Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues
Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues
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DOI：
10.1002/chem.201501304
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发表时间：
2015-08-03
影响因子：
4.3
通讯作者：
Shindo, Mitsuru
中科院分区：
文献类型：
--
作者：
Matsumoto, Kenji;Suyama, Masaki;Shindo, Mitsuru
Bongkrekic acid （BKA）是从cocovenenans伯克霍尔德菌中分离出来的一种腺嘌呤核苷酸转运子抑制剂，具有抑制细胞凋亡的作用，是研究细胞凋亡机制的重要工具。采用基于Kocienski-Julia烯化和Suzuki-Miyaura偶联的三组分聚合策略，实现了BKA的高效全合成。值得注意的是，b段被制备为新的双功能化耦合伙伴，这有助于缩短步骤数。与醇酸酯的扭选择性烯化也被应用于不饱和酯的高效构造。结果表明，1-甲基-2-氮杂金刚烷n -氧是最终氧化制备BKA的优良试剂。在全合成的基础上，制备了多个BKA类似物进行构效关系研究，结果表明羧酸部分对BKA的细胞凋亡抑制活性至关重要。更容易获得的BKA类似物也被开发出来，具有有效的细胞凋亡抑制活性。
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 segmentB 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.