Furoquinazolines as furocoumarin analogs: can we improve solubility without impairing biological activity?

Furocoumarins are well known photodynamic agents able to intercalate into DNA and to further react with the pyrimidine DNA bases under UVA irradiation, thereby blocking DNA processing and functions. Hence, psoralens (linear furocoumarins), such as 8-methoxypsoralen (8-MOP) or 5-methoxypsoralen (5-MOP), are commonly used in the photochemotherapy of psoriasis and related skin diseases. The ability of psoralens to form diadducts with DNA bases gives rise to crosslinking between DNA chains. For this reason the photochemotherapy with psoralens has some side effects such as skin phototoxicity and risk of skin cancer. In contrast to psoralens, angelicins (linear furocoumarins) generally show lower mutagenic activity. In order to reduce toxic effects of parent compounds, many isomers and/or isosters have been studied, but they all suffer from solubility problems in aqueous media, thus limiting in vitro studies and future therapeutic applications. To investigate if the solubility could be improved without affecting the reactivity of the parent compound toward DNA, new furoquinazoline compounds have been designed. The furoquinazoline nucleus maintains two key features of furocoumarins: a tricyclic planar system, required for DNA intercalation, and a non aromatic double bond, which could undergo photocycloaddition with DNA bases. The title compounds have been synthesized condensing the furan ring on the N-protected aminophenol, then cyclizing the quinazoline moiety with HTMA/K3Fe(CN)6 method. Both angular and linear isomers have been obtained from the same aminobenzofuran intermediate, thus they have been separated by flash-chromatography. To detect the kind of damage induced by these new compounds, linear flow dichroism measurements and DNA-photobinding studies have been performed. Moreover, reactive oxygen species formation and photooxidation of lipids and proteins were studied to determine the mechanism underlying phototoxicity demonstrated in Jurkat and NCTC-2544 cell lines specially by the linear derivative.