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Biomedical subjects

F Bordin

Publications and source records attributed to F Bordin.

At least 37 records · Page 2Linked to original sources
PubMed1994

2,6-Dimethyl-9-methoxy-4H-pyrrolo[3,2,1-ij]quinolin-4-one, a new compound with unusual photosensitizing properties.

Some photobiological properties of 2,6-dimethyl-9-methoxy-4H-pyrrolo[3,2,1-ij]quinolin-4-one (PQ) have been studied in comparison with 8-methoxypsoralen (8-MOP). In Ehrlich cells, PQ induced a moderate inhibition in DNA and RNA syntheses in the dark, which appeared to be more pronounced upon UVA irradiation. In contrast to 8-MOP, in the presence of UVA, PQ also affected protein synthesis. Likewise marked antiproliferative effects were also observed in the study of the clonal growth of CHO cells cultivated in vitro. Using alkaline elution and CHO cells, a moderate formation of single-strand breaks (SSBs) and of DNA-protein cross-links (DPCs) was observed by incubation in the dark; upon UVA irradiation the amount of both lesions increased greatly, whereas no inter-strand cross-links (ISCs) were formed. As expected, 8-MOP did not damage DNA in the dark, but induced SSBs, ISCs and DPCs in the presence of UVA. The induction of SSBs by both compounds seems to be directly related to a photochemical event rather than to incisions during DNA repair. As the induction of ISCs, and also the formation of DPCs by 8-MOP and UVA, appears to be based on a two-step reaction involving photo-bound 8-MOP-DNA moieties. In contrast, the formation of DPCs by PQ and UVA seems to involve photosensitization by free PQ molecules connected with SSB and DPC formation rather than with a DNA photo-binding activity. The PQ activity observed in the dark could probably be ascribed to a moderate inhibition of topoisomerases.

Animals↗
PubMed1994

4,6,4'-Trimethylangelicin induces interstrand cross-links in mammalian cell DNA.

4,6,4'-Trimethylangelicin, a well-known effective photosensitizer described as a pure monofunctional reactant with DNA, can induce interstrand cross-links in mammalian cell DNA in vivo (about 15% relative to 8-methoxypsoralen), as observed using alkaline elution and Chinese hamster ovary cells. Experiments performed using the two-step irradiation method and HeLa cells support these data. In contrast with 4,6,4'-trimethylangelicin, 4'-methylangelicin and 4,4'-dimethylangelicin do not form interstrand cross-links. These results are consistent with those recently reported by Chen et al. (X. Chen, J. Kagan, F. Dall'Acqua, D. Averbeck and E. Bisagni, J. Photochem. Photobiol. B: Biol, 22 (1994) 51-57) using pBR322 and M13 DNA. The cross-linking ability of 4,6,4'-trimethylangelicin does not seem to be related to a particular feature of these DNAs but to the compound itself.

Animals↗
PubMed1994

Pyrroloquinolinone methylderivatives, furocoumarin analogues: synthesis and biological activity.

Searching new photochemotherapeutic agents, a series of methylpirroloquinolinones were prepared by a new synthetic pathway, thus univocally obtaining the title compounds. The photobiological activity of some of these compounds was assayed; upon UVA activation, a marked capacity of inhibiting macromolecular synthesis in Ehrlich cells was observed, which appeared to be markedly high testing protein synthesis. Pyrroloquinolinones induced a strong inhibition of the clonal growing capacity of HeLa cells cultivated in vitro. Studying DNA photodamage in HL60 cells high amounts of single strand breaks and DNA-protein cross-links were detected. Pyrroloquinolines inhibited T2 bacteriophage infectivity, but induced no significant amounts of revertants in E. coli WP2 TM9, a strain very sensitive to DNA damage. On the contrary, 8-MOP, tested in the same experimental conditions exhibited an evident photomutagenecity. These data suggest that pyrroloquinolines induced antiproliferative effects by a mechanism in which DNA-photobinding practically does not takes place, and therefore different from that shown by known furocoumarins. Pyrroloquinolinones showed also a moderate antiproliferative activity in the dark.

Cell Division↗
PubMed1993

Furocoumarin sensitization induces DNA-protein cross-links.

