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Biomedical subjects

E Bisagni

Publications and source records attributed to E Bisagni.

At least 73 records · Page 4Linked to original sources
PubMed1985

(+/-)-2-Amino-3,4-dihydro-7-[2,3-dihydroxy-4-(hydroxymethyl)-1- cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ones: new carbocyclic analogues of 7-deazaguanosine with antiviral activity.

5-Allyl-2-amino-4,6-dihydroxypyrimidine (3) was chlorinated and ozonized to yield (2-amino-4,6-dichloro-pyrimidin-5-yl)acetaldehyde (5). Acetalization of 5 with ethanol afforded a new pyrimidine intermediate 6 which can lead to 2-amino-3,4-dihydro-7-alkyl-7H-pyrrolo[2,3-d]pyrimidin-4-ones and therefore to carbocyclic analogues of 7-deazaguanosine. The 7-substituent was a cyclopentyl analogue of the arabinofuranosyl moiety in 10a, lyxofuranosyl moiety in 10b, and ribofuranosyl moiety in 10c. Compounds 10a and 10b exhibited selective inhibitory activities against the multiplication of HSV1 and HSV2 in cell culture. Repeated administration of compound 10a at 10mg/kg ip to mice infected with HSV2 increased the number of survivors and lengthened significantly the mean survival time.

Animals↗
PubMed1984

[BD-40, intercalating 9-azaellipticine derivative, induces breaks in cellular DNA associated with protein bridges].

The nature of the lesions induced in cell DNA by BD-40, a chemical analog of Ellipticine was analyzed by submitting DNA from drug-treated cells to alkaline sucrose gradient centrifugation. DNA size reduction was only observed when cell lysates were digested by proteolytic enzymes. This result indicates that BD-40 induces DNA breaks which are masked by bridges involving DNA-protein interaction. This is a new type of DNA lesion induced in DNA by an intercalating agent.

Animals↗
PubMed1983

Antitumor amino-substituted pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinolines and pyrido[4,3-b]carbazole derivatives: synthesis and evaluation of compounds resulting from new side chain and heterocycle modifications.

New modifications of 10-[[3-(diethylamino)propyl]amino]-6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]i sisoquinoline (1b) and 1-[[3-(diethylamino)propyl]amino]-9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carba zole (4b), which display important antitumor properties, were performed either on the side chain or on the intercalating heterocycle. Side chains were introduced by direct substitution of the corresponding chloro derivatives and 6-N-methyl-9-hydroxypyrido[4,3-b]carbazoles analogues were prepared via 9-O-benzoyl-1-chloroellipticines. Evaluation of all new compounds shows no significant increase of in vitro cytotoxicity and percent ILS on the L1210 leukemia system by comparison with the model compounds 1b and 4b.

Animals↗
PubMed1983

Aza analogues of lucanthone: synthesis and antitumor and bactericidal properties.

Three types of aza analogues of lucanthone were synthesized for evaluation as antitumor drugs. None of the compounds was found to have significant cytotoxic effects either on Friend tumor cells or on L1210 leukemia cells. However, one of the target compounds, 5,10-dihydro-10-oxo-1-[[3-(diethylamino)propyl]amino]-3-methylpyrido [4,3-b]quinoline, was shown to have noticeable antibiotic properties.

Animals↗
PubMed1983

Likelihood of the new antitumoral drug 10-[gamma-diethylaminopropylamino]-6-methyl-5H-pyrido[3',4':4,5]pyrrolo [2,3-g]isoquinoline (BD-40), a pyridopyrroloisoquinoline derivative, to induce DNA strand breaks in vivo and its nonmutagenicity in yeast.

BD-40, a pyridopyrroloisoquinoline analogue of ellipticines, has dose-dependent cytostatic and cytotoxic effects on cultures of Saccharomyces cerevisiae. These inhibitory effects take place only in growing cells and are enhanced in the presence of oxygen. Among the different repair-deficient mutants examined, a mutant defective in DNA strand break repair (rad52-1) was found to be the most sensitive to such a toxic effect. A triple mutant blocked in the excision (rad2), the mutagenic (rad6), and the recombinogenic (rad52) repair pathways demonstrated the same sensitivity as the single rad52 mutant. Nuclear reversion and forward mutations as well as mitochondrial "petite" mutation were not induced by BD-40. These results indicate that: (a) the lesions induced in vivo by BD-40 are likely to be DNA strand breaks; (b) such damage is repairable in the wild type and is not of the mutagenic type; and (c) the excision pathway is not involved in such a repair of BD-40-induced lesions, and the mutagenic pathway plays a minor role. Since DNA strand breaks were not detected in vitro whether exposure of DNA to BD-40 was achieved in the presence or the absence of microsomal S-9 mix, it is suggested that an oxygen-dependent enzymatic processing, not linked to the microsomal monooxygenase complex, is required for the development of the cytotoxic activity of BD-40.

