DNA-interactive anticancer aza-anthrapyrazoles: Biophysical and biochemical studies relevant to the mechanism of action
| Autor: | Sara N. Richter, Stefano Moro, Barbara Gatto, Silvano Spinelli, Franco Zunino, Ernesto Menta, A. P. Krapcho, Manlio Palumbo, Claudia Sissi |
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| Předmět: |
Models
Molecular anticancer agents DNA interaction Aza-Anthrapyrazoles Stereochemistry Clostridium perfringens Intercalation (chemistry) Molecular Sequence Data DNA Footprinting Protonation Anthraquinones Antineoplastic Agents Thymus Gland Micrococcus chemistry.chemical_compound medicine Animals Deoxyribonuclease I Fluorometry Pyrazolones Pharmacology Binding Sites biology Base Sequence Chemistry Topoisomerase DNA Intercalating Agents Cell killing DNA Topoisomerases Type II Mechanism of action Ionic strength DNA Viral biology.protein Nucleic acid Molecular Medicine Pyrazoles Cattle medicine.symptom Mitoxantrone Oxidation-Reduction Plasmids |
| Zdroj: | Scopus-Elsevier |
| Popis: | The physicochemical and DNA-binding properties of anticancer 9-aza-anthrapyrazoles (9-aza-APs) were investigated and compared with the carbocyclic analogs losoxantrone (LX) and mitoxantrone (MX). Unlike their carbocyclic counterparts, the tested 9-aza-APs do not undergo self-aggregation phenomena. The pyridine nitrogen at position 9, missing in the carbocyclic derivatives, is involved in protonation equilibria at physiological pH. In addition, 9-aza-APs are electrochemically reduced at a potential intermediate between LX and MX. These data fully agree with quantum mechanical calculations. Binding to nucleic acids was examined by spectroscopic, chiroptical, and DNase I footprinting techniques as a function of ionic strength and base composition. The 9-aza-APs exhibit prominent affinity for DNA, with an important electrostatic contribution to the binding free energy. A very remarkable sequence preference pattern dramatically favors GC steps in double-helical DNA, whereas the carbocyclic reference compounds show a substantially lower selectivity for GC. A common DNA complexation geometry, considerably differing from that of MX, characterizes all anthrapyrazoles. Hence, bioisosteric substitution and ring-hydroxy deletion play an important role in defining the physicochemical properties and in modulating the affinity of anthrapyrazoles for the nucleic acid, the geometry of the intercalation complex, and the sequence specific contacts along the DNA chain. Drug stimulation of topoisomerase II-mediated DNA cleavage is remarkably attenuated in the aza-bioisosteric derivatives, suggesting that other non-enzyme-mediated cytotoxic mechanism(s), possibly connected with free radical production, are responsible for efficient cell killing. The biophysical and biochemical properties exhibited by 9-aza-APs contribute to clarifying the peculiar pharmacological profile of this family of compounds. |
| Databáze: | OpenAIRE |
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