Synthesis and photobiological properties of 4,8-dimethyl-5'-carboxypsoralen: a major metabolite of 4,5',8-trimethylpsoralen.
Recently a major metabolite of 4,5',8-trimethylpsoralen (TMeP) (a photochemotherapeutic agent), was isolated from the urine of mice and human volunteers receiving the drug orally; it was identified as 4,8-dimethyl-5'-carboxypsoralen. The synthesis of this compound has been carried out to obtain a distinct confirmation of the structure of the urinary metabolite and to study its photochemical and photobiological properties. The results obtained showed that this interaction and photoreaction with DNA are very poor; this fact can be correlated with the presence of the ionizable carboxylic group that undergoes a repulsion by the phosphate residues of the macromolecule. This hypothesis is confirmed by the higher interaction and photoreaction with DNA of the 4,8-dimethyl-5'-carboxypsoralen methyl ester in which, of course, the ionizable character is no more present. In connection with this very low photoreacting capacity with DNA, the synthesized metabolite proved lacking of photosensitizing effects on human and guinea pig skin. This fact provides an explanation of the very low photosensitizing properties of TMeP when given orally in contrast with the high activity after topical application.
D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D004487:Edema / Q000139:chemically induced; D004890:Erythema / Q000139:chemically induced; D011564:Furocoumarins / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D010777:Photochemistry; D012867:Skin / Q000187:drug effects; D014307:Trioxsalen / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
D011564:Furocoumarins; D004247:DNA; D014307:Trioxsalen