title: 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.
authors.affiliation: Institute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Masaki
authors.initials: M
authors.lastname: Suyama
authors.affiliation: Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujita
authors.affiliation: Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Takuya
authors.initials: T
authors.lastname: Moriwaki
authors.affiliation: Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Aso
authors.affiliation: Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Muroshita
authors.affiliation: Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuo
authors.affiliation: Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Keishi
authors.initials: K
authors.lastname: Monda
authors.affiliation: Institute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Okuda
authors.affiliation: Institute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Masato
authors.initials: M
authors.lastname: Abe
authors.affiliation: Institute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fukunaga
authors.affiliation: Institute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan).
authors.forename: Arihiro
authors.initials: A
authors.lastname: Kano
authors.affiliation: Institute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580 (Japan). shindo@cm.kyushu-u.ac.jp.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shindo
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001865:Bongkrekic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D019117:Burkholderia / Q000737:chemistry* / Q000302:isolation & purification; D003497:Cyclic N-Oxides / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C522607:2-azaadamantane N-oxyl; D003497:Cyclic N-Oxides; D001865:Bongkrekic Acid; D000218:Adamantane
keywords: apoptosis; bongkrekic acid; structure-activity relationships; synthesis design; total synthesis