SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF FUROCOUMARIN ISOSTERS

Furocoumarins are a group of natural and synthetic compounds, some of which are used for the photochemotherapeutic treatment of certain skin diseases. With the aim of decreasing the side-effects of furocoumarin photochemotherapy and possibly increasing the therapeutic effects of these drugs, some new furocoumarin isosters were synthesized. The chem ical synthesis of furocoumarin isosters at the furan ring, such as pyr rolo-, thieno-, oxazolo- and triazolocoumarins are reported. For all t hese compounds the key intermediate is a properly functionalized couma rin, to which the third heterocyclic ring is condensed by successive s teps. Linear and angular pyrrolo-, tetrahydrobenzo- and benzopyrroloco umarins show reduced photobiological activity, but have a strong antip roliferative effect in the dark, probably through an interaction with topoisomerases. Oxazolocoumarins are too unstable to be studied; triaz olocoumarins show very poor activity. Tienocoumarins have not yet been studied. Furocoumarin isosters at the benzene ring are represented by 8-azapsoralens. Chemical synthesis involves the key 8-azacoumarin in the place of coumarin. These compounds have photochemical and photobio logical properties which are very similar to those of psoralens. In pa rticular, 4,4',5'- is effective in the photochemotherapeutic treatment of psoriasis. Furoquinolinones and 4-azapsoralens are reported among the isosters at the pyrone ring. While the synthesis of pyrroloquinoli nones involves properly functionalized 7-aminoquinolinones as key inte rmediate, that of 4-azapsoralen requires a quite different synthetic p athway, involving a properly functionalized benzofuran derivative as k ey intermediate. Furoquinolinones have dramatically high activity both in the dark and under light activation; 4-azapsoralens have not yet b een investigated.