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
| Autor: | Paulina Gwarda, Jan Mazerski, Tomasz Laskowski, Zofia Gdaniec, Jakub Grynda, Witold Andrałojć |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular 0301 basic medicine Stereochemistry Intercalation (chemistry) lcsh:Medicine Drug development Antineoplastic Agents Sequence (biology) Molecular dynamics Molecular Dynamics Simulation Ligands 030226 pharmacology & pharmacy Article Adduct 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery Thymine Nucleotides Drug discovery and development Binding site lcsh:Science Nuclear Magnetic Resonance Biomolecular Antitumor activity Binding Sites Multidisciplinary Base Sequence Adenine Nucleotides lcsh:R DNA Triazoles Ligand (biochemistry) Intercalating Agents 030104 developmental biology chemistry Acridine Acridines Nucleic Acid Conformation lcsh:Q Solution-state NMR |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-14 (2020) |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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