Synthesis and anticancer activity of all known (-)-agelastatin alkaloids

Sunkyu Han, Dustin S. Siegel, Karen C. Morrison, Paul J. Hergenrother, Mohammad Movassaghi

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)11970-11984
Number of pages15
JournalJournal of Organic Chemistry
Volume78
Issue number23
DOIs
StatePublished - Dec 6 2013

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Alkaloids
Cells
Blood
Imidazoles
Confocal microscopy
Guanidine
Tubulin
Copper
Apoptosis
agelastatin A

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and anticancer activity of all known (-)-agelastatin alkaloids. / Han, Sunkyu; Siegel, Dustin S.; Morrison, Karen C.; Hergenrother, Paul J.; Movassaghi, Mohammad.

In: Journal of Organic Chemistry, Vol. 78, No. 23, 06.12.2013, p. 11970-11984.

Research output: Contribution to journalArticle

Han, Sunkyu ; Siegel, Dustin S. ; Morrison, Karen C. ; Hergenrother, Paul J. ; Movassaghi, Mohammad. / Synthesis and anticancer activity of all known (-)-agelastatin alkaloids. In: Journal of Organic Chemistry. 2013 ; Vol. 78, No. 23. pp. 11970-11984.
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