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Biomedical subjects

F Baccichetti

Publications and source records attributed to F Baccichetti.

At least 73 records · Page 4Linked to original sources
PubMed1981

4'-Methylangelicin derivatives: a new group of highly photosensitizing monofunctional furocoumarins.

The photobiological properties of three new angelicin derivatives carrying a methyl-group in 4' position at the furanic ring have been studied. In double-irradiation experiments on E. coli cells, they appeared to behave as monofunctional reactives towards DNA, similarly to the other angelicin derivatives previously studied. In short-term experiments such as the studies on macromolecular synthesis in Ehrlich ascites cells, in which the assay is performed that after irradiation, before DNA repair an intervene significantly, 4'-methylangelicin derivatives produced an inhibition of DNA and RNA synthesis 10 times higher than angelicin, the parent compound, and about 3.5 times higher than 4,5'-dimethylangelicin and psoralen, all assumed as reference compounds. In long-term experiments such as the studies on tumor transmission to healthy mice by injection of sensitized Ehrlich ascites cells, or on the survival of E. coli cells, in which DNA repair is active, 4'-methylangelicin derivatives appeared to be several times more active than angelicin and 4,5'-dimethylangelicin, and sometimes also more active than psoralen, a well-known, effective and cross-linking furocoumarin. While, as already observed, angelicin and 4,5'-dimethylangelicin failed to induce erythema on guinea-pig skin, 4'-methylangelicin derivatives proved to be phototoxic; however in comparison with the cross-linking psoralen, much higher amounts of substance and radiation doses were required. The erythema produced by 4'-methylangelicin derivatives presents some typical features of cross-linking furocoumarins, such as a long latency period and insensitivity to the anti-inflammatory drugs.

Animals↗
PubMed1981

Photoreactive water-soluble derivatives of psoralen.

Photobinding to DNA and cross-linking formation in vitro, as well as the skin photosensitizing activity on guinea pigs of two water-soluble derivatives of psoralen (5 and 8-diethylaminopropyloxypsoralen hydrochloride) have been studied. For purposes of comparison, the results have been correlated with those obtained, in the same experimental conditions, with 5- and 8-methoxypsoralen. The water-soluble 8-derivative showed an increased photoaddition to DNA and cross-linking formation, when compared with 8-methoxy-derivative; on the contrary, the water-soluble 5-derivative was less photoreactive than the corresponding 5-methoxy-derivative. The skin photosensitizing potency of 8-diethylaminopropyloxypsoralen (the more interesting of the two compounds) appears weaker than that of 8-methoxypsoralen after topical application, but higher after oral ingestion or subcutaneous injection.

Animals↗
PubMed1981

Pre-clinical evaluation of new antiproliferative agents for the photochemotherapy of psoriasis: angelicin derivatives.

To have, before the clinical evaluation, sufficiently predictive information about the antiproliferative and phototoxic effect of new potential agents for the photochemotherapy of psoriasis some simple tests have been worked out. The antiproliferative activity was evaluated studying the inhibition of DNA synthesis first in Ehrlich ascites tumor cells, and then in mouse skin in vivo, both by topical application and oral administration. The phototoxicity was studied by topical application on guinea-pig skin, and for the most interesting compounds also in man. A group of angelicin derivatives, which can photoreact with DNA forming only monofunctional adducts, was submitted to this evaluation; a number of such compounds proved to be very active, practically as active as psoralen and 8-methoxypsoralen (8-MOP), two bifunctional furocoumarins capable of inducing both monofunctional adducts and inter-strand cross-links in DNA. Methylangelicins having a marked lipophilic character were only a little more active in inhibiting the epidermal DNA synthesis of mouse when given orally in comparison with topical application, while angelicin derivatives carrying a polar group at the 4' position in the furanic ring were not very active by topical application, but much more effective after systemic administration. These results can be explained supposing a different ability of compounds to penetrate into mouse skin by topical application and the presence of some pharmacokinetic and metabolic factors. Contrary to bifunctional furocoumarins, the angelicin derivatives studied proved to be non-phototoxic on the skin of guinea-pig and also on that of man.

Animals↗
PubMed1981

Photochemotherapy of skin-diseases: comparative studies on the photochemical and photobiological properties of various mono- and bifunctional agents.

