Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues

Abstract

Bongkrekic acid (BKA), isolated from the bacterium Burkholderia cocovenenans, is an inhibitor of adenine nucleotide translocator, which inhibits apoptosis, and is thus an important tool for the mechanistic investigation of apoptosis. An efficient total synthesis of BKA has been achieved by employing a three-component convergent strategy based on Kocienski-Julia olefination and Suzuki-Miyaura coupling. It is noteworthy that segment B has been prepared as a new doubly functionalized coupling partner, which contributes to shortening of the number of steps. Torquoselective olefination with an ynolate has also been applied for the efficient construction of an unsaturated ester. Furthermore, it is revealed that 1-methyl-2-azaadamantane N-oxyl is an excellent reagent for final oxidation to afford BKA in high yield. Based on the total synthesis, several BKA analogues were prepared for structure-activity relationship studies, which indicated that the carboxylic acid moieties were essential for the apoptosis inhibitory activity of BKA. More easily available BKA analogues with potent apoptosis inhibitory activity were also developed.

A Novel Bongkrekic Acid Analog-Mediated Modulation of the Size of Lipid Droplets: Evidence for the Appearance of Smaller Adipocytes

“…We recently established a total synthesis method for BKA with high purity (>98%). 19) We also reported that chemically synthesized BKA promoted PPARγ transcriptional activity in MCF-7 breast cancer cells. 20) We herein investigated whether BKA, together with its analogs newly synthesized in this study ( Fig.…”

“…1) were synthesized using established methods. 19,21) The purities of these compounds were found to be >98% by HPLC or column chromatography. PIO and dexamethazone (DEX) were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan) (purity: 98%, HPLC).…”

Bongkrekic Acid as a Warburg Effect Modulator in Long-term Estradiol-deprived MCF-7 Breast Cancer Cells

“…BKA and BKA derivatives (BKA-2 and BKA-3) were synthesized according to established methods (18,19). BKA-1' and BKA-4 were newly synthesized according to previously described methods (18,19). The purities of these compounds were found to be >98% by high-performance liquid chromatography (HPLC) and column chromatography.…”

“…BKA may be obtained from commercial sources; however, its purity is generally low (approximately 90-95%). We originally established synthetic methods for BKA with high purity (>98%) (18). In the present study, we investigated whether BKA negatively affects the viability of LTED cells by comparing its effects on other breast cancer cell lines, namely, MCF-7 cells (i.e., the parental cells of LTED cells) and MDA-MB-231 cells.…”

Current Applications of Suzuki–Miyaura Coupling Reaction in The Total Synthesis of Natural Products: An update

“…Removal of the highly acidic proton on C23 in 405 may result in an allene or alkyne. On the other hand, coupling with 404 as segment of A successfully gave the desired product 405 , containing entire BKA scaffold, in excellent yield (Scheme ) …”