天然有機化合物討論会講演要旨集
Online ISSN : 2433-1856
第59回天然有機化合物討論会実行委員会
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14 栄養飢餓環境選択的がん細胞増殖阻害活性物質biakamide類の合成研究と作用機序解析 (口頭発表の部)
*石田 良典松本 紘和一井 さやか荒井 雅吉小林 資正古徳 直之
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会議録・要旨集 オープンアクセス

p. 79-84

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The microenvironment in tumor is suffered from limited supply of oxygen and nutrients. Some cancer cells such as pancreatic cancer are known to adapt these severe conditions and grow, together with acquiring resistance to cancer chemotherapy and irradiation. Therefore, selective growth inhibitors against cancer cells under nutrient-starved conditions have the potential to be anticancer drugs with novel mode of action, and to be chemical tools for elucidating the adaptation mechanism to the conditions. Recently, we isolated novel polyketides named biakamides A-D (1-4) as selective growth inhibitors against human pancreatic cancer PANC-1 cells under glucose-deprived conditions. In this work, total synthesis, structure-activity relationship (SAR) study, and mechanistic analysis of biakamides were executed. The planer structures of biakamides were elucidated by the detailed analyses of NMR spectra, and the stereostructure at C-23 of biakamide A, B was determined by modified Mosher method. Then, total syntheses of all stereoisomers at C-4 and C-6 of biakamides were executed, to determine the stereostructures of the natural product. Compare analyses of NMR/CD spectra and specific rotations of the synthetic isomers with those of natural products showed that the absolute stereochemistries of all biakamides are (4R, 6S). Next we explored the SAR of biakamides to develop easily accessible analogs, and to know the participation of the substructure to their activity against PANC-1 cells under glucose-deprived conditions. We found that dedimethyl biakamide C analog (9), which is easily accessible, possessed the comparable growth inhibitory activity under glucose-deprived condition to natural biakamide C. Then, we investigated the detailed SAR study using various analogs based on compound 9 as a scaffold. It revealed that the terminal acyl chain is important for interacting with target molecule, and structural modification of the amide part including thiazole is acceptable. On the contrary, whole structure of biakamide is necessary for exhibiting its activity. Finally, we tried to analyze the action mechanism of biakamides. Biakamide C reduced expression level of GRP78 and phosphorylation level of Akt (473Ser), known marker proteins of cancer cells adapted to nutrient-starved conditions. Besides, biakamide C selectively inhibited mitochondrial respiratory complex I. So, we designed and synthesized a probe 13, having a diazirine moiety and an alkyne moiety, to confirm the intracellular localization of biakamides. Fluorescence imaging study using photoaffinity labeling and click chemistry revealed that the probe 13 was selectively accumulated at mitochondria in PANC-1 cells. So, we concluded that the growth inhibitory activity of biakamides was caused by the inhibition of mitochondrial respiratory complex I.

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