Aerobiosis↗
PubMed1981

5-Methoxypsoralen, the melanogenic additive in sun-tan preparations, is tumorigenic in mice exposed to 365 nm u.v. radiation.

5-Methoxypsoralen (5 MOP), the melanogenic component present in several suntan preparations was synthesized and tested by topical applications in inbred XVII nc/Z albino mice combined with 365 nm irradiation with the aim of establishing the relative carcinogenic activity of this compound, as compared to 8-methoxypsoralen (8 MOP) and psoralen. 85% of the animals developed tumors and 25% had multiple tumors. Additional treatment with 12-O-tetradecanoylphorbol-13-acetate raised the tumor incidence to 100%. Tumors caused by 5 MOP show much longer latent periods than those induced by psoralen and 8 MOP. Most of the tumors were rapidly growing squamous cell carcinomas giving metastases in 20% of the animals. The possible long-term effects that might follow the use of 5 MOP in humans are discussed.

5-Methoxypsoralen↗
PubMed1980

Structure-activity relationships in a series of newly synthesized 1-amino-substituted ellipticine derivatives.

The synthesis of a series of 1-amino-substituted pyrido[4,3-b]carbazole derivatives, based on the substitution of corresponding 1-chloroellipticines, is reported. The cytotoxic properties on tumor cells grown in vitro, the in vivo acute toxicity of the most potent in vitro cytotoxic compounds, and the antitumor properties toward the L1210 leukemia system are described. No correlation between the apparent association constant to DNA and the in vitro cytotoxicity or the in vito antitumor efficiency could be observed in this series. 9-Hydroxylated derivatives were more cytotoxic in vitro than the corresponding 9-methoxylated compounds. However, their antitumor efficiencies on the in vivo experimental systems do not confirm the advantage of demethylation. The presence of a [(dialkylamino)alkyl]amino side chain at the 1 position of ellipticines increases the antitumor potency: 1-[[3-(diethylamino)propyl]amino]-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (5) is a very potent antitumor compound (% ILS of 134 on the L1210 leukemia system).

Alkaloids↗
PubMed1980

Antitumoral activity of dipyrido [4,3-b] [3,4-f] indoles on L 1210 leukemia.

Newly synthesized dipyrido [4,3-b] [3,4-f] indole compounds have a structural similarity with the DNA intercalating agents ellipticines (pyrido-carbazoles). The procedure of synthesis of these compounds allows the addition of a lateral chain in position 1 of the nucleus. Comparison is made between different substitutions and the resulting cytotoxic and antitumoral effects. The most active compound of the serie (1-gamma-diethyl amino propyl amino)-5-methyl-dipyrido [4,3-b] [3,4-f] indole (called here BD40) protects mice against L1210 leukemia. At the non-toxic dose of 20 mg/kg, particularly, a single infection of this compound given one day after inoculation of 10(5) L1210 cells resulted in an increased life span of 69 per cent with one survivor at 60 days. A combination of cyclophosphamide and BD40 had a synergic effect on the life span of L1210 inoculated mice. The antitumoral action of these drugs may be linked to their intercalative action upon biding to DNA.

Animals↗
PubMed1980

Intercalative binding to DNA of new antitumoral agents: dipyrido [4,3-b] [3,4-f] indoles.

The study of new intercalating DNA agents has led to the synthesis of dipyrido [4,3-b] [3,4-f] indole derivatives. These compounds bind preferentially to helical DNA and their affinity constants range from 10(6) to 10(7) M-1. The most active derivative against L1210 mouse leukemia produces viscosity changes in sheared fragments of linear DNA and in circular PM2 DNA on binding, indicating an intercalation process. The unwinding angle is estimated to be 18(0). This active derivative binds preferentially to A-T base pairs.

