5590-29-4Relevant academic research and scientific papers
Determination of binding modes and binding constants for the complexes of 6H-pyrido[4,3-b]carbazole derivatives with DNA
Shimazu, Akihito,Kawagoshi, Masashi,Takeda, Shoichi,Kurasaki, Haruaki,Kato, Asako,Morii, Nahoko,Sakai, Norio,Konakahara, Takeo
, p. 1094 - 1112 (2017)
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 Kafor the complexes, determined by quartz crystal microbalance (QCM), varied from 1.7?×?105to 4.5?×?107?M?1according to the substituents on the pyridocarbazole framework and the sequences of dsDNA. The binding constants Kaof 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 Kavalues 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 ln?Kaand the relative stabilities Srelof the complexes. Contrary to our expectation, there was no linear relationship between ln?Kaand IC50against Sarcoma-180, NIH3T3, and HeLa S-3 cell lines.
Design and synthesis of a peptide derivative of ametantrone targeting the major groove of the d(GGCGCC)2 palindromic sequence
Braud, Emmanuelle,De Franco, Michele,Demange, Luc,Ethève-Quelquejeu, Mélanie,Garbay, Christiane,Gresh, Nohad,Ongaro, Alberto,Ribaudo, Giovanni,Zagotto, Giuseppe
supporting information, p. 3624 - 3631 (2020/03/17)
In oncology, some DNA intercalating agents have been used in chemotherapy for years to eradicate cancer cells, but these drugs generally suffer from a lack of selectivity for malignant tissues and consequently induce major side-effects. We report herein the design and synthesis of an antitumor intercalating agent ametantrone complemented with two identical peptide arms including a central Lys residue in order to selectively target palindromic sequences of DNA of malignant cells. The peptide arms are linked to the ametantrone core through 1,2,3-triazole. According to our docking prediction, this compound should be double-stranded β-sheet structured, and it has been designed to interact with two guanine residues upstream from a central d(CpG)2 intercalation site on each DNA strand, owing to the H-bonds involving the Lys terminal side chain ammonium group of the peptide arms. This new ametantrone derivative has been obtained thanks to a convergent synthetic pathway, whose key steps were double nucleophilic substitution performed on the ametantrone core, followed by "double-site" 1,3-dipolar cycloaddition affording the 1,4-disubstituted triazole linker almost quantitatively. Preliminary binding assays performed by mass spectrometry proved its accuracy for DNA palindromic sequences. The cytotoxicity of this compound was evaluated on three cancer cell lines and one healthy cell line, and compared to that of mitoxantone, a dihydroxylated analog of ametantrone. Such a peptide derivative was about ten-fold less cytotoxic than mitoxantrone on these cancer cell lines, but about fifty times less cytotoxic on healthy cells. This study could open new avenues towards the design of targeted intercalating agents.