The antiproliferative activity of the classic photochemotherapeutic agents, that is bifunctional psoralens (8-methoxypsoralen, 8-MOP; 5-methoxypsoralen, 5-MOP; 4,5',8-trimethylpsoralen, TMP) as well as of those more recently proposed, that is, monofunctional furocoumarins (methylangelicins and 3-carbethoxypsoralen, 3-CPs) is ascribed to their capacity to photo-induce lesions in DNA. In this connection while bifunctional agents photo-induce both mono- and bifunctional (inter-strand cross-linkages) damages in the macromolecule both in vitro and in vivo, monofunctional furocoumarins photodamage DNA only through monofunctional lesions. To have a direct and precise comparison between the classic agents (8-MOP, 5-MOP, TMP) and those recently proposed (4,5'-dimethylangelicin, 4,5'-DMA; 3-CPs), we have made a comparative study of the capacity of the various compounds to form the dark complex with DNA as well as of their capacity to induce mono- and bifunctional damages in the macromolecule. A comparative study on the antiproliferative activity in terms of capacity to inhibit DNA and RNA synthesis in Ehrlich ascites tumor cells as well as of the capacity to inhibit epidermal DNA synthesis in mice is also reported. The emerging picture can give a precise comparison in terms of both photobinding to DNA, as well as antiproliferative and skin-phototoxic activities between the classic agents 8-MOP, 5-MOP, TMP and the new monofunctional agents 4,5'-DMA and 3-CPs.

Chemical Phenomena↗
PubMed1981

A new water soluble derivative of 4,5'-dimethylangelicin as a potential agent for photochemotherapy.

A water soluble derivative of 4,5'-dimethylangelicin (I) having a long chain linking an amino group to the planar furocoumarinic moiety, that is 4'-N,N-dimethylaminoethoxymethyl-4,5'-dimethylangelicin (III), has been prepared. This compound is able to form effectively the intercalated complex with DNA like the previously prepared 4'-aminomethyl-4,5'-dimethylangelicin (II), however while the compound (II) showed very poor photobinding to DNA, the new derivative (III) shows high photobinding to the macromolecule. It is proposed that these data illustrate the importance of the geometry of intercalation for the subsequent covalent photobinding to the macromolecule. Also some photophysical data of (II) and of (III) appear to confirm the critical role of the position assumed by the chromophore of the two compounds when intercalated in duplex DNA. The compound (III) displays high photobiological effects, also in terms of antiproliferative activity as shown by its capacity to inhibit DNA and RNA synthesis in Ehrlich cells, the growth of an E. coli culture and the infectivity of T2 phage. (III) on the basis of these properties seems to deserve a clinical evaluation of its potential photochemotherapeutic activity in the treatment of psoriasis.

Animals↗
PubMed1981

Carbomethoxy-derivatives of psoralen: interactions with DNA and photobiological properties.

The dark and photochemical interactions with DNA in vitro as well as the photobiological properties of two psoralen derivatives having a carbomethoxy-group inserted in 3 or 5' position of the furocoumarin nucleus were studied. 3-Carbomethoxy-4',8-dimethylpsoralen photoreacts with DNA in vitro to a very small extent and, as a consequence, it appears to be photobiologically ineffective. On the contrary, 5'-carbomethoxy-4,8-dimethylpsoralen appears very interesting, showing a photobinding and cross-linking capacity with DNA in vitro higher than that of 8-MOP. A similarly higher photobiological activity was also demonstrated, with respect to this reference compound, in experiments on inhibition of DNA and RNA synthesis in Ehrlich ascites tumor cells, and on the killing of bacteria and of T2 bacteriophage. Finally, this compound inhibited the tumor transmitting capacity of Ehrlich ascites tumor cells.

Animals↗
PubMed1981

Photochemical and photobiological properties of 4,5'-dimethylpsoralen, a bifunctional contaminant of synthetic 4,5'-dimethylangelicin.

4,5'-Dimethylpsoralen, a bifunctional furocoumarin, can be formed as an impurity in the synthesis of its angular isomer, that is 4,5'-dimethylangelicin; the latter has recently been proposed as a potential monofunctional agent for photochemotherapy. To have precise information on the possible modifications of the photochemical and photobiological properties of synthetic 4,5'-dimethylangelicin caused by the presence of its linear isomer, we have studied the interactions of the latter with DNA in both the ground and the excited state and its photobiological activity. 4,5'-Dimethylpsoralen photobinds much more effectively to DNA than its angular isomer and is capable to form effectively inter-strand cross-linkages in DNA while dimethylangelicin is unable to form these bifunctional adducts in DNA. Dimethylpsoralen shows a strong skin-phototoxicity while angelicin lacks this activity. Moreover the antiproliferative activity of the psoralen derivative in terms of DNA synthesis inhibition in Ehrlich cells and of inhibition of infectivity of T2 phages, is about four times higher than that of the angular isomer. These data stress the necessity of the absence of the isomeric linear furocoumarin in the synthetic 4,5'-dimethylangelicin because its presence can markedly modify the photobiological and phototherapeutic properties of the angelicin derivative.

Animals↗
PubMed1980

Antiviral activity of some congeners of tilorone.

