n →π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines
Copyright © 2020 American Chemical Society. Epithiodiketopiperazines (ETPs) are a structurally complex class of fungal natural products with potent anticancer activity. In ETPs, the diketopiperazine ring is spanned by a disulfide bond that is constrained in a high-energy eclipsed conformation. We em...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Chemical Society (ACS)
2021
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| Online Access: | https://hdl.handle.net/1721.1/136169 |
| _version_ | 1811077303605657600 |
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| author | Kilgore, Henry R Olsson, Chase R D’Angelo, Kyan A Movassaghi, Mohammad Raines, Ronald T |
| author_facet | Kilgore, Henry R Olsson, Chase R D’Angelo, Kyan A Movassaghi, Mohammad Raines, Ronald T |
| author_sort | Kilgore, Henry R |
| collection | MIT |
| description | Copyright © 2020 American Chemical Society. Epithiodiketopiperazines (ETPs) are a structurally complex class of fungal natural products with potent anticancer activity. In ETPs, the diketopiperazine ring is spanned by a disulfide bond that is constrained in a high-energy eclipsed conformation. We employed computational, synthetic, and spectroscopic methods to investigate the physicochemical attributes of this atypical disulfide bond. We find that the disulfide bond is stabilized by two n→π∗ interactions, each with large energies (3-5 kcal/mol). The n→π∗ interactions in ETPs make disulfide reduction much more difficult, endowing stability in physiological environments in a manner that could impact their biological activity. These data reveal a previously unappreciated means to stabilize a disulfide bond and highlight the utility of the n→π∗ interaction in molecular design. |
| first_indexed | 2024-09-23T10:40:49Z |
| format | Article |
| id | mit-1721.1/136169 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:40:49Z |
| publishDate | 2021 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1361692021-10-28T04:28:06Z n →π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines Kilgore, Henry R Olsson, Chase R D’Angelo, Kyan A Movassaghi, Mohammad Raines, Ronald T Copyright © 2020 American Chemical Society. Epithiodiketopiperazines (ETPs) are a structurally complex class of fungal natural products with potent anticancer activity. In ETPs, the diketopiperazine ring is spanned by a disulfide bond that is constrained in a high-energy eclipsed conformation. We employed computational, synthetic, and spectroscopic methods to investigate the physicochemical attributes of this atypical disulfide bond. We find that the disulfide bond is stabilized by two n→π∗ interactions, each with large energies (3-5 kcal/mol). The n→π∗ interactions in ETPs make disulfide reduction much more difficult, endowing stability in physiological environments in a manner that could impact their biological activity. These data reveal a previously unappreciated means to stabilize a disulfide bond and highlight the utility of the n→π∗ interaction in molecular design. 2021-10-27T20:31:14Z 2021-10-27T20:31:14Z 2020 2021-09-09T15:10:04Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/136169 en 10.1021/JACS.0C06477 Journal of the American Chemical Society Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Kilgore, Henry R Olsson, Chase R D’Angelo, Kyan A Movassaghi, Mohammad Raines, Ronald T n →π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines |
| title | n →π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines |
| title_full | n →π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines |
| title_fullStr | n →π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines |
| title_full_unstemmed | n →π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines |
| title_short | n →π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines |
| title_sort | n π interactions modulate the disulfide reduction potential of epidithiodiketopiperazines |
| url | https://hdl.handle.net/1721.1/136169 |
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