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

Lugar: CAMBRIDGE; Año: 2018 vol. 16 p. 2170 - 2184

1477-0520

Photodynamic therapy (PDT) is an emerging clinical treatment currently used against a wide range of both cancerous and noncancerous diseases. The search of new active photosensitizers as well as the development of novel selective delivery systems are the major challenges faced by PDT. We investigated herein three chloroharmine derivatives (6-, 8- and 6,8-dichloroharmine) with quite promising intrinsic photochemical tuneable properties and their capability to photoinduce DNA damage in order to elucidate the underlying photochemical mechanisms. Data revealed that the three compounds are quite efficient photosensitizers. Briefly, the overall extent of photo-oxidative DNA damage induced by both 8-chloro-substituted βCs is higher than that induced by 6-chloro-harmine. The predominant type of lesions generated also depends on the position of the chlorine atom in the βC?s ring. Both 8-chloro-substituted βCs mostly oxidize purines via type I mechanism, whereas 6-chloro-harmine mainly behaves as a ?clean? artificial photonuclease inducing single-strand breaks and site of base loss via proton transfer and hydrolytic (HO-) concerted attack. The latter finding represents an exception to the general photosensitizing reactions and, to the best of our knowledge, this is the first time that this process is well documented. The controlled and selective production of different oxygen-independent lesions could be fine-tuned by the relative position of the chlorine atom in the βC 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