Studies on a series of polymethine cyanine dyes and analogs (1-24) show that certain near-infrared cyanines are capable of damaging DNA in the absence of light and external reducing agents. Experimental results imply that in this DNA thermal cleavage, the cyanine reduces Cu(II) to Cu(I) which reacts with O₂ to generate the reactive oxygen species (ROS) O₂^∙- and ∙OH. The formation of these ROS is also thought to be responsible for the irreversible bleaching of the dyes in aqueous solutions. A correlation between structural features and DNA thermal cleavage activity as well as dye bleaching is suggested. Long polymethine chains appear to confer instability to cyanines in aqueous solutions and further contribute to undesired thermal DNA cleavage. These drawbacks can be overcome by introducing an electron-withdrawing group to the polymethine bridge of the cyanine dye.