Synthesis and Anticancer Activity of All Known (鈭?-Agelastatin Alkaloids

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• 作者：Sunkyu Han ; Dustin S. Siegel ; Karen C. Morrison ; Paul J. Hergenrother ; Mohammad Movassaghi
• 刊名：Journal of Organic Chemistry
• 出版年：2013
• 出版时间：December 6, 2013
• 年：2013
• 卷：78
• 期：23
• 页码：11970-11984
• 全文大小：743K
• 年卷期：v.78,no.23(December 6, 2013)
• ISSN：1520-6904

文摘

The full details of our enantioselective total syntheses of (鈭?-agelastatins A鈥揊 (1鈥?b>6), the evolution of a new methodology for synthesis of substituted azaheterocycles, and the first side-by-side evaluation of all known (鈭?-agelastatin alkaloids against nine human cancer cell lines are described. Our concise synthesis of these alkaloids exploits the intrinsic chemistry of plausible biosynthetic precursors and capitalizes on a late-stage synthesis of the C-ring. The critical copper-mediated cross-coupling reaction was expanded to include guanidine-based systems, offering a versatile preparation of substituted imidazoles. The direct comparison of the anticancer activity of all naturally occurring (鈭?-agelastatins in addition to eight advanced synthetic intermediates enabled a systematic analysis of the structure鈥揳ctivity relationship within the natural series. Significantly, (鈭?-agelastatin A (1) is highly potent against six blood cancer cell lines (20鈥?90 nM) without affecting normal red blood cells (>333 渭M). (鈭?-Agelastatin A (1) and (鈭?-agelastatin D (4), the two most potent members of this family, induce dose-dependent apoptosis and arrest cells in the G2/M-phase of the cell cycle; however, using confocal microscopy, we have determined that neither alkaloid affects tubulin dynamics within cells.