connected to the inhibition of cytochrome <i>c</i> 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