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S Cros

Publications and source records attributed to S Cros.

At least 37 records · Page 2Linked to original sources
PubMed1989

2,3-bis(2-pyridyl)-5,8-quinoxalinediones with metal chelating properties: synthesis and biological evaluation.

The synthesis of 2,3-bis(2-pyridyl)-5,8-quinoxalinediones has been carried out in order to provide new antitumor drugs related to streptonigrin. Some derivatives have been found to possess significant cytotoxic properties and their mechanism of action has been studied. They were found to induce single-strand cleavage of covalently closed circular DNA (ccc-DNA). This biological activity requires an apparent in situ reduction (NADH activation) of the quinone to a hydroquinone or semiquinone radical, is facilitated by the presence of Cu(II), and involves activation of molecular oxygen to highly reactive radical species. Thus, although less active than the parent drugs, these molecules provide an attractive rationale for the observed cytotoxic and antitumor potency, as well as the cell-free single strand DNA cleavage efficacy of that family of drugs.

Animals↗
PubMed1989

Heterocyclic quinones. XVI. Pharmacomodulation in the series of 11H-indolo[3,2-c]quinolinediones: synthesis, cytotoxicity and antitumor activity of 3-substituted 11H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline-1,4-diones.

With the aim of obtaining new antitumor drugs more active than previously described 11H-indolo[3,2-c]quinoline-1,4-diones and 7,8,9,10-tetrahydro-11H-indolo[3,2-c]quinoline-1,4-diones, the synthesis and activities of a series of 3-substituted 11H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline-1,4-diones and of 7,8,9,10-tetrahydro-11H-pyrido-[3',4':4,5]pyrrolo[3,2-c] quinoline-1,4-diones were studied. Some quinones were more cytotoxic in vitro towards L1210 leukemia cells but were not active in vivo towards murine P388 leukemia.

Animals↗
PubMed1989

Heterocyclic quinones. XIV. Pharmacomodulation in a series of 11H-indolo[3,2-c]quinolinediones: synthesis and cytotoxicity of 8-substituted 11H-indolo[3,2-c]quinoline-7,10-diones.

4-Chloro-8-methoxy-11H-indolo[3,2-c]quinoline could be obtained from 8-chloro-2,3-dihydro-1H-quinolin-4-one and 4-methoxyphenylhydrazine by applying Fischer's indole synthesis. Its nitration led to the 7-nitro derivative which was reduced to 7-amino-4-chloro-8-methoxy-11H-indolo[3,2-c]quinoline when Raney nickel was employed as a catalyst and to 7-amino-8-methoxy-11H-indolo[3,2-c]quinoline when palladium charcoal was used. Oxidation of the amines by potassium nitrosodisulfonate produced the corresponding 11H-indolo[3,2-c]quinoline-7,10-diones. Displacement of the methoxy group by (N,N-diethylamino)ethylamine or by N-methylpiperazine afforded the 8-aminoquinones. The quinones unsubstituted at the 4-position were more cytotoxic than the previously described 2-methoxy-11H-indolo[3,2-c]quinoline-1,4-diones.

Animals↗
PubMed1988

The biooxidation of cytotoxic ellipticine derivatives: a key to structure-activity relationship studies?

In the family of ellipticine derivatives, those with an amino-phenol or a masked amino-phenol structure are among the most cytotoxic compounds. Preliminary studies on 9-hydroxy- or 9-methoxyellipticines have shown that these molecules behave as "pro-alkylating" agents. In order to rationalize the "biooxidative alkylation" process for various ellipticine derivatives, we report in the present article (i) their electrochemical oxidation parameters, (ii) their biochemical oxidation, (iii) the ability of the oxidized forms to form adducts with nucleophiles, (iv) the biological activities, and (v) the electronic properties of oxidized forms. We present some possible correlations between the oxidizability, the electrophilicity of the oxidized derivatives, and the biological activities of the corresponding drugs.

Alkaloids↗
PubMed1987

Physicochemical and pharmacological properties of the antitumor ellipticine derivative 2-(diethylamino-2-ethyl)9-hydroxy ellipticinium-chloride, HCl.

