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

• Published in: Journal of organic chemistry Vol. 78; no. 23; pp. 11970 - 11984
• Main Authors: Han, Sunkyu, Siegel, Dustin S, Morrison, Karen C, Hergenrother, Paul J, Movassaghi, Mohammad
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 06.12.2013; Amer Chemical Soc
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HeLa Cells; HL-60 Cells; Humans; Molecular Conformation; Physical Sciences; Science & Technology; Stereoisomerism; Structure-Activity Relationship; U937 Cells; ELECTROORGANIC CHEMISTRY; ORGANIC-SYNTHESIS; ACYLIMINIUM ION; FORMAL SYNTHESIS; COUPLING REACTIONS; ALKYNYLIODONIUM SALTS; RUTHENIUM-CATALYZED OXIDATION; MICROTUBULE DYNAMICS; STEREOCONTROLLED SYNTHESIS; SPONGE AGELAS-DENDROMORPHA
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo4020112

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.