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 chemical synthesis of furocoumarin isosters at the furan ring, such as pyrrolo-, thieno-, oxazolo- and triazolocoumarins are reported. For all these compounds the key intermediate is a properly functionalized coumarin, to which the third heterocyclic ring is condensed by successive steps. Linear and angular pyrrolo-, tetrahydrobenzo- and benzopyrrolocoumarins show reduced photobiological activity, but have a strong antiproliferative effect in the dark, probably through an interaction with topoisomerases. Oxazolocoumarins are too unstable to be studied; triazolocoumarins 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 photobiological properties which are very similar to those of psoralens. In particular, 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 pyrroloquinolinones involves properly functionalized 7-aminoquinolinones as key intermediate, that of 4-azapsoralen requires a quite different synthetic pathway, involving a properly functionalized benzofuran derivative as key intermediate. Furoquinolinones have dramatically high activity both in the dark and under light activation; 4-azapsoralens have not yet been investigated.
Guiotto
A
A
Department of Pharmaceutical Sciences of the University, Padova, Italy.
Chilin
A
A
Manzini
P
P
Dall'Acqua
F
F
Bordin
F
F
Rodighiero
P
P
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D003864:Depression, Chemical; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D012867:Skin / Q000187:drug effects / Q000378:metabolism
D011564:Furocoumarins; D004247:DNA