2-(Diethylamino-2-ethyl)9-hydroxyellipticinium-chloride, HCl (DHE), a new congener of the antitumor agent elliptinium acetate (Celiptium) (NMHE), has recently been selected for phase I clinical trials. NMHE has a methyl group at nitrogen 2 on the ellipticine ring while DHE possesses a basic diethylaminoethyl chain at this position. Compared to NMHE, the presence of the diethylaminoethyl side chain results in the following: a significant increase in the lipophilicity of the drug; no significant modification in either the binding constant values to DNA or the ability to intercalate between DNA base pairs; a marked decrease in the unwinding angle value of supercoiled DNA; and no significant change in the alteration of the catalytic activity of topoisomerase II in vitro. DHE appears to act as a simple reversible intercalating agent as shown by the selective mutagenic effect on Salmonella TA 1977 tester strain and by its inability to induce the SOS functions in a sfiA lac fusion containing Escherichia coli strain. From a pharmacological point of view, the presence of the diethylaminoethyl chain results in a 2-fold increase in the cytotoxicity to L1210 cultured cells, a strong increase in the antitumor efficiency on experimental murine tumors such as L1210 and P388 leukemia, B16 melanoma, M 5076 reticulosarcoma, and colon 38 adenocarcinoma, and finally an objective decrease in the acute and subacute toxicity in mice, rat, and macaque. The absence of significant differences in the interaction of NMHE and DHE with their potential targets in vitro leads to the hypothesis that the superiority of DHE in terms of cytotoxicity and antitumor efficiency may be due to an increase in the diffusion across cellular membrane and a more favorable biodistribution in vivo.

Adenocarcinoma↗
PubMed1986

Ribose as the preferential target for the oxidized form of elliptinium acetate in ribonucleos(t)ides. Biological activities of the resulting adducts.

The covalent binding of the oxidized form of elliptinium acetate, an antitumor drug, to various ribonucleos(t)ides is described. In the absence of a strong nucleophile on the bases, e.g., a sulfhydryl group, the main target of this quinone imine derivative is the sugar moiety. With unmodified regular bases, the first electrophilic addition always occurs on the 2'-oxygen of ribose (more slowly for pyrimidine than for purine); in a second step, cyclization of the reoxidized product leads to a spiro derivative: only one stereoisomer is detected with purine nucleoside; the other stereoisomer appears as a minor product (10-20%) with nucleotides and pyrimidine nucleosides. With modified bases, no change is observed except for bases exhibiting an additional strong nucleophilic center: oxidized elliptinium alkylates thioguanine and thioguanosine on the sulfur atom and in this last case not on the ribose moiety. All spiro derivatives are less cytotoxic than the parent compound even if the base is an antimetabolite (azauridine); however, thio-elliptinium adducts maintain high cytotoxicity.

Alkaloids↗
PubMed1984

Fluosol 43 intravascular persistence in mice measured by 19F nmr.

Quantitative determination of the intravascular persistence of F-tri-n-butylamine (FC 43 as Fluosol 43) in mice was carried out using 19F nmr spectroscopy. The method allows the direct study of whole blood, neither separation nor extraction of the sample being required. Accuracy (reproducibility) is better than +/- 3%, and is comparable to that of the gas chromatographic (gc) method. The sensitivity of detection is less than that of the gc method but is sufficient for this biological study. It was observed that the intravascular elimination of F-tri-n-butylamine follows a non-linear kinetic and becomes faster about 40 h after the injection. This phenomenon may be explained by the size-increase of the FC 43 droplets in the emulsion. Indeed, at about 40 h after injection, the level of Pluronic F-68 in the bloodstream was no longer sufficient to maintain the stability of the FC-43 droplets. They therefore tended to coalesce forming larger droplets that were phagocytosed more rapidly by the histiocytes of the reticuloendothelial system.

Animals↗
PubMed1984

Pharmacological and preclinical toxicological studies of 1,2-diaminocyclohexane(isocitrato)platinum(II).

The antitumor activity of a new highly water-soluble platinum derivative, (1,2-diaminocyclohexane)(isocitrato)platinum(II) (NSC 350602; PHIC), was studied in L1210 leukemia cells inoculated into mice. PHIC was found to be active for i.p. graft-i.p. treatment, i.p. graft-i.v. treatment, and i.v. graft-p.o. treatment. A significant activity was observed on early and advanced L1210 leukemia even when the treatment was delayed 6 days after the graft. A comparison between the activities of PHIC, cisplatin (NSC 119875), and (4-carboxyphthalato)(1,2-diaminocyclohexane)-platinum(II) (NSC 271674; DACCP) for i.p. graft-i.p. treatment indicated that the highest activity was observed for divided doses rather than single dose in the case of PHIC and DACCP and not for cisplatin. Under these conditions, PHIC gave larger treated versus control survival time values or a greater number of surviving animals than did cisplatin and DACCP. No cross-resistance between PHIC and cisplatin could be detected in L1210 leukemia cells resistant to cisplatin. Mutagenicity studies on Salmonella typhimurium revealed that PHIC is far less mutagenic than cisplatin on TA100 and TA98 strains. Other pharmacological parameters, such as growth inhibition rate of cultured L1210 cells, penetration, and DNA binding in L1210 cells inoculated in mice, were compared for PHIC and cisplatin together with their in vitro rates of hydrolysis and platinum:DNA adducts. No nephrotoxicity was detected with PHIC at the maximum nonlethal dose level in mice in contrast to results with cisplatin. A preclinical study was conducted in baboons at 100, 150, and 200 mg/kg. No nephrotoxicity could be detected at a dose of 100 mg/kg without prehydration for six courses at 3-week intervals. At 200 mg/kg, an increase of blood creatinine was controlled by prehydration. Gastrointestinal toxicity was mild during the three regimens. Phase I clinical trials are under way.

