A strong preference for the TA/TA dinucleotide step discovered for an acridine-based, potent antitumor dsDNA intercalator, C-1305: NMR-driven structural and sequence-specificity studies - Publication - Bridge of Knowledge

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A strong preference for the TA/TA dinucleotide step discovered for an acridine-based, potent antitumor dsDNA intercalator, C-1305: NMR-driven structural and sequence-specificity studies

Abstract

Triazoloacridinone C-1305, a potent antitumor agent recommended for Phase I clinical trials, exhibits high activity towards a wide range of experimental colon carcinomas, in many cases associated with complete tumor regression. C-1305 is a well-established dsDNA intercalator, yet no information on its mode of binding into DNA is available to date. Herein, we present the NMR-driven and MD-refined reconstruction of the 3D structures of the d(CGATATCG)2:C-1305 and d(CCCTAGGG)2:C-1305 non-covalent adducts. In both cases, the ligand intercalates at the TA/TA site, forming well-defined dsDNA:drug 1:1 mol/mol complexes. Orientation of the ligand within the binding site was unambiguously established by the DNA/ligand proton-proton NOE contacts. A subsequent, NMR-driven study of the sequence-specificity of C-1305 using a series of DNA duplexes, allowed us to confirm a strong preference towards TA/TA dinucleotide steps, followed by the TG/CA steps. Interestingly, no interaction at all was observed with duplexes containing exclusively the AT/AT, GG/CC and GA/TC steps.

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DOI:
Digital Object Identifier (open in new tab) 10.1038/s41598-020-68609-8
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Category:
Articles
Type:
artykuły w czasopismach
Published in:
Scientific Reports no. 10,
ISSN: 2045-2322
Language:
English
Publication year:
2020
Bibliographic description:
Laskowski T., Andrałojć W., Grynda J., Gwarda P., Mazerski J., Gdaniec Z.: A strong preference for the TA/TA dinucleotide step discovered for an acridine-based, potent antitumor dsDNA intercalator, C-1305: NMR-driven structural and sequence-specificity studies// Scientific Reports -Vol. 10,iss. 1 (2020), s.11697-
DOI:
Digital Object Identifier (open in new tab) 10.1038/s41598-020-68609-8
Sources of funding:
  • Grant NCN 2017/01/X/NZ7/00752
Verified by:
Gdańsk University of Technology

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