Psoralens: a search for more effective derivatives for photochemotherapeutic regimens.

The objective of our studies under the National Toxicology Program on psoralens was to evaluate a new furocoumarin derivative that would be highly efficacious and yet possess little or no systemic toxicity while also having a short effective biologic half-life. In addition, this work allowed for the development of a test system for compound evaluation of various psoralen derivatives. A guinea pig model was used first, followed by definitive studies in hairless mice for evaluation of the phototoxic potentialities of 32 furocoumarins and 4 benzofuran derivatives. Rank order depends on whether the derivative is administered topically or orally; methyl furocoumarins were the most potent topical photosensitizers, but they were weak when orally administered. On the other hand, aminomethyl derivatives as a group were most potent of all the derivatives when orally administered but were mediocre topical photosensitizers. The standard for these studies, 8-methoxypsoralen (8-MOP), was mediocre in topical and oral regimens. Specific dose-response studies revealed the 5'-aminomethyl-4,4',8-trimethylpsoralen derivative to be six times more potent than 8-MOP. Moreover, the dose-response curve indicated that the response of the 5'-aminomethyl derivative is eliminated three to four times faster than is 8-MOP. No straightforward relationship between molecular structure and photosensitizing power was found. These results underscore the need for oral and topical evaluation of a given test sensitizer as well as for determination of the chemical nature, temporal distribution, and metabolic fate of its photochemically active form.