Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids

• Main Authors: Han, Sunkyu (Contributor), Siegel, Dustin S. (Contributor), Morrison, Karen C. (Author), Hergenrother, Paul J. (Author), Movassaghi, Mohammad (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Chemistry (Contributor)
• Format: Article
• Language: English
• Published: American Chemical Society (ACS), 2015-02-25T16:19:32Z.
• Subjects: Article
• Online Access: Get fulltext

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.
National Institute of General Medical Sciences (U.S.) (GM074825)