Determination of binding modes and binding constants for the complexes of 6H-pyrido[4,3-b]carbazole derivatives with DNA

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 K-a for the complexes, determined by quartz crystal microbalance (QCM), varied from 1.7 x 10(5) to 4.5 x 10(7) M-1 according to the substituents on the pyridocarbazole framework and the sequences of dsDNA. The binding constants K-a of pyridocarbazole derivatives possessing the 2-(omega-amino)alkyl group and 5-(omega-amino)alkylcarbamyl group were larger than those of the corresponding omega-ureido derivatives. These omega-amino compounds exhibited strong GC base-pair preference in complexation. The K-a values decreased with the increasing NaCl concentration. It was clarified by a molecular modeling that the framework of the 2-tethered omega-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 lnk(a) and the relative stabilities S-rel of the complexes. Contrary to our expectation, there was no linear relationship between Ink(a) and IC50 against Sarcoma-180, NIH3T3, and HeLa S-3 cell lines. (C) 2016 Elsevier Ltd. All rights reserved.