Animals↗
PubMed1979

[Experimental bases and primary trials of photochemotherapy of psoriasis by a non-cancerigenic monofunctional furocoumarin, 3-carbethoxypsoralen].

The carcinogenic risk of the photochemotherapy (PUVA) with bifunctional furocoumarins such as 8-methoxypsoralen (8-MOP) forming cross-links in cellular DNA has initiated a search for active but less dangerous psoralens. The 3-carbethoxypsoralen (3-CPs), studied in the yeast Saccharomyces cerevisiae, has been very photoactive on DNA forming only monoadditions to DNA. In Mice it was demonstrated that after local or intra-peritoneal administration, 3-CPs is non toxic, non erythematogenic and non carcinogenic in contrast to 8-MOP. A limited study on ten psoriatic patients has shown that after local application 3-CPs exhibits about the same therapeutic activity as 8-MOP.

Animals↗
PubMed1979

Photochemotherapy (PUVA) of psoriasis using 3-carbethoxypsoralen, a non-carcinogenic compound in mice.

The carcinogenic risk of photochemotherapy (PUVA) with bi-functional furocoumarins such as 8-methoxypsoralen (8-MOP) which form cross-links in cellular DNA has initiated a search for active but less hazardous psoralens. A new compound, 3-carbethoxypsoralen (3-CPs), studied in the yeast Saccharomyces cerevisiae (eukaryote), has been shown to be very photoactive on DNA and to form only mono-additions to DNA. These lesions appear to be more easily repaired than the cross-links induced by 8-MOP. 3-CPs produces less nuclear genetic events such as nuclear mutations and mitotic crossovers, but more cytoplasmic 'petite' mutations (damage to mitochondrial DNA) than 8-MOP. In mice it was demonstrated that after local or intra-peritoneal administration, in contrast to 8-MOP, 3-CPs is non-toxic, non-erythematogenic, and non-carcinogenic. A study of ten psoriatic patients had shown that local applications of 3-CPs plus UV-A exhibit about the same therapeutic activity for the clearing of psoriatic lesions as local treatment with 8-MOP plus UV-A, but without any localized hyperpigmentation.

Animals↗
PubMed1978

Biological effects and repair of damage photoinduced by a derivative of psoralen substituted at the 3,4 reaction site: photoreactivity of this compound and lethal effect in yeast.

A newly synthesized linear psoralen derivative, 3-carbethoxypsoralen is shown to bind to yeast nucleic acids after 365 nm light treatment. As compared to 8-methoxypsoralen, a well-known bifunctional furocoumarin, 3-carbethoxypsoralen exhibits a high photoaffinity for DNA in vivo. Both compounds bind and photoreact more efficiently in vivo than in vitro. In contrast to 8-methoxypsoralen, 3-carbethoxypsoralen does not form cross-links in yeast DNA as demonstrated by heat denaturation-reassociation studies at least in the range of doses used. Thus 3-carbethoxypsoralen reacts as a monofunctional compound. Wild-type cells of Saccharomyces cerevisiae are 6 times more resistant to 3-carbethoxypsoralen than to 8-methoxypsoralen plus 365 nm light treatment in terms of lethal effect. In comparison to angelicin, another monofunctional (but angular) furocoumarin, 3-carbethoxypsoralen is more photoreactive. When the photoaffinity for DNA of 8-methoxypsoralen and 3-carbethoxypsoralen are considered in relation to photoinduced cell killing, it is clear that monoadducts are very efficiently repaired in wild-type cells. In contrast to the additivity obtained with 8-methoxypsoralen, a synergistic interaction of the two different repair pathways blocked by the rad2 and the rad9 mutation is observed after 3-carbethoxypsoralen plus 365 nm light. Dark holding experiments show that the excision repair function which is present in wild-type and rad9-4 cells is important for dark recovery.

Coumarins↗
PubMed1977

[Cytotoxic and antitumor activity of a new series of heterocyclic compounds: dipyrido (4,3-b) (3,4-f) indoles].

Among newly synthesized compounds derived from the dipyrido [4,3-b] [3,4-f] indole nucleus, two have proved to be particularly active in vitro and in vivo. Their cytotoxic effects on cultured cells have been determined. At non toxic doses, they displayed a pronounced inhibitory effect on experimental L1210 Leukemia. These compounds have a strong affinity for DNA molecules.

Animals↗