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. Ou...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2015
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| Online Access: | http://hdl.handle.net/1721.1/95515 https://orcid.org/0000-0003-3080-1063 |
| _version_ | 1826211919009153024 |
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| author | Han, Sunkyu Siegel, Dustin S. Morrison, Karen C. Hergenrother, Paul J. Movassaghi, Mohammad |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Han, Sunkyu Siegel, Dustin S. Morrison, Karen C. Hergenrother, Paul J. Movassaghi, Mohammad |
| author_sort | Han, Sunkyu |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:13:12Z |
| format | Article |
| id | mit-1721.1/95515 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:13:12Z |
| publishDate | 2015 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/955152022-10-02T01:26:08Z Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids Han, Sunkyu Siegel, Dustin S. Morrison, Karen C. Hergenrother, Paul J. Movassaghi, Mohammad Massachusetts Institute of Technology. Department of Chemistry Han, Sunkyu Siegel, Dustin S. Movassaghi, Mohammad 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. National Institute of General Medical Sciences (U.S.) (GM074825) 2015-02-25T16:19:32Z 2015-02-25T16:19:32Z 2013-10 2013-09 Article http://purl.org/eprint/type/JournalArticle 0022-3263 1520-6904 http://hdl.handle.net/1721.1/95515 Han, Sunkyu, Dustin S. Siegel, Karen C. Morrison, Paul J. Hergenrother, and Mohammad Movassaghi. “Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids.” The Journal of Organic Chemistry 78, no. 23 (December 6, 2013): 11970–11984. https://orcid.org/0000-0003-3080-1063 en_US http://dx.doi.org/10.1021/jo4020112 Journal of Organic Chemistry Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Han, Sunkyu Siegel, Dustin S. Morrison, Karen C. Hergenrother, Paul J. Movassaghi, Mohammad Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids |
| title | Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids |
| title_full | Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids |
| title_fullStr | Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids |
| title_full_unstemmed | Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids |
| title_short | Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids |
| title_sort | synthesis and anticancer activity of all known agelastatin alkaloids |
| url | http://hdl.handle.net/1721.1/95515 https://orcid.org/0000-0003-3080-1063 |
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