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Biomedical subjects

C Monneret

Publications and source records attributed to C Monneret.

At least 37 records · Page 2Linked to original sources
PubMed1998

Heterocyclic nucleoside analogues by cycloaddition reactions of 1-vinylthymine with 1,3-dipoles.

1,3-Dipolar cycloaddition of 1-vinylthymine to azides, nitrile oxides, nitrones and nitronates has been investigated as a route to heterocyclic nucleoside analogues in which the nucleoside ribose moiety has been replaced by an alternative heterocycle. Reaction of 1-vinylthymine with highly reactive nitrile oxides affords 1-(isoxazolin-5-yl)thymine products in excellent yield at room temperature. The less reactive nitrone dipoles undergo cycloaddition to 1-vinylthymine at elevated temperature to afford 1-(isoxazolidin-5-yl)thymine cycloadducts in good-to-moderate yields, but show a tendency to eliminate thymine from the cycloaddition products over long reaction times. Azide cycloadditions to 1-vinylthymine proceed only under forcing conditions to which the fragile triazoline products are unstable.

Heterocyclic Compounds↗
PubMed1998

Doxorubicin prodrugs with reduced cytotoxicity suited for tumour-specific activation.

The three new hydrophilic prodrugs 2, 3 and 4 have been prepared from methyl (4-hydroxymethyl-2-nitrophenyl 2,3,4-tri-O-acetyl-beta-D-glucopyranosid)uronate (5) and doxorubicin. Their low cytotoxicity, efficient release of doxorubicin after hydrolysis by beta-D-glucuronidase, and in the cases of 2 and 3 stability at pH 7.2 fulfil the preliminary requirement for their use in antibody-directed enzyme prodrug therapy or prodrug monotherapy.

Antibiotics, Antineoplastic↗
PubMed1998

Synthesis of self-immolative glucuronide-based prodrugs of a phenol mustard.

The design and synthesis of the mustard pro-prodrugs which can be used in ADEPT is reported. Prodrugs 1 and 2 include a glucuronide group which is connected to the drug via an aromatic and/or aliphatic bis-carbamate spacer. The design of these new prodrugs takes advantage of a spontaneous 1,6-elimination and/or an intramolecular cyclization reaction after enzymatic cleavage. Thus, enzymatic-catalyzed hydrolysis of the glucuronyl moiety of 1 by Escherichia coli beta-glucuronidase results in the liberation of the parent mustard drug 20 with formation of CO2, 2-nitro-4-hydroxymethylphenol 19 and dimethylimidazolidinone 21. Surprisingly, prodrug 2 was not cleaved under the same conditions. According to in vitro experiments, prodrugs 1 and 2 were approximately 50- and 80-fold less cytotoxic than the parent drug and, when treated with beta-glucuronidase, the level of cytotoxic activity of 1 became comparable to that of the drug. Stability of 1 in phosphate buffer was satisfactory. These results demonstrate that 1 is a prodrug that can be specifically activated to release the cytotoxic agent.

Antineoplastic Agents↗
PubMed1997

A 3D QSAR study of a series of HEPT analogues: the influence of conformational mobility on HIV-1 reverse transcriptase inhibition.

Quantitative structure-activity relationships (QSAR) have been established for 87 analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), a potent inhibitor of the HIV-1 reverse transcriptase (RT). Of these 87 nonnucleoside RT inhibitors, 9 novel HEPT analogues were used in the study and the others were taken from the literature. The predictive ability of these relationships has been evaluated using a large set of 54 compounds which were not used to derive the activity model. Descriptors related to the conformational changes were found to be an important factor which underlies RT inhibitory activity in the HEPT series. Indeed, the QSAR model provides evidence concerning the conformational transformations the molecules may undergo during the inhibition process. The established relationships are supplementary to the experimental study on the binding of HEPT type inhibitors to RT by Hopkins et al. (J. Med. Chem. 1996, 39, 1589-1600). The present study suggests a quantitative interpretation of the structure-activity relationships which otherwise cannot be explained within the framework of the crystal inhibitor-protein model. This information is pertinent to the further design of new HEPT type RT inhibitors.

