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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 t...

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Detalles Bibliográficos
Autores principales: Vasilyeva, Aksana, Clodfelter, Jill E., Gorczynski, Michael J., Gerardi, Anthony R., King, S. Bruce, Salsbury, Freddie, Scarpinato, Karin D.
Formato: Texto
Lenguaje:English
Publicado: SAGE-Hindawi Access to Research 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946608/
https://www.ncbi.nlm.nih.gov/pubmed/20936178
http://dx.doi.org/10.4061/2010/162018
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author Vasilyeva, Aksana
Clodfelter, Jill E.
Gorczynski, Michael J.
Gerardi, Anthony R.
King, S. Bruce
Salsbury, Freddie
Scarpinato, Karin D.
author_facet Vasilyeva, Aksana
Clodfelter, Jill E.
Gorczynski, Michael J.
Gerardi, Anthony R.
King, S. Bruce
Salsbury, Freddie
Scarpinato, Karin D.
author_sort Vasilyeva, Aksana
collection PubMed
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.
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spelling pubmed-29466082010-10-08 Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response Vasilyeva, Aksana Clodfelter, Jill E. Gorczynski, Michael J. Gerardi, Anthony R. King, S. Bruce Salsbury, Freddie Scarpinato, Karin D. J Nucleic Acids Research Article 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. SAGE-Hindawi Access to Research 2010-09-13 /pmc/articles/PMC2946608/ /pubmed/20936178 http://dx.doi.org/10.4061/2010/162018 Text en Copyright © 2010 Aksana Vasilyeva et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Vasilyeva, Aksana
Clodfelter, Jill E.
Gorczynski, Michael J.
Gerardi, Anthony R.
King, S. Bruce
Salsbury, Freddie
Scarpinato, Karin D.
Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response
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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946608/
https://www.ncbi.nlm.nih.gov/pubmed/20936178
http://dx.doi.org/10.4061/2010/162018
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