Determination of binding modes and binding constants for the complexes of 6H-pyrido[4,3-b]carbazole derivatives with DNA
| Autor: | Akihito Shimazu, Norio Sakai, Haruaki Kurasaki, Nahoko Morii, Takeo Konakahara, Shoichi Takeda, Asako Kato, Masashi Kawagoshi |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Molecular model Stereochemistry Cell Survival Clinical Biochemistry Intercalation (chemistry) Stacking Carbazoles Pharmaceutical Science 010402 general chemistry 01 natural sciences Biochemistry chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery Tumor Cells Cultured Molecule Animals Humans Binding site Molecular Biology Alkyl chemistry.chemical_classification Binding Sites Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Carbazole Organic Chemistry DNA Binding constant 0104 chemical sciences chemistry NIH 3T3 Cells Quartz Crystal Microbalance Techniques Molecular Medicine HeLa Cells |
| Zdroj: | Bioorganicmedicinal chemistry. 25(3) |
| ISSN: | 1464-3391 |
| Popis: | The binding modes and binding constants for the complexes of forty types of pyridocarbazole derivatives 1-40 with double stranded DNAs (dsDNAs) were reported. The binding modes were determined by a combination of a deflection spectroscopy and orientation of the corresponding molecule in the DNA-based film with chain alignment. All of the compounds exhibited the intercalation-binding mode. Its binding constants Ka for the complexes, determined by quartz crystal microbalance (QCM), varied from 1.7×105 to 4.5×107M-1 according to the substituents on the pyridocarbazole framework and the sequences of dsDNA. The binding constants Ka of pyridocarbazole derivatives possessing the 2-(ω-amino)alkyl group and 5-(ω-amino)alkylcarbamyl group were larger than those of the corresponding ω-ureido derivatives. These ω-amino compounds exhibited strong GC base-pair preference in complexation. The Ka values decreased with the increasing NaCl concentration. It was clarified by a molecular modeling that the framework of the 2-tethered ω-amino derivative was completely overlapped with the stacking GC base-pairs leading to the formation of the stable intercalative-complex, and that the framework of the 5-tethered ureido derivative was half overlapped leading to the formation of the unstable complex. Furthermore, there were good linear relationships between lnKa and the relative stabilities Srel of the complexes. Contrary to our expectation, there was no linear relationship between lnKa and IC50 against Sarcoma-180, NIH3T3, and HeLa S-3 cell lines. |
| Databáze: | OpenAIRE |
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