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Biomedical subjects

F Carlassare

Publications and source records attributed to F Carlassare.

At least 37 records · Page 2Linked to original sources
PubMed1992

Photobiological activity of certain new methylazapsoralens.

The photobiological activity of a series of psoralen isosters carrying a nitrogen atom at 8 position, new potential drugs for the photochemotherapy of hyperproliferative skin diseases, have been studied; the more active derivatives appeared to be 5,4'-dimethyl-8-azapsoralen and 3,4,4'-trimethyl-8-azapsoralen which induced a strong inhibition of DNA synthesis in Ehrlich ascites cells, very similar to that provoked by 8-methoxypsoralen, the furocoumarin at present used in photochemotherapy. Such compounds induced a small amount of inter-strand DNA cross-links and were non phototoxic when assayed on guinea-pig skin; however, both derivatives appeared to be highly mutagenic in E. coli WP2 TM6. This strain contains the plasmid R46 and it is proficient in DNA repair, and therefore monoadducts do not should be mutagenic in such a strain. Because the first steps of excision, which remove monoadducts, and of the main cross-link repair use the same enzymes (produced by the uvrABC complex), in the presence of a great number of monofunctional lesions, it is possible that there are not sufficient enzyme molecules for removing cross-links according this pathway, which could be repaired by a second one, uvrABC independent and based on glycosilase activity, which works at reduced levels and is much less accurate.

Animals↗
PubMed1991

4,4',5'-trimethyl-8-azapsoralen, a new-photoreactive and non-skin-phototoxic bifunctional bioisoster of psoralen.

Photochemical and photobiological properties of a new isoster of psoralen, 4,4',5'-trimethyl-8-azapsoralen (4,4',5'-TMAP), have been studied. This compound shows a high DNA-photobinding rate, higher than that of 8-methoxypsoralen (8-MOP), forming both monoadducts and inter-strand cross-links. The yield of cross-links, however, is markedly lower than that of 8-MOP. Antiproliferative activity of 4,4',5'-TMAP, in terms of DNA synthesis inhibition in Ehrlich ascites tumor cells, is higher than that of 8-MOP. Mutagenic activity on E. coli WP2 R46+ cells appeared similar to or even lower than that of 8-MOP. This new compound applied on depilated guinea pig skin and irradiated with UVA did not show any skin-phototoxicity. On the basis of these properties 4,4',5'-TMAP appears to be a potential photochemotherapeutic agent.

Animals↗
PubMed1991

In vitro and in vivo behaviour of narciclasine released from matrices based on poly (2-hydroxyethyl methacrylate).

Narciclasine (1,2,3,7-tetrahydroxy-8,9-methylendioxy-1,2,3,4-tetrahydrophena ntridone) is a natural substance with strong antimitotic effects on cells and potential antitumor activity. Its release form a hydrogel matrix was studied with the purpose of avoiding the concentration spikes of the parenteral administration. The matrix prepared by gamma ray polymerization of a mixture of 2-hydroxyethyl methacrylate (85%) and trimethylolpropane trimethacrylate (15%) was found to release narciclasine for several days, according to a diffusion controlled mechanism. In agreement with its antimitotic effect, narciclasine inhibited the growth rate of healthy mice, when the drug-loaded matrix was introduced subcutaneously. Antitumor effect was observed in an experimental model of Erlich ascitic tumor when low amounts of tumor cells were inoculated. No effect was observed at high concentrations of inoculum or towards solid tumors (Sarcoma 180). This behaviour was related to the rapid clearance of narciclasine from the body which prevented the reaching of sufficient therapeutical concentrations. A pharmacokinetic investigation carried out by an original method of assay demonstrated that narciclasine was accumulated in significant amounts in the kidney only and eliminated in urine with a half time of less than 20 min.

Alkaloids↗
PubMed1991

Methylangelicins: structure activity studies on the role of methyl groups present in 3,4 and 4',5' photoreactive sites.

The effect of the introduction of one, two or three methyl groups at the level of 3,4 or 4',5' photoreactive site of angelicin, in terms of extent of intercalation and DNA-photobinding, was studied. The introduction of one methyl group both in the 3 or 4 and in 4' or 5' position increases the affinity of angelicin toward DNA for the molecular complex formation and enhances the DNA-photobinding, even if to a different extent. The increase is more pronounced for occupancy of 5' or 4' position; much less pronounced is the enhancement in the case of 3 or 4 positions. The introduction of two methyl groups in 3,4 or in 4',5' positions leads to an increased capacity to form the intercalated complex with DNA; the photoreactivity is also enhanced, but to a larger extent for 4',5'-dimethylangelicin. No steric hindrance, therefore, seems to be exerted by the introduction of one or two methyl groups at the level of the photoreactive sites of angelicin. The introduction of a third methyl group in 4',5'-dimethyl or in 3,4-dimethylangelicin exhibits a strong enhancement of the DNA photobinding; in particular 4,4',5'-trimethylangelicin appears the most photoreactive towards DNA. Angelicins carrying methyl groups in 3,4 positions exhibit lower antiproliferative activity than derivatives carrying methyl groups in 4',5' positions. No correlation was observed between antiproliferative activity and DNA-photobinding; may be that the presence of methyl groups in 3,4 or in 4',5' positions affects the type of cycloadducts formed. The different ratio of adducts may affect the antiproliferative effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Synthesis and photobiological properties of acetylpsoralen derivatives.

