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Biomedical subjects

F Carlassare

Publications and source records attributed to F Carlassare.

At least 55 records · Page 3Linked to original sources
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

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

Comparative mutagenicity of linear and angular furocoumarins in Escherichia coli strains deficient in known repair functions.

Four furocoumarins, two having a linear molecule, psoralen and 8-methyl-psoralen and two having an angular molecule, angelicin and 4,5'-dimethyl-angelicin were tested for mutagenesis in Escherichia coli B wild type and in various strains deficient in known repair systems. The results indicate that both monoadducts and crosslinks are mutagenic. The mutagenic efficiency of the furocourmarins ranks in the following order 8-methylpsoralen psoralen greater than angelicin greater than 4,5'-dimethylangelicin.

DNA Repair↗
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

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↗
PubMed1976

DNA repair and recovery in Escherichia coli after psoralen and angelicin photosensitization.

The correlation between DNA repair and recovery of biological functions was studied using three wild type strains of Escherichia coli and two skinphotosensitizing furocoumarins, psoralen and angelicin, which are well known specific reagents of the pyrimidine bases of DNA. In addition to mono-adducts psoralen is able to form a high number of inter-strand cross-links, while angelicin forms only mono-adducts. Both of these damages were repaired, in a short time, in the following way: at first DNA was cut into small pieces that were then rejoined into molecules of normal size, free from cross-links, while the furocoumarin residue was split from DNA almost quantitatively. Recovery of biological functions was studied performing photosensitization experiments in such a manner that the same amounts of psoralen or of angelicin were linked to bacterial DNA. DNA synthesis, tested just after the damage, was inhibited in a similar extent by both drugs. The same bacteria, however, showed a very different colony-forming capacity; angelicin was much less effective than psoralen with a D37 dose about 2.7 times higher. A similar picture was obtained studying DNA synthesis at different times after photosensitization: in the bacteria damaged by angelicin it was restored while no recovery was observed in cells photosensitized by psoralen. These results suggest that both mono-adducts and cross-links can be chemically repaired more or less in a quantitative measure, but that repair of cross-links in much less effective on cell recovery; this behaviour is very probably connected with the different repair mechanisms of mono-adducts and of cross-links.

Coumarins↗
PubMedDate not supplied

Photobiological properties of 1-(3'-hydroxypropyl)-4,6,8-trimethylfur.

A new furoquinolinone derivative, 1-(3'-hydroxypropyl)-4,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HPFQ, 4), was prepared, in which the nitrogen atom in position 1 carries a hydroxypropyl chain. The antiproliferative activity of HPFQ was studied in comparison with its analogue 1,4,6,8-tetramethylfuro[2,3-h]quinolin-2(1H)-one (FQ) and 8-methoxypsoralen (8-MOP). By incubation in the dark, HPFQ, although retaining antitopoisomerase II activity, appeared less effective than FQ. Upon UVA irradiation, HPFQ produced little amounts of singlet oxygen, but detectable levels of superoxide anion; like FQ, HPFQ induced numbers of DNA-protein cross-links, but no interstrand cross-links in mammalian cells. The HPFQ phototoxicity was comparable to that of FQ and 8-MOP, while mutagenic activity, scored in two Escherichia coli strains, seemed much less remarkable.

Cell Division↗