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.