Self-association and unique DNA binding properties of the anti-cancer agent TAS-103, a dual inhibitor of topoisomerases I and II.
The objective of our study was to investigate the self-association and DNA-binding properties of the DNA topoisomerases I (Topo I) and II (Topo II) dual inhibitor: 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinoline-7-one dihydrochloride (TAS-103), by means of 1H-NMR and 31P-NMR spectroscopy, structure computation techniques, thermal melting study, and UV-Visible spectroscopy. In aqueous solution, all chemical shifts of TAS-103 underwent upfield shifts depending with an increase in concentration. The two-dimensional (2D)-NMR spectra and structure computations indicated that TAS-103 self-associated through pi-pi stacking and hydrophobic interactions of the aromatic chromophores. Thermal melting indicated that the binding of TAS-103 to DNA with a potency equal to that of ethidium bromide (EtBr). The UV-Visible spectra of TAS-103 titrated by several DNA exhibited hypochromic and hypsochromic effects. The 31P-NMR spectrum of the 6:1 TAS-103/d(CGCGAATTCGCG)(2) complex showed two broadening signals. 2D-NMR spectra of the 1:1 TAS-103/d(CGCGAATTCGCG)(2) complex indicated that the chemical shift differences of the DNA are very small. However, those of the terminal region are relatively large. The chemical shift differences of TAS-103 showed that the proton resonances except H2 underwent downfield shifts. From these observations, we conclude that TAS-103 binds to DNA by two modes. The major binding mode is on the surface (outside binding) and the minor binding mode by intercalation.
Ishida
Keisuke
K
Chemistry Laboratory, Taiho Pharmaceutical Co., Ltd., 1-27 Misugidai, Hanno, Saitama 357-8527, Japan.
Asao
Tetsuji
T
D000634:Aminoquinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D002417:Cattle; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007192:Indenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007192:Indenes; D009838:Oligodeoxyribonucleotides; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA; C106647:6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one