4'-METHYL DERIVATIVES OF 5-MOP AND 5-MOA - SYNTHESIS, PHOTOREACTIVITY, AND PHOTOBIOLOGICAL ACTIVITY

The synthesis and photobiological activity of four new 4'-methyl deriv atives 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 poly deoxyribonucleotides. Photoreaction experiments showed that, unlike 8- MOP (8-methoxypsoralen) and 5-MOP, both angular derivatives bind thymi ne and cytosine with the same efficiency. The principal nucleoside-pso ralen monoadducts were isolated and characterized after enzymatic dige stion or acid hydrolysis. Biological activity studies revealed a good correlation with the extent of covalent photoaddition. Moreover, the t wo angular derivatives and the 4,4'-dimethyl-5-methoxypsoralen were un able to induce skin erythema, in striking contrast with the reference drugs, 8-MOP and 5-MOP; only the 3,4'-dimethyl-5-methoxypsoralen cause d erythema, although to a substantially lower extent than that induced by the two parent compounds.