4'-Methyl derivatives of 5-MOP and 5-MOA: synthesis, photoreactivity, and photobiological activity.
The synthesis and photobiological activity of four new 4'-methyl derivatives of 5-MOP (5-methoxypsoralen) and 5-MOA (5-methoxyangelicin), i.e., 4,4'-dimethyl-5-methoxypsoralen, 3,4'-dimethyl-5-methoxypsoralen, 4,4'-dimethyl-5-methoxyangelicin, and 3,4'-dimethyl-5-methoxyangelicin, are described. All these compounds photobind efficiently to DNA. The DNA-photobinding process was investigated using various nucleic acid structures such as double-helix DNA, bacterial DNA, and synthetic polydeoxyribonucleotides. Photoreaction experiments showed that, unlike 8-MOP (8-methoxypsoralen) and 5-MOP, both angular derivatives bind thymine and cytosine with the same efficiency. The principal nucleoside-psoralen monoadducts were isolated and characterized after enzymatic digestion or acid hydrolysis. Biological activity studies revealed a good correlation with the extent of covalent photoaddition. Moreover, the two angular derivatives and the 4,4'-dimethyl-5-methoxypsoralen were unable to induce skin erythema, in striking contrast with the reference drugs, 8-MOP and 5-MOP; only the 3,4'-dimethyl-5-methoxypsoralen caused erythema, although to a substantially lower extent than that induced by the two parent compounds.
Centro di Studio sulla Chimica del Farmaco e dei Prodotti Biologicamente Attivi del CNR, Padova, Italy.
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Anselmo
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Conconi
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Antonello
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Uriarte
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Caffieri
D000078223:5-Methoxypsoralen; D000818:Animals; D004247:DNA / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism; D011564:Furocoumarins / Q000737:chemistry*; D006168:Guinea Pigs; D008730:Methoxsalen / Q000031:analogs & derivatives* / Q000737:chemistry; D010100:Oxygen / Q000378:metabolism; D011119:Polynucleotides / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy*; D012867:Skin / Q000187:drug effects
D004269:DNA, Bacterial; D011564:Furocoumarins; D011119:Polynucleotides; C038161:4,4'-dimethylangelicin; D000078223:5-Methoxypsoralen; D004247:DNA; D010100:Oxygen; D008730:Methoxsalen