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

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.