Synthesis of 2,2'-Bis(3,6,9-triazanonyl)-4,4'-bithiazole and related compounds as new DNA cleavage agents.
Two new bithiazole derivatives, 2,2'-bis(3,6,9-triazanonyl)- and 2,2'-bis(3,7,11-triazaundecyl)-4,4'-bithiazoles (3a, b), were readily synthesized in six steps using the corresponding dialkylenetriamine as starting materials. Under physiological conditions, 5.0 microM 3a exhibited significant DNA cleavage activity in the presence of Co(II), whereas even at 50 micriM, 3b exhibited no DNA cleavage activity. Furthermore, it was demonstrated that 3a forms a 1 : 2 complex with Co(II) ions, whereas 3b does not. These conclusions were based on measurements of stoichiometries of the bithiazole-cobalt complexes obtained by the Job continuous variation method. In contrast, 3a, which contains diethylenetriamine moieties, showed decreased affinity for Calf Thymus (CT) DNA compared with that of 3b, which contains dipropylenetriamine moieties. These findings indicate that the structure of the two aminoalkyl side chains attached at the 2- and 2'-positions of the 4,4'-bithiazole ring significantly influence the formation of cobalt complexes, and affects the compound's ability to cleave DNA as well as its affinity for double-stranded DNA.
Division of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kobe-Gakuin University, 1-1-3 Minatojima, Chuou-ku, Kobe 650-8586, Japan. sasaki@pharm.kobegakuin.ac.jp
Hideaki
H
Sasaki
D003035:Cobalt / Q000737:chemistry; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D053837:DNA Cleavage / Q000187:drug effects*; D004278:DNA, Superhelical / Q000187:drug effects; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013050:Spectrometry, Fluorescence; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013056:Spectrophotometry, Ultraviolet; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
C526059:2,2'-bis(3,6,9-triazanonyl)-4,4'-bithiazole; D004278:DNA, Superhelical; D007202:Indicators and Reagents; D013844:Thiazoles; D003035:Cobalt; D004247:DNA