An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells
A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorh...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/21/9/474 |
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| author | Maria Orfanoudaki Emily A. Smith Natasha T. Hill Khalid A. Garman Isaac Brownell Brent R. Copp Tanja Grkovic Curtis J. Henrich |
| author_facet | Maria Orfanoudaki Emily A. Smith Natasha T. Hill Khalid A. Garman Isaac Brownell Brent R. Copp Tanja Grkovic Curtis J. Henrich |
| author_sort | Maria Orfanoudaki |
| collection | DOAJ |
| description | A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorhabdins averaged sub-micromolar potency against the MCC cell lines tested and most of the active compounds showed selectivity towards virus-positive MCC cell lines. An investigation of structure–activity relationships resulted in an expanded understanding of the crucial structural features of the discorhabdin scaffold. Mechanistic cell death assays suggested that discorhabdins, unlike many other MCC-active small molecules, do not induce apoptosis, as shown by the lack of caspase activation, annexin V staining, and response to caspase inhibition. Similarly, discorhabdin treatment failed to increase MCC intracellular calcium and ROS levels. In contrast, the rapid loss of cellular reducing potential and mitochondrial membrane potential suggested that discorhabdins induce mitochondrial dysfunction leading to non-apoptotic cell death. |
| first_indexed | 2024-03-10T22:31:03Z |
| format | Article |
| id | doaj.art-61e47a2f5e1f4a3185a9940ee073d5ee |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-03-10T22:31:03Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-61e47a2f5e1f4a3185a9940ee073d5ee2023-11-19T11:42:06ZengMDPI AGMarine Drugs1660-33972023-08-0121947410.3390/md21090474An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma CellsMaria Orfanoudaki0Emily A. Smith1Natasha T. Hill2Khalid A. Garman3Isaac Brownell4Brent R. Copp5Tanja Grkovic6Curtis J. Henrich7Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USAMolecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USADermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20891, USADermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20891, USADermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20891, USASchool of Chemical Sciences, University of Auckland, Auckland 1142, New ZealandMolecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USAMolecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USAA library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorhabdins averaged sub-micromolar potency against the MCC cell lines tested and most of the active compounds showed selectivity towards virus-positive MCC cell lines. An investigation of structure–activity relationships resulted in an expanded understanding of the crucial structural features of the discorhabdin scaffold. Mechanistic cell death assays suggested that discorhabdins, unlike many other MCC-active small molecules, do not induce apoptosis, as shown by the lack of caspase activation, annexin V staining, and response to caspase inhibition. Similarly, discorhabdin treatment failed to increase MCC intracellular calcium and ROS levels. In contrast, the rapid loss of cellular reducing potential and mitochondrial membrane potential suggested that discorhabdins induce mitochondrial dysfunction leading to non-apoptotic cell death.https://www.mdpi.com/1660-3397/21/9/474Merkel cell carcinomadiscorhabdinstructure–activity relationshipmechanism of action |
| spellingShingle | Maria Orfanoudaki Emily A. Smith Natasha T. Hill Khalid A. Garman Isaac Brownell Brent R. Copp Tanja Grkovic Curtis J. Henrich An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells Marine Drugs Merkel cell carcinoma discorhabdin structure–activity relationship mechanism of action |
| title | An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells |
| title_full | An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells |
| title_fullStr | An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells |
| title_full_unstemmed | An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells |
| title_short | An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells |
| title_sort | investigation of structure activity relationships and cell death mechanisms of the marine alkaloids discorhabdins in merkel cell carcinoma cells |
| topic | Merkel cell carcinoma discorhabdin structure–activity relationship mechanism of action |
| url | https://www.mdpi.com/1660-3397/21/9/474 |
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