Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids
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Movassaghi_synthesis and.pdf
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Author(s)
Han, Sunkyu
Siegel, Dustin S.
Morrison, Karen C.
Hergenrother, Paul J.
Movassaghi, Mohammad
Date Issued
October 2013
Journal
Journal of Organic Chemistry
Publisher
American Chemical Society (ACS)
Citation
Han, Sunkyu, Dustin S. Siegel, Karen C. Morrison, Paul J. Hergenrother, and Mohammad Movassaghi. “Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids.” The Journal of Organic Chemistry 78, no. 23 (December 6, 2013): 11970–11984.
Version
Author's final manuscript
Abstract
The full details of our enantioselective total syntheses of (−)-agelastatins A–F (1–6), the evolution of a new methodology for synthesis of substituted azaheterocycles, and the first side-by-side evaluation of all known (−)-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 (−)-agelastatins in addition to eight advanced synthetic intermediates enabled a systematic analysis of the structure–activity relationship within the natural series. Significantly, (−)-agelastatin A (1) is highly potent against six blood cancer cell lines (20–190 nM) without affecting normal red blood cells (>333 μM). (−)-Agelastatin A (1) and (−)-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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1021/jo4020112
