EFFECT OF STRUCTURAL ALTERATIONS ON PHOTOSENSITIZING POTENCY OF FUROCOUMARINS (PSORALENS) AND RELATED COMPOUNDS

[摘要] The investigations reported here are a continuation of earlier work. They were designed to show the chemical structure essential for the initiation of biological photosensitization by furocoumarins (psoralens). The effect of variations in the chemical structure of furocoumarins (e.g., psoralens, isopsoralens, pseudo- psoralens, isopseudopsoralens) and other related compounds upon their photosensitizing potency has been studied. The development of erythema in mammalian skin after topical application of these compounds in various concentrations and irradiation with ultraviolet light (wavelengths 320-420 m[mu]) was used as an index of photosensitizing activity. None of the compounds tested evoked a stronger erythemal response than unsubstituted psoralen. Methyl substitution at positions 4, 8, 4[image] or 5[image] of psoralen did not reduce the photosensitizing potency of the molecule, but methyl substitution at position 3 reduced it significantly. The photosensitizing activity of 4, 5[image], 8-trimethyl-psoralen, which is as potent as psoralen, decreased progressively when the methyl group at position 8 was replaced by N(CH3)2, CN, NH2 or Cl groups. Hydrogenation of the furan ring of psoralen resulted in complete loss of photosensitizing potency. Despite their close similarity to psoralen, furocoumarins derived from hydroquinone or catechol that possess either a linear or angular structure were inactive: e.g., pseudopsoralens (4,5[image]-dimethyl and 4-methyl-5-n-propyl) and isopseudopsoralens (4 or 5[image]-methyl; 4,5[image] and 4,7-dimethyl; 4,5[image], 7-trimethyl, etc.). No erythema was induced by other aromatic, tri-cyclic compounds with linear structure: e.g., benzodifuran, furo-chromones, pyronocoumarins, naphthofurans, and naphtho-[alpha]-pyrones. Several resorcinol derivatives induced very slight erythema. Thus, the ability to sensitize cutaneous tissue to light with wavelengths between 320 and 400 m[mu] is a unique characteristic of the psoralen-ring system. Any structural change other than methyl substitution (e.g., methyl groups at the 4, 4[image], 5[image] and 8 positions) that markedly alters the electronic configuration of the psoralen molecule mitigates or destroys its photosensitizing potency. The mechanisms by which psoralens and ultraviolet light (wavelengths greater than 320 m