After irradiation at 3655 A of an aqueous frozen solution containing thymine and psoralen, a new photocompound was isolated by column chromatography. It contains a furocoumarin and a pyrimidinemoiety linked together by the formation of a cyclobutane ring (see formulas I1 and IU). By irradiation at 2537 A in acetic acid solution, the photocompound breaks up again yielding psoralen and thymine. From an aqueous frozen solution containing cytosine and psoralen irradiated at 3655 A, an analogous photocompound was obtained, which, however, consists of the addition to psoralen of a uracil molecule, instead of a cytosine one (IV, V). It has been stated that the hydrolytic deamination of the cytosine moiety to the uracil one takes place during the working up of the photocompound in aqueous solution after irradiation. Substances with properties similar to those above were obtained from bergapten (5-methoxy-psoralen) and thymine, from psoralen and thymidine or thymidylic acid, irradiated at 3655 A.The new substances may be considered as model compounds in explaining the photoreactions which take place between the skin-photosensitizing furocoumarins and DNA upon irradiation at 3655 A.
a b s t r a c tTetanus and botulinum neurotoxins cause paralysis by cleaving SNARE proteins within the cytosol of nerve terminals. They are endocytosed inside acidic vesicles and the pH gradient across the membrane drives the translocation of their metalloprotease L domain in the cytosol. This domain is linked to the rest of the molecule by a single interchain disulfide bridge that has to be reduced on the cytosolic side of the membrane to free its enzymatic activity. By using specific inhibitors of the various cytosolic protein disulfides reducing systems, we show here that the NADPH-thioredoxin reductase-thioredoxin redox system is the main responsible for this disulfide reduction. In addition, we indicate auranofin, as a possible basis for the design of novel inhibitors of these neurotoxins.
The possible presence of methylpsoralens as undesired inquinants in synthetic methylangelicins has been avoided through a synthetic pathway starting from umbelliferones carrying a methyl group in the 6-position. The new 6-methylangelicins show a high affinity toward DNA, forming in the dark a molecular complex; the complexed angelicins under UV-A irradiation photobind effectively to the macromolecule, forming only monoadducts. The new compounds show an evident antiproliferative activity by inhibiting DNA synthesis on Ehrlich cells; great differences, however, can be seen between the various compounds. All the compounds are lacking of skin erythemogenic activity. Some of the new 6-methylangelicins, evaluated in terms of mutagenic activity, demonstrate to be less effective than 8-methoxypsoralen (8-MOP), used for a comparison. On the basis of antiproliferative activity, lack of skin phototoxicity, and low mutagenicity, two compounds have been chosen for clinical evaluation. The compounds tested on seven psoriatic patients by topical application and UV-A irradiation proved to be more effective than 8-MOP, used in the same conditions.
Some benzopsoralens, carrying a hydroxymethyl or a diethylaminomethyl group at the 3, 5, 8, and 11 positions, were prepared, and their biological activity was compared with that of 4-(hydroxymethyl)benzopsoralen (BP). 5-(Hydroxymethyl)benzopsoralen (7b), 11-(hydroxymethyl)benzopsoralen (7c), and 11-(diethylaminomethyl)benzopsoralen (8c) induced marked antiproliferative effects in mammalian cells by simple incubation in the dark; this activity appeared to be related to their ability to inhibit topoisomerase II. Benzopsoralens appeared to be more active, especially BP and 7c, upon UVA activation. Compounds carrying a methyl group at the 4 position together with a hydroxymethyl or diethylaminomethyl at the 8 position (7d and 8d, respectively) were also effective, although to a lower extent; instead, a substituent at the 3 position canceled all activity. Benzopsoralens did not induce interstrand cross-links in DNA in vitro, as seen in the induction of cytoplasmic <> mutations and double-strand breaks in yeast. This behavior is also compatible with their low mutagenic activity in E. coli WP2 and with the absence of any phototoxicity on the skin. For these features, benzopsoralens seem to be interesting potential drugs for PUVA photochemotherapy and photopheresis. The activity shown in the dark is not sufficient for their possible use as antitumor drugs, but it does offer a new model for the study of topoisomerase inhibitors.
The capacity of some linear and angular furocoumarins to induce DNA-protein cross-links by UVA (320-400 nm) irradiation has been evaluated in Chinese hamster ovary cells. Two linear furocoumarins, psoralen and 8-methoxypsoralen appeared to be capable of inducing DNA-protein cross-links to a noticeable extent. 4'-Methylangelicin and 4,4'-dimethylangelicin formed only reduced amounts of DNA-protein cross-links, while angelicin and 4,6,4'-trimethylangelicin seemed to be unable to induce significant levels of this lesion. The biological significance of this damage remains to be elucidated, but it might have an important role in furocoumarin sensitization. In the examined compounds, the capacity for inducing DNA-protein cross-links appears to be a property of the skin phototoxic furocoumarins. This result suggests the hypothesis of a connection between this damage and the formation of skin erythemas.
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