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

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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 mu M). (-)-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.
Publisher
AMER CHEMICAL SOC
Issue Date
2013-12
Language
English
Article Type
Article
Keywords

SPONGE AGELAS-DENDROMORPHA; RUTHENIUM-CATALYZED OXIDATION; MARINE SPONGE; COUPLING REACTIONS; THIOL ESTERS; CORAL SEA; STEREOCONTROLLED SYNTHESIS; SIGMATROPIC REARRANGEMENT; ELECTROORGANIC CHEMISTRY; ABSOLUTE-CONFIGURATION

Citation

JOURNAL OF ORGANIC CHEMISTRY, v.78, no.23, pp.11970 - 11984

ISSN
0022-3263
DOI
10.1021/jo4020112
URI
http://hdl.handle.net/10203/201289
Appears in Collection
CH-Journal Papers(저널논문)
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