Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents
Platinum-based anticancer drugs act therapeutically by forming DNA adducts, but suffer from severe toxicity and resistance problems, which have not been overcome in spite of decades of research. And yet defined chromatin targets have generally not been considered in the drug development process. Her...
| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
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2015
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| Online Access: | https://hdl.handle.net/10356/81033 http://hdl.handle.net/10220/39105 |
| _version_ | 1811684338417270784 |
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| author | Chin, Chee Fei Dröge, Peter Ang, Wee Han Chua, Eugene Yue Dao Davey, Gabriela Elzbieta Davey, Curtis Alexander |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Chin, Chee Fei Dröge, Peter Ang, Wee Han Chua, Eugene Yue Dao Davey, Gabriela Elzbieta Davey, Curtis Alexander |
| author_sort | Chin, Chee Fei |
| collection | NTU |
| description | Platinum-based anticancer drugs act therapeutically by forming DNA adducts, but suffer from severe toxicity and resistance problems, which have not been overcome in spite of decades of research. And yet defined chromatin targets have generally not been considered in the drug development process. Here we designed novel platinum-intercalator species to target a highly deformed DNA site near the nucleosome center. Between two seemingly similar structural isomers, we find a striking difference in DNA site selectivity in vitro, which comes about from stereochemical constraints that limit the reactivity of the trans isomer to special DNA sequence elements while still allowing the cis isomer to efficiently form adducts at internal sites in the nucleosome core. This gives the potential for controlling nucleosome site targeting in vivo, which would engender sensitivity to epigenetic distinctions and in particular cell type/status-dependent differences in nucleosome positioning. Moreover, while both compounds yield very similar DNA-adduct structures and display antitumor cell activity rivalling that of cisplatin, the cis isomer, relative to the trans, has a much more rapid cytotoxic effect and distinct impact on cell function. The novel stereochemical principles for controlling DNA site selectivity we discovered could aid in the design of improved site discriminating agents. |
| first_indexed | 2024-10-01T04:27:02Z |
| format | Journal Article |
| id | ntu-10356/81033 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:27:02Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | ntu-10356/810332023-02-28T16:59:50Z Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents Chin, Chee Fei Dröge, Peter Ang, Wee Han Chua, Eugene Yue Dao Davey, Gabriela Elzbieta Davey, Curtis Alexander School of Biological Sciences Biological Sciences Platinum-based anticancer drugs act therapeutically by forming DNA adducts, but suffer from severe toxicity and resistance problems, which have not been overcome in spite of decades of research. And yet defined chromatin targets have generally not been considered in the drug development process. Here we designed novel platinum-intercalator species to target a highly deformed DNA site near the nucleosome center. Between two seemingly similar structural isomers, we find a striking difference in DNA site selectivity in vitro, which comes about from stereochemical constraints that limit the reactivity of the trans isomer to special DNA sequence elements while still allowing the cis isomer to efficiently form adducts at internal sites in the nucleosome core. This gives the potential for controlling nucleosome site targeting in vivo, which would engender sensitivity to epigenetic distinctions and in particular cell type/status-dependent differences in nucleosome positioning. Moreover, while both compounds yield very similar DNA-adduct structures and display antitumor cell activity rivalling that of cisplatin, the cis isomer, relative to the trans, has a much more rapid cytotoxic effect and distinct impact on cell function. The novel stereochemical principles for controlling DNA site selectivity we discovered could aid in the design of improved site discriminating agents. MOE (Min. of Education, S’pore) MOH (Min. of Health, S’pore) Published version 2015-12-16T08:54:44Z 2019-12-06T14:19:59Z 2015-12-16T08:54:44Z 2019-12-06T14:19:59Z 2015 Journal Article Chua, E. Y. D., Davey, G. E., Chin, C. F., Droge, P., Ang, W. H., & Davey, C. A. (2015). Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents. Nucleic Acids Research, 43(11), 5284-5296. 0305-1048 https://hdl.handle.net/10356/81033 http://hdl.handle.net/10220/39105 10.1093/nar/gkv356 25916851 en Nucleic Acids Research © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 13 p. application/pdf |
| spellingShingle | Biological Sciences Chin, Chee Fei Dröge, Peter Ang, Wee Han Chua, Eugene Yue Dao Davey, Gabriela Elzbieta Davey, Curtis Alexander Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents |
| title | Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents |
| title_full | Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents |
| title_fullStr | Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents |
| title_full_unstemmed | Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents |
| title_short | Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents |
| title_sort | stereochemical control of nucleosome targeting by platinum intercalator antitumor agents |
| topic | Biological Sciences |
| url | https://hdl.handle.net/10356/81033 http://hdl.handle.net/10220/39105 |
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