Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response
Mismatch repair proteins modulate the cytotoxicity of several chemotherapeutic agents. We have recently proposed a “death conformation” of the MutS homologous proteins that is distinguishable from their “repair conformation.” This conformation can be induced by a small molecule, reserpine, leading...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2010-01-01
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| Series: | Journal of Nucleic Acids |
| Online Access: | http://dx.doi.org/10.4061/2010/162018 |
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| _version_ | 1849399037258629120 |
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| author | Aksana Vasilyeva Jill E. Clodfelter Michael J. Gorczynski Anthony R. Gerardi S. Bruce King Freddie Salsbury Karin D. Scarpinato |
| author_facet | Aksana Vasilyeva Jill E. Clodfelter Michael J. Gorczynski Anthony R. Gerardi S. Bruce King Freddie Salsbury Karin D. Scarpinato |
| author_sort | Aksana Vasilyeva |
| collection | DOAJ |
| description | Mismatch repair proteins modulate the cytotoxicity of several chemotherapeutic agents. We have recently proposed a “death conformation” of the MutS homologous proteins that is distinguishable from their “repair conformation.” This conformation can be induced by a small molecule, reserpine, leading to DNA-independent cell death. We investigated the parameters for a small reserpine-like molecule that are required to interact with MSH2/MSH6 to induce MSH2/MSH6-dependent cytotoxic response. A multidisciplinary approach involving structural modeling, chemical synthesis, and cell biology analyzed reserpine analogs and modifications. We demonstrate that the parameters controlling the induction of MSH2/MSH6-dependent cytotoxicity for reserpine-analogous molecules reside in the specific requirements for methoxy groups, the size of the molecule, and the orientation of molecules within the protein-binding pocket. Reserpine analog rescinnamine showed improved MSH2-dependent cytotoxicity. These results have important implications for the identification of compounds that require functional MMR proteins to exhibit their full cytotoxicity, which will avoid resistance in MMR-deficient cells. |
| format | Article |
| id | doaj-art-9dcf76a2d46946c4ba5aba5171c200da |
| institution | Kabale University |
| issn | 2090-021X |
| language | English |
| publishDate | 2010-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Nucleic Acids |
| spelling | doaj-art-9dcf76a2d46946c4ba5aba5171c200da2025-08-20T03:38:26ZengWileyJournal of Nucleic Acids2090-021X2010-01-01201010.4061/2010/162018162018Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic ResponseAksana Vasilyeva0Jill E. Clodfelter1Michael J. Gorczynski2Anthony R. Gerardi3S. Bruce King4Freddie Salsbury5Karin D. Scarpinato6Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USADepartment of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USADepartment of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USADepartment of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USADepartment of Physics, Wake Forest University, Winston-Salem, NC 27109, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USAMismatch repair proteins modulate the cytotoxicity of several chemotherapeutic agents. We have recently proposed a “death conformation” of the MutS homologous proteins that is distinguishable from their “repair conformation.” This conformation can be induced by a small molecule, reserpine, leading to DNA-independent cell death. We investigated the parameters for a small reserpine-like molecule that are required to interact with MSH2/MSH6 to induce MSH2/MSH6-dependent cytotoxic response. A multidisciplinary approach involving structural modeling, chemical synthesis, and cell biology analyzed reserpine analogs and modifications. We demonstrate that the parameters controlling the induction of MSH2/MSH6-dependent cytotoxicity for reserpine-analogous molecules reside in the specific requirements for methoxy groups, the size of the molecule, and the orientation of molecules within the protein-binding pocket. Reserpine analog rescinnamine showed improved MSH2-dependent cytotoxicity. These results have important implications for the identification of compounds that require functional MMR proteins to exhibit their full cytotoxicity, which will avoid resistance in MMR-deficient cells.http://dx.doi.org/10.4061/2010/162018 |
| spellingShingle | Aksana Vasilyeva Jill E. Clodfelter Michael J. Gorczynski Anthony R. Gerardi S. Bruce King Freddie Salsbury Karin D. Scarpinato Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response Journal of Nucleic Acids |
| title | Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response |
| title_full | Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response |
| title_fullStr | Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response |
| title_full_unstemmed | Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response |
| title_short | Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response |
| title_sort | parameters of reserpine analogs that induce msh2 msh6 dependent cytotoxic response |
| url | http://dx.doi.org/10.4061/2010/162018 |
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