The activity of four tilorone analogous compounds against three different strains of E. coli bacteriophages T1, T2 and phiX-174, was studied. Among the compounds we tested, only a fluorene derivative (2,7-bis-2-[2-(diethylamino)acetyl]fluorene) yielded a high inhibition of phage growth, to a greater extent with respect to tilorone, used as a reference compound. This activity, not due to a toxic effect on the host bacteria, did not appear connected with a complex formation between the drug and DNA. In fact, among the studied compounds, this is not the one showing the highest binding parameters with DNA; in addition, when the mature virions were incubated in the presence of the drug and then diluted and assayed for their plaque-forming capacity, this drug turned out to be practically ineffective. Fluorene derivative appears to be an antiviral drug acting on an unidentified metabolic process of phage growth, and therefore it is a model for new antiviral drugs showing a selective activity.

Antiviral Agents↗
PubMed1979

Tryptophan metabolism in animals with dermatitis. I) In Rats.

Tryptophan metabolism "via kynurenine" after load of amino-acid has been studied in urine of rats before and after induction of experimental light-conditioned dermatitis with psoralen. Tryptophan load in animals during the acute phase of dermatitis (one day after induction) causes a markedly increased urinary excretion of total metabolites in comparison with that obtained before dermatitis. After six days of dermatitis, when the skin damage was in repair, the excretory values after tryptophan load in rats are only slightly increased indicating that the metabolic disturbance is correlated with the skin damage.

Animals↗
PubMed1979

Tryptophan metabolism in animals with dermatitis. II) In guinea pigs.

Tryptophan load in guinea pigs after induction of a photodermatitis from psoralen caused marked increase of urinary excretion of total metabolites "via kynurenine" in comparison with that obtained before dermatitis. Xanthurenic acid is the metabolite which showed the most increased levels in urine during dermatitis. This dermatitis from furocoumarin caused an alteration of tryptophan metabolism in guinea pigs as well as rats, but species differences in the excretion of metabolites after amino acid load are observed.

Animals↗
PubMed1979

lambda-Prophage induction by furocoumarin photosensitization.

Furocoumarin photosensitization induces lambda-prophage from lysogenic Escherichia coli cells; this effect is clearly due to the photoreaction that furocoumarins give with DNA, and it appears connected with the formation of monoadducts rather than of diadducts (cross-links).

Coliphages↗
PubMed1979

Diethylaminoalkyloxycoumarin and -furocoumarin derivatives.

Four series of diethylaminoalkoxyderivatives of coumarin (at the positions 4 and 7) and furocoumarin (at the positions 5 and 8) have been prepared, in order to study their complexing capacity with DNA, these compounds having a double possibility of interaction, that is intercalation of the aromatic moiety between two base pairs and formation of an electrostatic bond between their terminal amino group and a phosphoric group of DNA. Some biological effects connected with the interaction with DNA have also been studied. The results obtained showed that coumarin derivatives have a low complexing capacity and lack any biological activity. The furocoumarin derivatives showed a markedly increased complexing capacity both in respect to the coumarin derivatives and to the parent furocoumarin (psoralen, as well as its 5- and 8-methoxy derivatives) and proved able to inhibit DNA and RNA synthesis in Ehrlich ascites tumor cells, as well as the growth of Staphylococcus aureus and of various strains of Escherichia coli. This activity was generally low but was constantly higher in 5-than in 8-derivatives, the same behavior being found with regard to the complexing capacity with DNA. A good correlation between the ability to form complexes with DNA and the capacity to inhibit cells growth was clearly evidenced.

Animals↗
PubMed1979

Interaction between DNA and some congeners of tilorone.

Four compounds having a molecular structure analogous to that of tilorone and tilorone itself, taken as a reference compound, were examined for complex formation ability with DNA. While the association constants of the various complexes were almost the same, the r values in saturation conditions (that is the highest number of molecules bound per nucleotide of DNA) increased with the size of the planar moiety or with the length of the two basic side chains of the molecules. Concerning the structure of the complexes, it was evidenced by means of flow dichroism measurements that the non-covalent binding to DNA occurs via an intercalative mode. Moreover, it was observed that by decreasing the ionic strength, the affinity of the drugs for the macromolecule increases, indicating that in complex formation, electrostatic forces exerted between the DNA phosphate residues and the positively charged nitrogen of the side chains of the drugs are involved. It seems also possible that, in this condition, and in the presence of high concentrations of the drug, a secondary binding consisting only of electrostatic interactions outside of the helix takes place. In connection with the complexing ability with DNA, the examined compounds proved able to inhibit DNA and RNA synthesis in Ehrlich ascites tumor cells. A correlation was found between complexing ability and inhibitory activity on nucleic acid synthesis.

Animals↗