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Intercalation-enhanced “Click” Crosslinking of DNA


Tera, Masayuki; Harati Taji, Zahra; Luedtke, Nathan W (2018). Intercalation-enhanced “Click” Crosslinking of DNA. Angewandte Chemie, 130(47):15631-15635.

Abstract

DNA–DNA cross‐linking agents constitute an important family of chemotherapeutics that non‐specifically react with endogenous nucleophiles and therefore exhibit undesirable side effects. Here we report a cationic Sondheimer diyne derivative “DiMOC” that exhibits weak, reversible intercalation into duplex DNA (Kd=15 μm) where it undergoes tandem strain‐promoted cross‐linking of azide‐containing DNA to give DNA‐DNA interstrand crosslinks (ICLs) with an exceptionally high apparent rate constant kapp=2.1×105 m−1 s−1. This represents a 21 000‐fold rate enhancement as compared the reaction between DIMOC and 5‐(azidomethyl)‐2′‐deoxyuridine (AmdU) nucleoside. As single agents, 5′‐bispivaloyloxymethyl (POM)‐AmdU and DiMOC exhibited low cytotoxicity, but highly toxic DNA‐DNA ICLs were generated by metabolic incorporation of AmdU groups into cellular DNA, followed by treatment of the cells with DiMOC. These results provide the first examples of intercalation‐enhanced bioorthogonal chemical reactions on DNA, and furthermore, the first strain‐promoted double click (SPDC) reactions inside of living cells.

Abstract

DNA–DNA cross‐linking agents constitute an important family of chemotherapeutics that non‐specifically react with endogenous nucleophiles and therefore exhibit undesirable side effects. Here we report a cationic Sondheimer diyne derivative “DiMOC” that exhibits weak, reversible intercalation into duplex DNA (Kd=15 μm) where it undergoes tandem strain‐promoted cross‐linking of azide‐containing DNA to give DNA‐DNA interstrand crosslinks (ICLs) with an exceptionally high apparent rate constant kapp=2.1×105 m−1 s−1. This represents a 21 000‐fold rate enhancement as compared the reaction between DIMOC and 5‐(azidomethyl)‐2′‐deoxyuridine (AmdU) nucleoside. As single agents, 5′‐bispivaloyloxymethyl (POM)‐AmdU and DiMOC exhibited low cytotoxicity, but highly toxic DNA‐DNA ICLs were generated by metabolic incorporation of AmdU groups into cellular DNA, followed by treatment of the cells with DiMOC. These results provide the first examples of intercalation‐enhanced bioorthogonal chemical reactions on DNA, and furthermore, the first strain‐promoted double click (SPDC) reactions inside of living cells.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Uncontrolled Keywords:General Medicine
Language:English
Date:19 November 2018
Deposited On:07 Mar 2019 07:59
Last Modified:07 Mar 2019 08:12
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1521-3757
OA Status:Closed
Publisher DOI:https://doi.org/10.1002/ange.201808054
Project Information:
  • : FunderSNSF
  • : Grant ID205320_165949
  • : Project TitleLive-cell imaging of DNA conformation and metabolism
  • : FunderDr. Helmut Legerlotz‐Stiftung
  • : Grant ID
  • : Project Title

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