Anti-HIV Agents↗
PubMed1997

Synthesis and anti-HIV activity of novel N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT).

A series of 33 N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (1, HEPT) were synthesized and evaluated for their anti-HIV-1 activity. In particular, the influence of substitution of the terminal hydroxy group of the acyclic structure of HEPT and the structural rigidity of this side chain were investigated. Halo (7, 8), azido (9), and amino (10-15) derivatives were synthesized from HEPT via the p-tosylate derivative 6. Acylation of the primary amine 15 afforded the amido analogs 16-20. The diaryl derivatives 26-29 were prepared by reaction of HEPT, or of the 6-(2-pyridylthio) analog 23, with diaryl disulfides in the presence of tri-n-butylphosphine. Compounds 39-41, in which the N-1 side chain is rigidified by incorporation of an E-configured double bond, were obtained by palladium(0)-catalyzed coupling of several different 6-(arylthio)uracil derivatives (37, 38) with allyl acetates 33. Compounds 13, 40a,c,d,f, and 41, incorporating an aromatic ring at the end of the acyclic side chain, were found to be more potent than the known diphenyl-substituted HEPT analog BPT (2), two of them, 40c,d, being 10-fold more active.

Anti-HIV Agents↗
PubMed1997

Preparation and anti-HIV activity of N-3-substituted thymidine nucleoside analogs.

A series of 22 derivatives of AZT substituted at the N-3 position of the thymine base were prepared and evaluated for anti-HIV activity in cell culture (Lai strain of HIV-1 in CEM-c113 cells). The AZT analogs bearing a N-3 amino group (7), a hydroxyalkyl chain (12f), and a phosphonomethyl (12k) substituent displayed activities in the 0.045-0.082 microM range. The analogs 12d, 12e, 12q, 15, and 19 were active at <0.5 microM concentration. Compound 18 in which two molecules of AZT are connected at N-3 via a two-carbon link and "dimer" 11 also displayed significant activity. To obtain information concerning the mechanism of RT inhibition by these AZT analogs, compounds 7, 12d, 12e, and 12q were incubated with recombinant HIV-1 RT in the presence of poly(A)-oligo[dT(12-18)] and poly(C)-oligo[dG(12-18)] template-primers. In contrast to AZT-TP (control), none of these nucleosides displayed any significant inhibition of RT in the recombinant enzyme assay, indicating that phosphorylation is a necessary prerequisite for activity.

Anti-HIV Agents↗
PubMed1997

[Enantioselective synthesis of anthracyclines].

Enantioselective synthesis of new anthracyclinones is reported by chiral pool synthesis, using readily available lactose or glucose as starting materials. Glycosidation of such aglycones with various carbohydrates, including or not an amino function, led to anthracyclines endowed with significant antitumor activity but having some cross-resistance with daunorubicin and doxorubicin. Lowered cross-resistance was observed when the anthracycline beared an alkyl side-chain at C-9 and a morpholinyl residue at C-4'.

Antibiotics, Antineoplastic↗
PubMed1996

Enhanced topoisomerase II-induced DNA breaks and free radical production by a new anthracycline with potent antileukemic activity.

In a previous study we reported that a new anthracycline derivative (moflomycin) exhibited a higher antileukemic activity compared to other anthracyclines, such as daunorubicin and doxorubicin. To explain the superior antileukemic effect of moflomycin and to disclose a possible structure-activity relationship, we investigated the three main mechanisms by which anthracyclines are though to exert their antitumor effect: DNA binding, free radical production and topoisomerase II inhibition. The DNA interaction was assessed both by DNA binding and DNA unwinding assays, free radical generation was studied by electron spin resonance, and topoisomerase II interaction by analysis of the stimulation of enzyme-induced DNA breaks. The results showed a higher free radical production and a greater stimulation of topoisomerase II-mediated DNA cleavage by moflomycin than doxorubicin, associated with a lower DNA affinity. The different biochemical characteristics of moflomycin, particularly its interaction with topoisomerase II, are related to the structural modifications performed on the chromophore. These properties, associated with a higher stability of the molecule induced by the presence of an iodine atom on the sugar moiety, are probably responsible for the higher antileukemic activity of this compound.

