1H-[1,2,4]Triazolo[4,3-a]pyridin-4-ium and 3H-[1,2,4]triazolo[4,3-a]quinolin-10-ium derivatives as new intercalating agents for DNA

Two new cationic DNA intercalators, 3-phenyl-1-(6-phenylpyridin-2-yl)-1H-[1,2,4]triazolo[4,3-a]pyridin-4-ium (1a)(+) and 1-phenyl-3-(6-phenylpyridin-2-yl)-3H-[1,2,4]triazolo[4,3-a]quinolin-10-ium (1b)(+), were synthesized from 2-chloropyridine and 2-chloroquinoline, respectively, in a four-step procedure. Generation of the hydrazine, followed by condensation with an aldehyde to give a hydrazone and subsequent Buchwald-Hartwig amination gave a mixture of E- and Z-configured N,N-functionalized hydrazones. Finally, oxidative cyclisation gave rise to the formation of the cationic DNA intercalators, whose molecular structures were determined by single-crystal X-ray diffraction analysis of the hexafluorophosphate and tribromide salt of (1a)(+) and (1b)(+), respectively. The intercalative binding of (1a)PF6 and (1b)PF6 to ctDNA was confirmed by means of UV, CD and luminescence spectroscopy, determination of the DNA melting temperature and by rheology measurements.