Photobiological properties of 3-psoralenacetic acids

Some 4,8-dimethyl-3-psoralenacetic acids with different substitutions in the furan ring were synthesized and studied. All the planned psoralenacetic acids bear methyl groups in the 4 and 8 positions of the benzopyrone nucleus and are variousy substituted at the furan ring: compound 1 and 2 bear one or two methyl groups the 4’ and in the 5’ position, respectively; compound 3 presents a bulky tert-butyl in the 4’ position, while compound 4 presents the two positions of the furan ring substituted with a further condensed cyclohexane nucleus. These psoralenacetic acids showed to be a novel class of psoralen derivatives characterized by an interesting photobiological profile. The carboxylic group at the 3 position, useful to confer hydrophilic properties, appeared to be detrimental for the classical intercalation into DNA, because of repulsive interactions with the positive surface of the macromolecule. Nevertheless, the new derivatives possess a notable photoantiproliferative activity, due to a peculiar mechanism of action consisting in a decarboxylation step before exerting their photobiological activity. The most active compound 2 is able to induce a noteworthy photocytotoxic effect, with GI50 values submicromolar on human tumor cell lines, and none effect in the dark. The involvement of DNA photodamage and ROS formation after UVA light-mediated decarboxylation are responsible for its biological activity, as demonstrated comparing the activity profile of the decarboxylated analogue. In conclusion, compound 2 could thus be considered as a prodrug, inactive without UVA light but activated upon specific irradiation, thus preventing unselective side effects, opening new perspective for agents to be employed in PUVA therapy.