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Biomedical subjects

A Guiotto

Publications and source records attributed to A Guiotto.

At least 55 records · Page 3Linked to original sources
PubMed1984

6-Methylangelicins: a new series of potential photochemotherapeutic agents for the treatment of psoriasis.

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.

Animals↗
PubMed1984

Chemical basis of the photosensitizing activity of angelicins.

Angelicins are a group of compounds that show marked photobiologic activity on various substrates; some of them have been proposed as potential agents for the photochemotherapy of skin diseases. A good correlation exists between the photosensitizing activity of these compounds and their capacity to induce monofunctional lesions to DNA; therefore, we believe the chemical nature of these photolesions, we isolated from the products of hydrolysis of the photocombinations between 5 angelicins (angelicin, 4-methyl, 5-methyl, 5'-methyl, and 5,5'-dimethylangelicin) and DNA, the corresponding new fluorescent monoadducts between the 4',5'-double bond of the furocoumarins and the 5,6-double bond of thymine.

Animals↗
PubMed1983

4'-Methylangelicins: new potential agents for the photochemotherapy of psoriasis.

Three derivatives of angelicin (1) [4'-methyl-, 4,4'-dimethyl-, and 4',5-dimethylangelicin (2a-c)] have been prepared with the aim of obtaining new agents for the photochemotherapy of psoriasis. These compounds form a complex in the dark with DNA that shows an affinity for the macromolecule higher than that of the parent angelicin (1). A correlation between their octanol/water partition coefficients and the association constants of the complexes has been observed. Compounds 2a-c photobind to DNA to a much higher extent than 1 and also more effectively than 8-methoxypsoralen (8-MOP), taken as reference compound. When activated with UV-A, the three compounds strongly inactivate T2 phage and inhibit epidermal DNA synthesis in mice. Moreover, they show a mutagenic activity markedly lower than that of 8-methoxypsoralen on Escherichia coli wild-type strain. Due to its lack of skin phototoxicity, its low mutagenic activity, and its antiproliferative activity, 2c was chosen for clinical evaluation. It proved to be effective in clearing psoriasis in two patients.

Animals↗
PubMed1983

A study of the relationship between photosensitizing and therapeutic activity of 4,5',8-trimethylpsoralen, and its major metabolite 4,8-dimethyl, 5'-carboxypsoralen.

The molecular basis for the clinically observed differences in the skin photosensitizing activity and therapeutic effectiveness of the topically applied and orally administered drug trimethylpsoralen (TMP) was investigated. TMP, when tested topically, is a very potent photosensitizing and therapeutically effective furocoumarin in the treatment of psoriasis. When administered orally, however, it is significantly less photosensitizing and therapeutically a less effective drug than the commonly used furocoumarin 8-methoxypsoralen. This decreased reactivity of oral TMP is attributable to its poor solubility and rapid in vivo metabolic transformation to several inactive (nonphotosensitizing) metabolites, one of which is referred to as 4,8-dimethyl,5'-carboxypsoralen (DMeCP). The supporting evidence has been obtained by: (a) isolation of the urinary metabolite DMeCP and subsequent comparison of its properties with the synthetically prepared DMeCP and its methyl ester; (b) examining the dark and photochemical interactions of TMP, DMeCP, and DMeCP methyl ester with DNA and determining their ability to form interstrand cross-links with DNA; and (c) studying the inhibition of DNA and RNA synthesis in Ehrlich ascites tumor cells and the killing of bacteria and T2 bacteriophages. The structure-activity relationship of TMP and DMeCP also has been examined in normal human subjects and in patients with psoriasis. The order of topical therapeutic effectiveness in terms of ability to clear psoriasis plaques appeared to be: TMP greater than 8-MOP greater than DMeCP methyl ester greater than DMeCP. The data also suggest the methyl ester of DMeCP to be an interesting nonphotosensitizing furocoumarin that photoconjugates to DNA better than 8-MOP and is therapeutically effective in psoriasis.

Animals↗
PubMed1983

7-Methyl and 4,7-dimethylallopsoralen: monofunctional photoreagents toward DNA as potential photochemotherapeutic agents in hyperproliferative conditions.