Animals↗
PubMed1983

Heterocyclic Quinones. 4. A new highly cytotoxic drug: 6,7-bis(1-aziridinyl)-5,8-quinazolinedione.

With the aim of obtaining new antitumoral agents, a series of 5,8-quinazolinediones was prepared. 5-Amino-6-methoxyquinazoline was oxidized by Fremy's salt to give 6-methoxy-5,8-quinazolinedione. Nucleophilic substitution reaction at C6, electrophilic substitution at C7, and synthesis of 7-amino-6-methoxy-5,8-quinazolinedione, the parent compound of streptonigrin, were studied. These compounds were tested for cytotoxic properties on L1210 leukemia cells in vitro. One of them, 6,7-bis(1-aziridinyl)-5,8-quinazolinedione, which exhibits a high cytotoxic activity (ID50 = 0.08 microM), was further screened in standard antitumor systems, including L1210 leukemia, P388 lymphocytic leukemia, sarcoma 180, and B16 melanocarcinoma. This drug gives a significant antitumoral effect on P388 leukemia but is inactive on other experimental models. Moreover, this compound was found to be highly mutagenic for Salmonella typhimurium TA98 and TA100 strains (Ames test), suggesting that DNA damage could be responsible for its cytotoxicity.

Animals↗
PubMed1983

Mutagenicity and cytotoxicity of five antitumor ellipticines in mammalian cells and their structure-activity relationships in Salmonella.

The mutagenicity and cytotoxicity of five antitumor compounds (ellipticines) were investigated in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay and in six strains of Salmonella. All five compounds (ellipticine, 9-methoxyellipticine, 9-hydroxyellipticine, 9-aminoellipticine, and 2-methyl-9-hydroxyellipticinium) were cytotoxic and mutagenic in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay in the presence or absence of Aroclor 1254-induced rat liver S9, and all except the last compound were mutagenic in Salmonella. Based on the reversion pattern obtained in various frame-shift and DNA repair-proficient (uvrB+) or -deficient (uvrB) strains of Salmonella in the presence or absence of S9, the first three compounds appear to cause frame-shift mutations by both intercalation and covalent bonding with DNA; thus, these are classified as reactive intercalators. However, 9-aminoellipticine intercalates only weakly and may instead exert its mutagenic activity primarily (or exclusively) by forming a covalent adduct with DNA. Compared to the published antitumor data obtained in mice, the results in Salmonella and Chinese hamster ovary cells suggest that the ability of ellipticine, 9-methoxyellipticine, and 9-hydroxyellipticine to intercalate with DNA, induce frame-shift mutations, and cause cell killing is associated with and may be the basis for their antitumor activity. The observation that the ellipticines are mutagenic in mammalian cells suggests that these antitumor agents may be carcinogenic.

Alkaloids↗
PubMed1982

[Teratogenic effects of 9-hydroxy-ellipticine in mouse embryo].

Administered to pregnant Mice of Swiss strain, at stages of 9 to 12 days of gestation and at doses of 15 to 50 mg/kg, 9-hydroxy-ellipticine acts as an acute teratogen; it induces in embryos, cleft palate and limb deformities. Histological examination of embryos from mothers treated by a dose of 30 mg/kg at day 10 or 11 revealed defects in the eyes, spinal cord and a reduction in the number of germinal cells.

Alkaloids↗
PubMed1981

Influence of inducers of monooxygenases on cytotoxic efficiency of ellipticine on leukemia L1210 cells.

The effects of some inducers of microsomal cytochrome P450-dependent monooxygenases on the metabolic bioactivation and the cytotoxicity of the antitumoral drug ellipticine (ELPT) were studied. Rate of growth of leukemia L1210 cells was measured in vitro in the absence and presence of ELPT or measured when the ELPT was metabolically transformed by noninbred Sprague-Dawley rat liver microsomes. The animals used were either untreated or pretreated by various inducers such as phenobarbital, 3-methylcholanthrene, beta-naphthoflavone, 2,3,7,8-tetrachlorodibenzo-p-dioxin, Aroclor 1254, or ELPT. The transformation of ELPT into its two main metabolites, 9-hydroxyellipticine (9-OHE) and 7-hydroxyellipticine, was studied and measured by high-pressure liquid chromatography in conjunction with the determination of cytotoxic activity. A large variability was observed in the bioactivation and cytotoxic efficiency of ELPT mediated by the different microsomal preparations: The more P448 and/or P1-450 forms of cytochrome were induced, the more the 9-OHE was produced and the more the cytotoxicity toward L1210 cells was enhanced. These features were compared with those elicited by the activation of cyclophosphamide, which was transformed into cytotoxic metabolites by the cytochrome P450 form specifically induced by phenobarbital-type inducers.

Alkaloids↗