DNA damage photo-induced by chloroharmine isomers: hydrolysis versus oxidation of nucleobases

YAÑUK, JUAN G.; DENOFRIO, M. PAULA; RASSE-SURIANI, FEDERICO A. O.; VILLARRUEL, FERNANDO D.; FASSETTA, FEDERICO; GARCÍA EINSCHLAG, FERNANDO S.; ERRA-BALSELLS, ROSA; EPE, BERND; CABRERIZO, FRANCO M.

ORGANIC & BIOMOLECULAR CHEMISTRY

ROYAL SOC CHEMISTRY

Año: 2018 vol. 16 p. 2170 - 2184

1477-0520

Photodynamic therapy (PDT) is an emerging clinical treatment currently being used against a wide rangeof both cancerous and noncancerous diseases. The search for new active photosensitizers as well as thedevelopment of novel selective delivery systems are the major challenges faced in the application of PDT.We investigated herein three chloroharmine derivatives (6-, 8- and 6,8-dichloroharmines) with quitepromising intrinsic photochemical tunable properties and their ability to photoinduce DNA damage inorder to elucidate the underlying photochemical mechanisms. Data revealed that the three compoundsare quite efficient photosensitizers. The overall extent of photo-oxidative DNA damage induced by both8-chloro-substituted β-carbolines is higher than that induced by 6-chloro-harmine. The predominanttype of lesion generated also depends on the position of the chlorine atom in the β-carboline ring. Both8-chloro-substituted β-carbolines mostly oxidize purines via type I mechanism, whereas 6-chloroharmine mainly behaves as a ?clean? artificial photonuclease inducing single-strand breaks and site ofbase loss via proton transfer and concerted (HO−-mediated) hydrolytic attack. The latter finding represents an exception to the general photosensitizing reactions and, to the best of our knowledge, this isthe first time that this process is well documented. The controlled and selective production of differentoxygen-independent lesions could be fine-tuned by simply changing the substituent groups in theβ-carboline ring. This could be a promising tool for the design and development of novel photo-therapeutic agents aimed to tackle hypoxic conditions shown in certain types of tumours.