Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/81033
Title: Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents
Authors: Chin, Chee Fei
Dröge, Peter
Ang, Wee Han
Chua, Eugene Yue Dao
Davey, Gabriela Elzbieta
Davey, Curtis Alexander
Keywords: Biological Sciences
Issue Date: 2015
Source: 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.
Series/Report no.: Nucleic Acids Research
Abstract: 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.
URI: https://hdl.handle.net/10356/81033
http://hdl.handle.net/10220/39105
ISSN: 0305-1048
DOI: 10.1093/nar/gkv356
Rights: © 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
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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