The biological activity of some benzopsoralen derivatives, prepared with the aim of obtaining new drugs for photochemotherapy, has been studied. The more interesting compounds are 4-hydroxymethyl-4',5'-benzopsoralen and 4-hydroxymethyl-4',5'-tetrahydro-benzopsoralen, which were found to be active in the dark also: DNA and RNA synthesis were both inhibited in Ehrlich cells, even if in a partially reversible fashion, while protein synthesis remained unaffected. In Chinese hamster ovary cells cultured in vitro, the clonal growth was strongly inhibited by incubation in the dark with both drugs, while a number of chromosomal aberrations was observed in the fraction of growing cells. Using alkaline elution, DNA strand breaks were detected. In addition, in the presence of aphidicolin, a specific inhibitor of DNA polymerase, the clonal growing capacity was completely restored; in contrast, the number of DNA strand breaks remained unchanged. All these results suggest that DNA topoisomerases are probably the target of these two benzopsoralens. These compounds are also good sensitizers; by UV-A irradiation they have a good capacity to produce singlet oxygen, but they appeared to be unable to induce erythemas on guinea-pig skin. Under UV-A light, they induced a strong inhibition of DNA synthesis in Ehrlich cells. Thus, benzopsoralens appear to be capable of inducing strong antiproliferative effects by two different mechanisms, by UV-A irradiation and in the dark.
The effect of certain chemicals known as singlet oxygen quenchers on the photoreaction between 8‐MOP and DNA has been studied in vitro; sodium azide, l,4‐diazabicyclo‐(2,2,2)‐octane, p‐carotene and dimethylsolfoxide (used as a solvent) appeared to be capable of reducing significantly the 8‐MOP ability to induce both monoadducts and cross‐links in DNA. Therefore, these chemicals seem to be not useful in studying the singlet oxygen implication in the induction of biological effects of 8‐MOP sensitization.
The furocoumarin derivative 3,4'-dimethyl-8-methoxypsoralen (DMe-8-MOP) exhibits remarkable antiproliferative activity, but is devoid of skin phototoxicity. To gain insight into this peculiar behaviour we investigated non-covalent and covalent binding of DMe-8-MOP to calf thymus DNA, along with DNA-synthesis inhibition and mutagenic activity. The non-covalent interaction of DMe-8-MOP with the nucleic acid is quite poor as shown by equilibrium dialysis, spectroscopic, chiroptical and hydrodynamic techniques. However, it exhibits relevant photobinding ability to DNA using both isolated nucleic acid samples and cellular systems. Unlike the large majority of congeners, DMe-8-MOP undergoes predominantly photochemical monoaddition to the double helical polynucleotide. Upon examination of the products obtained by enzymatic hydrolysis of DMe-8-MOP photomodified DNA, the formation of an unusual furan side adduct is proposed, which could account for the peculiar photochemical and photobiological properties of the 3,4'-dimethyl furocoumarin derivative.
With the aim of studying the biosynthesis of psoralen and bergapten, two furocoumarins present in the leaves of “Ficus carica” (Moraceae), the Authors, continuing preceding researchs on this topic, have fed the leaves with the following labelled precursors: 4′,5′-dihydropsoralen, 4′,5′-dihydrobergapten, 7-hydroxycoumarin, 5,7-dihydroxycoumarin and 5-methoxy-7-hydroxycoumarin.The results obtained indicate that all these substances are certain biogenetic precursors for psoralen and bergapten.On the basis of the results obtained the biosynthetic pathway of furocoumarins seems to involve first of all the formation of a coumarinic derivative 7-hydroxylated, then an isoprenylation reaction which leads to the formation of the hydrogenated furan ring, finally dehydrogenation of the 4′,5′-dihydrofurocoumarins to psoralen and bergapten.
The Authors have studied the biosynthesis of some furocoumarins contained in Ruta graveolens. Labeled 5,7- and 7,8-dihydroxycoumarins have been administered to the herb, however practically no incorporation of radioactivity was observed in the isolated furocoumarins. Moreover, with the aim to study in a more detailed way the role of rutaretin and marmesin, trapping experiments have been performed administering to the herb labeled umbelliferone together with unlabeled rutaretin and marmesin respectively. A very effective incorporation was observed into marmesin, in lesser extent into rutaretin.In trapping experiments carried out using labeled rutaretin together with unlabeled marmesin and “vice versa”, the results obtained clearly show that while marmesin was converted into rutaretin in a very effective way, rutaretin was transformed into marmesin only in a smaller extent.The Authors suggest the biogenetic origin of rutaretin and moreover formulate a new and more detailed aspect of the scheme for the biosynthetic pathway of furocoumarins in Ruta graveolens.
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