7-Methyl- (1 a) and 4,7-dimethylallopsoralen (1 b), prepared about ten years ago and till now considered non-photosensitizing agents, have been re-investigated for studying their photochemical and photobiological properties. They form a molecular complex with DNA in the ground state, undergoing intercalation between two base pairs of the macromolecule. By successive irradiation with U.V.-A they covalently photobind to DNA inducing only the formation of mono-adducts. They are not able to induce erythema on guinea pig skin, but show evident antiproliferative activity on various biological substrates. Compound (1 b) shows both photochemical and photobiological properties at a degree higher than that of compound (1 a).

Animals↗
PubMed1981

Receptor sites in DNA for the dark and photochemical interactions with 4,5'-dimethylangelicin, a potential agent for the photochemotherapy.

The study of the interactions in the ground state between 4,5'-dimethylangelicin, an angular furocoumarin, and various synthetic and natural DNA samples have evidenced the presence in the macromolecule of preferred sequences suitable for binding the small ligand. They are represented by an alternate sequence of purine and pyrimidine bases in each strand of the macromolecule, without difference between the two base pairs A-T and C-G. The study of the photochemical interactions between the same DNA samples and the 4,5'-dimethylangelicin shows that preferred sites are present in the macromolecule for the covalent addition of the furocoumarin to the macromolecule too. These sites however have more strict requirements than those useful for dark binding; they are in fact represented by alternate sequences of A-T in each strand such as those present in poly [d(A-T)] . poly-[d(A-T)]. Moreover fluorescence studies made on the same DNA samples irradiated in the presence of the furocoumarin suggest that the alternate C-G regions favour formation of 4'-5'-fluorescent adducts.

Base Composition↗
PubMed1981

New monofunctional reagents for DNA as possible agents for the photochemotherapy of psoriasis: derivatives of 4,5'-dimethylangelicin.

With the aim of obtaining new agents for the photochemotherapy of psoriasis, we have prepared monofunctional reagents for DNA by starting from 4,5'-dimethylangelicin (2), an angular furocoumarin, and introducing in a 4'-(hydroxymethyl) (3), 4'-(methoxymethyl) (4), or 4'-(aminomethyl) group (5), in way analogous to what other authors have done previously on trioxsalen, a DNA bifunctional reagent. These new compounds form complexes with DNA in the ground state and by successive irradiation (UV-A) undergo monofunctional photoaddition to the macromolecule. Photobinding to DNA was highest for 3 and gradually lower for 4 and 5, respectively. These compounds do not form interstrand photocross-linkages in DNA and do not show any skin phototoxicity. Fluorimetric studies show that their 4',5' double bond is involved in the photoaddition to DNA. Their photobiological activity evaluated on Ehrlich ascites tumor cells and on T2 phages was strictly connected with their photobinding to DNA. The effect of the introduction of hydroxymethyl and methoxymethyl groups in angular 2 is somewhat similar to that previously described for trioxsalen: the introduction of an aminomethyl group in 2 markedly increases the affinity in the dark for DNA but under UV-A irradiation strongly inhibits photobinding to the macromolecule. By contrast, in the analogous derivative of trioxsalen both the affinity for DNA in the dark and the photobinding to DNA increased.

Animals↗
PubMed1981

Methylangelicins: new potential agents for the photochemotherapy of psoriasis. Structure-activity study on the dark and photochemical interactions with DNA.

The interactions both in the ground and in the excited state between various methylangelicins, previously prepared with the aim to increase the low photobiological activity of the parent angelicin 1, and DNA have been studied. In general, the new methylangelicins show an increased capacity to photobind monofunctionally to DNA and a parallel increment of photobiological activity in comparison with the parent 1. This increase appears to be connected with various factors, such as the augmented affinity toward DNA for the dark complex formation and the electronic effect connected with the introduction into 1 of one or two methyl groups. The new compounds, on the basis of their photobiological activity and their lack of skin phototoxicity, appear as possible agents for the photochemistry of skin diseases characterized by cell hyperproliferation.

Chemical Phenomena↗
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

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

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↗
PubMed1979

Synthesis and photobiological properties of 4,8-dimethyl-5'-carboxypsoralen: a major metabolite of 4,5',8-trimethylpsoralen.

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.

Administration, Oral↗