The capacity of some linear and angular furocoumarins to induce DNA-protein cross-links by UVA (320-400 nm) irradiation has been evaluated in Chinese hamster ovary cells. Two linear furocoumarins, psoralen and 8-methoxypsoralen appeared to be capable of inducing DNA-protein cross-links to a noticeable extent. 4'-Methylangelicin and 4,4'-dimethylangelicin formed only reduced amounts of DNA-protein cross-links, while angelicin and 4,6,4'-trimethylangelicin seemed to be unable to induce significant levels of this lesion. The biological significance of this damage remains to be elucidated, but it might have an important role in furocoumarin sensitization. In the examined compounds, the capacity for inducing DNA-protein cross-links appears to be a property of the skin phototoxic furocoumarins. This result suggests the hypothesis of a connection between this damage and the formation of skin erythemas.

Animals↗
PubMed1992

Different superstructural features of the complexes between spermine and the light responsive elements of the two pea genes rbcS-3A and rbcS-3.6. Gel electrophoresis and circular dichroism studies.

Two light responsive elements (LREs), DNA sequences, 62 base pairs long, relevant to the light control during transcription of the pea genes rbcS-3A and rbcS-3.6, were synthesized and ligated to obtain multimers with defined superstructural features. Their gel electrophoretic mobilities were studied in the presence of the tetracation, spermine, since it was previously suggested, on the basis of theoretical analysis, that spermine can increase DNA bending and thus could be useful in revealing DNA superstructural features. In fact, the difference between the curvatures of the two LREs, derived from gel electrophoresis retardation ratios, increases in the presence of spermine. Circular dichroism spectra of the complexes between spermine and the two LREs, at different neutralization ratios, show that the polyamine is able to induce the formation of asymmetric arrangements of complexes of molecules. The chirality of these complexes appears dramatically different for the two LREs, suggesting that their different superstructural features give rise to different interactions with the polyamine.

Animals↗
PubMed1992

Biological properties of some benzopsoralen derivatives.

The biological activity of some benzopsoralen derivatives, prepared with the aim of obtaining new drugs for photochemotherapy, has been studied. The more interesting compounds are 4-hydroxymethyl-4',5'-benzopsoralen and 4-hydroxymethyl-4',5'-tetrahydro-benzopsoralen, which were found to be active in the dark also: DNA and RNA synthesis were both inhibited in Ehrlich cells, even if in a partially reversible fashion, while protein synthesis remained unaffected. In Chinese hamster ovary cells cultured in vitro, the clonal growth was strongly inhibited by incubation in the dark with both drugs, while a number of chromosomal aberrations was observed in the fraction of growing cells. Using alkaline elution, DNA strand breaks were detected. In addition, in the presence of aphidicolin, a specific inhibitor of DNA polymerase, the clonal growing capacity was completely restored; in contrast, the number of DNA strand breaks remained unchanged. All these results suggest that DNA topoisomerases are probably the target of these two benzopsoralens. These compounds are also good sensitizers; by UV-A irradiation they have a good capacity to produce singlet oxygen, but they appeared to be unable to induce erythemas on guinea-pig skin. Under UV-A light, they induced a strong inhibition of DNA synthesis in Ehrlich cells. Thus, benzopsoralens appear to be capable of inducing strong antiproliferative effects by two different mechanisms, by UV-A irradiation and in the dark.

Animals↗
PubMed1992

2-substituted 1H-pyrrolo [3,2-h] quinoline derivatives: synthesis and aspects of their biological activity.

Certain 2-substituted 1H-pyrrolo [3,2-h] quinolines have been prepared and their biological activity in mammalian cells and in some microorganisms have been studied. These compounds represent a simplified ellipticine heterocyclic moiety: in addition they have a different ring condensation, leading to an angular molecular structure instead of a linear one. In mammalian cells all compounds appeared to be able of inducing an antiproliferative effect and an extensive DNA fragmentation, similarly to ellipticine, even if to a reduced extent. The new derivatives behaved in a comparable way also on some microorganisms, such as T2 bacteriophage (which appears to be less sensitive than mammalian cells) and in mutagenesis tests carried out with E. coli WP2 TM9 and S. typhimurium TA 98, which are reverted by base substitution and frame-shift mutagens, respectively. Similarly to the reference compound, all ellipticine analogues appeared to be no mutagenic. The obtained results suggest that they induce the antiproliferative activity in mammalian cells mainly as topoisomerase inhibitors, similarly to ellipticine itself. Therefore, they represent an interesting model to design new potential anticancer drugs.

