Semisynthetic studies identify mitochondria poisons from botanical dietary supplements¡ªGeranyloxycoumarins from Aegle marmelos

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• 作者：Jun Li^a ; ^&dagger ; ; Fakhri Mahdi^a ; Lin Du^a ; ^&Dagger ; ; Mika B. Jekabsons^b ; Yu-Dong Zhou^a ; ^{ydzhou@olemiss.edu} ; Dale G. Nagle^a ; ^c ; ^{dnagle@olemiss.edu}
• 关键词：ZEGHXNCKKXBSHJ-BKWQBPKISA-N ; INDTZNYQNROCGV-LQUAAPKLSA-N ; XXIJAXDMARSSBX-KEDDETGJSA-N ; YRFIJMKHSNJANR-RAANRXCMSA-N ; RGIBFXLLLNMYOY-YZLPGLLOSA-N
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 April, 2013
• 年：2013
• 卷：21
• 期：7
• 页码：1795-1803
• 全文大小：434 K

文摘

Bioassay-guided isolation and subsequent structure elucidation of a Bael tree Aegle marmelos lipid extract yielded two unstable acylated geranyloxycoumarin mixtures (1-2), six geranyloxycoumarins (3-8), (+)-9¡ä-isovaleroxylariciresinol (9), and dehydromarmeline (10). In a T47D cell-based reporter assay, 1 and 2 potently inhibited hypoxia-induced HIF-1 activation (IC₅₀ values 0.18 and 1.10 ¦Ìg mL^?1, respectively). Insufficient material and chemical instability prevented full delineation of the fatty acyl side chain olefin substitution patterns in 1 and 2. Therefore, five fatty acyl geranyloxycoumarin ester derivatives (11-15) were prepared from marmin (3) and commercial fatty acyl chlorides by semisynthesis. The unsaturated C-6¡ä linoleic acid ester derivative 14 that was structurally most similar to 1 and 2, inhibited HIF-1 activation with comparable potency (IC₅₀ 0.92 ¦ÌM). The octanoyl (11) and undecanoyl (12) ester derivatives also suppressed HIF-1 activation (IC₅₀ values 3.1 and 0.87 ¦ÌM, respectively). Mechanistic studies revealed that these geranyloxycoumarin derivatives disrupt mitochondrial respiration, primarily at complex I. Thus, these compounds may inhibit HIF-1 activation by suppressing mitochondria-mediated hypoxic signaling. One surprising observation was that, while less potent, the purported cancer chemopreventive agent auraptene (8) was found to act as a mitochondrial poison that disrupts HIF-1 signaling in tumors.