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Biomedical subjects

F Bordin

Publications and source records attributed to F Bordin.

At least 55 records · Page 3Linked to original sources
PubMed1988

Synthesis and photobiological activity of new N,N-disubstituted 4-amino-3-chloroangelicins.

The synthesis of a series of new N,N-disubstituted 4-amino-3-chloroangelicins (4-amino-3-chloro-2H-furo[2,3-h]-1-benzopyran-2-ones) starting from N,N-disubstituted (E)-5-aminomethylene-6,7-dihydrobenzo[b]furan-4(5H)-ones is described. Their capacity of inhibiting DNA synthesis in Ehrlich ascites tumor cells by U.V.-A light irradiation as well as their phototoxic activity on guinea-pig skin have been studied and the data computed by probit analysis; the results are discussed in the light of the modifications introduced in the molecular structure.

Animals↗
PubMed1986

Photobiological activity of certain pyranocoumarin derivatives: potential agents for the photochemotherapy of psoriasis.

The photobiological properties of a series of pyranocoumarin derivatives having linear (xanthyletines) and angular structure (seselins) have been studied; while the linear derivative carrying the methyl geminal group, typical of the parent natural compound, appeared to be entirely inactive in all tests performed, very probably because of the steric hindrance in the dark interaction with DNA, 4 substances lacking in this group showed a marked capacity for inhibiting DNA synthesis in Ehrlich cells. In particular, 4,6-dimethyl-8-desmethylseselin proved to be about 7 times more active than 8-MOP. Practically all compounds were capable of inducing cross-links in DNA, but this feature, marked in the linear compounds, is very much reduced in the angular ones; this property appears to be clearly related to the mutagenicity in the light and with the skin phototoxicity, which are both marked in the former and low or absent in the latter. In the dark, while all compounds are non-mutagenic in the absence of metabolic activation, in the presence of microsomial enzymes pyranocoumarins become mutagens; only the xanthyletine derivative carrying a geminal methyl group at the 8 position was not activated, suggesting that the enzymes metabolize the pyranic ring.

Animals↗
PubMed1985

Photobiological properties of some water-soluble 5-MOP and 8-MOP derivatives.

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.

5-Methoxypsoralen↗
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

Bis-pyridoquinolines as new bifunctional intercalators for DNA.

With the aim of obtaining new bifunctional intercalators for DNA, a new series of bis-pyridoquinolines were synthesized by joining two tricyclic planar moieties through a flexible chain. For preparing the corresponding potential monofunctional intercalators also a series of mono-pyridoquinolines were prepared by chemical synthesis by joining the same chromophore with a flexible side-chain. The melting profiles of the complexes between two bis-pyridoquinolines and DNA showed two different thermal transitions supporting the bis-intercalation of the ligand with the macromolecule. On the other hand, two mono-pyridoquinolines showed only one transition in the melting profile indicating a behaviour consistent with a mono-intercalation. The antiproliferative activity was tested in terms of DNA synthesis inhibition in Ehrlich ascite tumor cells; the examined bis-intercalating agent showed to be much more active than the tested mono-intercalating compound.

Aminoquinolines↗
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↗
PubMed1984

Synthesis and photobiological activity of N,N-disubstituted 4-amino-3-chloro-2H-thieno[2,3-h]-1-benzopyran-2-ones, 7-thioisosteres of 4-amino-3-chloroangelicins.

A convenient synthesis of a series of N,N-disubstituted 4-amino-3-chloro-2H-thieno[2,3-h]-1-benzopyran-2-ones (IV), which are 7-thioisosteres of 4-amino-3-chloroangelicins, was accomplished via dehydrochlorination and dehydrogenation of the 1,4-cycloadducts obtained by reaction of dichloroketene with N,N-disubstituted (E)-5-aminomethylene-6,7-dihydrobenzo-[b]thiophen-4(5H)-ones . Some aspects of the photobiological activity of these thioangelicins were studied; three of them (IV a, e, f) appeared to inhibit DNA synthesis in Ehrlich ascites tumor cells. The most active compound, namely 3-chloro-4-morpholino-7-thioangelicin (IV e), afforded 70% of the antiproliferative effect of 8-MOP, but unlike this reference compound was unable to induce erythema on guinea pig skin. However, compounds (IV a, f) produced a slight erythema, thus suggesting that a relationship between antiproliferative and phototoxic effects does not exist.

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

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↗