Animals↗
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↗
PubMed1992

Different interactions of spermine with a "curved" and a "normal" DNA duplex: (CA4T4G)n and (CT4A4G)n. Gel electrophoresis and circular dichroism studies.

Two nucleotide sequences, (CA4T4G)n and (CT4A4G)n, are generally considered as prototypes of a "curved" and a "normal" DNA duplex on the basis of their different behaviour with respect to physico-chemical and/or biochemical properties. We have studied their gel electrophoretic mobilities in the presence of the biologically significant tetracation spermine and have found that spermine causes a decrease of the gel electrophoretic mobility of "curved" DNA, but does not influence that of "normal" DNA. Circular dichroism spectra of the complexes between spermine and the two examined DNAs show dramatically different features. These findings suggest that different DNA superstructures are relevant in interactions not only with proteins, but also with polycations, such as spermine.

Base Sequence↗
PubMed1991

Angelicins, angular analogs of psoralens: chemistry, photochemical, photobiological and phototherapeutic properties.

Angelicin and some of its derivatives are naturally occuring compounds which show interesting photobiological properties. In this review various aspects of angelicin and its derivatives have been reported. The natural occurrence and the chemical synthesis both of naturally occurring and synthetic angelicins have been reviewed. Photochemical and photophysical properties of angelicins have been considered with particular reference to the capacity to generate active forms of oxygen, photoreactions with nucleic acids, proteins and unsaturated fatty acids. Photobiological effects have been considered: skin phototoxicity, antiproliferative effects, genotoxicity, ability to induce hemolysis in erythrocytes, inactivation of prokaryotic and eukaryotic microorganism and of viruses. The ability of some angelicins to induce photocarcinogenesis has been reviewed as well as in the activity as photochemotherapeutic agents.

Animals↗
PubMed1991

Photochemical and photobiological properties of 4,8-dimethyl-5'-acetylpsoralen.

The photochemical and photobiological properties of 4,8-dimethyl-5'-acetylpsoralen (AcPso), proposed for the photochemotherapy of some skin diseases, were investigated. The photoreaction of AcPso with DNA is weaker in the presence of air than in a nitrogen atmosphere, in terms of total photobinding and DNA cross-linking; when UVA irradiation is performed in air, AcPso behaves as a monofunctional reagent. The quenching effect of oxygen is related to the high capacity of AcPso to produce singlet oxygen. Furthermore, it is demonstrated that AcPso photoadducts are better producers of singlet oxygen than free AcPso in solution. Using DNA sequencing methodology, two modes of DNA photosensitization by AcPso are shown, these lead to the formation of photoadducts mainly at T residues (and at C to a lesser extent) and to photo-oxidized G residues probably via singlet oxygen. Chemical or enzymatic cleavage were used as probes in these experiments. A rapid assay for the detection of the photodynamic effect of a photosensitizer on DNA, involving oxygen, is also described. Finally, the cytotoxicity and genotoxicity of AcPso on E. coli WP2 cells appear to be related to its ability to form photoadducts, in particular cross-links, rather than to its capacity to produce singlet oxygen.

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

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

Relationship between DNA replicon size and SCE induction in BALB/c and BALB/Mo mouse lymphocytes.

We studied the DNA replicon size in BALB/c and BALB/Mo mouse lymphocytes by the method of bromodeoxyuridine photolysis. After treatment of the BALB/Mo lymphocytes in vitro with mitomycin C, the average DNA replicon size appeared to be significantly smaller than that observed in BALB/c lymphocytes treated similarly. In these conditions an increased susceptibility to SCE induction in BALB/Mo lymphocytes had been observed. In the presence of both mitomycin C and cordycepin (an antiviral drug), both the DNA replicon size and the SCE frequency returned to normal values.

Animals↗