In an investigation to find monofunctional reactants for DNA which can act as new agents in the photochemotherapy of psoriasis, we have synthesized and studied some methylpsoralen derivatives which contain an acetyl group at one of the two reactive sites of the furocoumarin skeleton (at the 3 or 5' positions). The compounds do not react easily with DNA; their photobiological properties (e.g. the lack of an ability to inhibit DNA synthesis in Ehrlich ascites tumour cells, to induce T2 phage sensitization and to induce erythema in guinea-pig skin) are exactly in line with this behaviour. Some interesting features are shown by 4,8-dimethyl-5'-acetylpsoralen: it is capable of producing a very large amount of singlet oxygen--an order of magnitude higher than the other compounds and 8-methoxypsoralen (used as reference). In spite of this property, 4,8-dimethyl-5'-acetylpsoralen is non-phototoxic to the skin, and its other photobiological properties appear to be in line with its lack of interaction with DNA rather than its enhanced singlet oxygen production.

Acetylation↗
PubMed1990

6-Methylangelicins: new monofunctional photochemotherapeutic agents for psoriasis.

The monofunctional furocoumarins, the 6-methylangelicins, were tested for their antiproliferative activity with various animal models and for genotoxicity in micro-organisms and in mammalian cells. The most active compound was 6,4,4'-trimethylangelicin, which showed a high antiproliferative effect and reduced genotoxicity in comparison with 8-methoxypsoralen (8-MOP). Some of these compounds were also tested clinically by topical application on 17 patients with psoriasis. They appeared to be more active than 8-MOP in clearing psoriasis without inducing skin phototoxicity. The methylangelicins also caused skin pigmentation.

Animals↗
PubMed1989

1H-pyrrolo[2,3-f]quinoline and isoquinoline derivatives: synthesis and antiproliferative activity.

Fischer indol synthesis is reported for the preparation of some 2-substituted 1H-pyrrolo[2,3-f]quinoline and isoquinoline derivatives having a structural correlation with naturally occurring compound ellipticine. The prepared compounds proved capable of forming in vitro molecular complexes with native double-stranded DNA by intercalation between two base pairs and showed a relatively good activity in inhibiting the DNA synthesis in Ehrlich ascites tumor cells.

Animals↗
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

Genotoxic activity of some water-soluble derivatives of 5-methoxypsoralen and 8-methoxypsoralen.

This paper shows some results obtained by assaying the genotoxic activity on procaryotic and eucaryotic cells of some water-soluble psoralen derivatives. In particular, six newly synthesized derivatives of 5-methoxypsoralen (5-MOP) and of 8-methoxypsoralen (8-MOP) were tested; in previous studies they showed a strong anti-proliferative activity and a slight phototoxic effect; moreover, in view of a clinical use in the therapy of hyperproliferative skin diseases, these drugs should be less toxic than their parent compounds because of their good water solubility which could lead to a more efficient absorption and excretion. All the compounds tested here have shown genotoxic activity on both procaryotic and eucaryotic systems: however, on the procaryotic cells the water-soluble derivatives were less genotoxic than their respective parent compounds 5-MOP and 8-MOP. Quite different results were obtained on V79 Chinese hamster cells, showing that, in general, the 8-methoxy-derivatives are more mutagenic than the methoxy-ones, although the 5-MOP itself was shown to be highly genotoxic in this system. This fact confirms that a conclusive estimate of the genotoxic risk related to the use of new drugs cannot be drawn from the results obtained on a single biological system.

5-Methoxypsoralen↗
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

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↗
PubMed1981

Mutagenicity in Salmonella typhimurium of some angelicin derivatives proposed as new monofunctional agents for the photochemotherapy of psoriasis.

A series of angelicin derivatives were tested for their mutagenic activity with and without near-ultraviolet irradiation (NUV) in Salmonella typhimurium strains. After irradiation with NUV, the tested compounds induced different numbers of revertants in strain TA100, indicating that the mutational events involved are base substitutions. In the dark, 3 chemicals behaved as frame-shift mutagens causing reversion in strain TA98.

Furocoumarins↗
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↗