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Three new psoralens with methyl groups on carbons involved in their reactive double bonds (compounds 9-11 in Scheme 1) were synthesized from the corresponding 7-hydroxycoumarins by cyclization of acetonyl derivatives of the latter in an alkaline medium. In preliminary tests, the new methyl-substituted psoralens exhibited considerable interaction in the dark with DNA, good photoreactivity against the macromolecule, and also interesting antiproliferative activity.

Arthroplasty with poly(methyl methacrylate) (PMMA) bone cement induces late loosening phenomena that compromise the prosthetic stability. As free radicals are inflammatory mediators and cytotoxic, it seemed useful to investigate whether PMMA induces the liberation of free radicals and/or cytotoxicity. The effect of PMMA interaction on cultured human fibroblasts was accessed by the cell viability test (MTT), and by the measurement of lipoperoxides in the incubation medium. The incubation with the medium exposed to PMMA induced a significant reduction in the viability and a significant increase in lipoperoxide liberation (vs control). These data suggest that PMMA is cytotoxic. This effect seems to be mediated by lipoperoxide and possibly by other free radicals, and may explain the peri-implant loosening phenomena that compromise the prosthetic stability.

The tricyclic structure of known natural photochemotherapeutic drugs such as 8-methoxypsoralen and 5-methoxypsoralen is often taken as a model in the search of new photosensitizer agents with less phototoxic and mutagenic effects. This paper describes the synthesis, characterization, photobinding to DNA, photobiological properties and computational chemistry of some 8-methoxypsoralen derivatives bearing two or three methyl groups at the key positions of the two photoactive double bonds. Results showed that photoreactivity and photobiological behaviour depend on the pattern of methyl substitutions. Antiproliferative activity in cell lines shows good correlation with DNA interaction data.

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.

Four compounds derived from the furocoumarin, benzodipyrone and benzodifuran nucleus respectively, have been synthesized. They have molecular structures analogous to that of tilorone, namely an aromatic tricyclic moiety and two basic chains linked to the nucleus through ester or amido groups. Like tilorone, the new compounds efficiently from complexes with DNA, consisting in an intercalation of the planar aromatic moiety between two base pairs and an electrostatic interaction of the positively charged nitrogen atoms of the side chains with the phosphate groups of the macromolecule. When tested for their capacity to stimulate interferon production in mice, the compounds showed different activities; in particular the diethylamino ethyl ester of bis-benzodifuranic acid (III) proved to be twice as active as tilorone, assayed in the same experimental conditions for comparison purposes.

3-Amino- and 3-oxy-derivatives of psoralen, thus having electron-donating groups at the 3-position of the alpha-pyronic ring, were prepared and studied as regards their capacities of interaction and photoreaction with native DNA in vitro. Very interesting properties were shown especially by the 3-amino-derivatives, namely 3-amino-4'-methylpsoralen and 3-diethylaminoacetylamido-4'-methylpsoralen, having a very high photobinding capacity with DNA and behaving as pure, or fairly pure, monofunctional reagents. These properties appear to be quite suitable for the therapeutic treatment of psoriasis and other skin diseases characterized by an increased reproducing activity of epidermal cells.

The photobiological properties of a number of water-soluble psoralen derivatives have been investigated. The compounds are characterized by the presence of protonated diethylaminoalkyloxy side-chains at position 5 or 8. Thus they are strictly related to the photochemotherapeutic agents 5-MOP and 8-MOP. Inhibition of DNA synthesis by the above compounds has been evaluated in mouse skin in vivo and in Ehrlich ascites tumor cells. In the latter experiments, inhibition of tumor transmitting capacity has been demonstrated by injection of irradiated cells into healthy animals. Finally, skin erythema formation has been studied in albino guinea pigs. The photobiological responses were quite remarkable in all cases. In general, derivatives at position 5 exhibit stronger antiproliferative effects, while the 8 isomers display higher skin phototoxicity.