Antibiotics, Antineoplastic↗
PubMed1995

A new anthracycline with potent antileukemic activity exhibits reduced mutagenicity.

The mutagenicity of a new anthracycline (moflomycin) with potent antileukemic activity was studied by the Ames test in four strains of Salmonella typhimurium (TA97a, TA98, TA100 and TA102), and compared to the mutagenicity of doxorubicin, widely used as antineoplastic agent. Unlike doxorubicin, moflomycin displayed no mutagenic activity in strains TA98 and TA100. Low mutagenicity was only observed in TA102 strain and was not enhanced after metabolic activation. This result indicates that moflomycin induce mutagenicity by reverting base-pair substitution. The structural changes in the sugar moiety may be involved in the reduced mutagenicity of moflomycin. The low mutagenicity of moflomycin shown in this study enhances the potential advantage of this new derivative which displays a high antileukemic activity.

Antibiotics, Antineoplastic↗
PubMed1995

Prodrugs of anthracycline antibiotics suited for tumor-specific activation.

The two novel prodrugs 4 and 11 have been prepared from tetra-O-acetyl-D-galactopyranose and doxorubicin in three and six steps, respectively. Their low cytotoxicity, high stability in plasma and, in the case of 11, efficient hydrolysis in the presence of alpha-galactosidase, fulfill preliminary conditions for their use in combination with monoclonal antibody-enzyme conjugates.

Animals↗
PubMed1994

Fusion protein mediated prodrug activation (FMPA) in vivo.

A two component system, consisting of a fusion protein and an appropriate prodrug, suited to perform selective tumor therapy in vivo, is presented. The fusion protein, owing to its humanized carcinoembryonic antigen (CEA)-specific variable region, specifically binds to CEA-expressing tumors and has an enzymatic activity comparable to human beta-glucuronidase. The prodrug is a nontoxic glucuronide-spacer-derivative of doxorubicin decomposing to doxorubicin by enzymatic deglucuronidation. In vivo studies in nude mice bearing human CEA-expressing tumor xenografts revealed that 7 d after injection of 20 mg/kg fusion protein, a high specificity ratio (> 100:1) was obtained between tumor and plasma. Injection of 250 mg/kg of prodrug at d 7 resulted in tumor therapeutic effects superior to conventional chemotherapy without any detectable toxicity. These superior therapeutic effects that were observed using established human tumor xenografts can be explained by the approx 10-fold higher drug concentrations found in tumors of mice treated with fusion protein and prodrug than in those treated with the maximal tolerable dose of drug alone.

Animals↗
PubMed1993

Synthesis and antitumor activity of isodoxorubicin analogues.

The synthesis and biological activity of the new 4-demethoxyanthracyclines 15, 22, and 23 are reported. They were obtained from synthetic 9-deacetyl-9-(hydroxymethyl)-4-demethoxydaunomycinone (isopropylidene derivative 9) and from 4-azido- or 4-amino-2,4,6-trideoxy-L- lyxo-hexoses. Anthracycline 22 (hydrochloride salt), the most active compound in the series, was slightly more potent than doxorubicin in vitro against three cell lines (L1210, HT29, A549). It was found to exhibit similar antitumor activity in vivo (iv route) against L1210 leukemia, but was less active than doxorubicin against three human tumors in a subrenal capsule assay LXF, A549, and HT29).

Animals↗
PubMed1992

Synthesis of a phenyl beta-avobioside derivative of the disaccharide component of avoparcins.

The synthesis of the phenyl beta-glycoside of avobiose, a disaccharide fragment present in the antibiotic avoparcin, is reported. It is based on glycosylation of phenyl 3,4,6-tri-O-benzyl-beta-D-glucopyranoside with 2,3,6-trideoxy-4-O-p-nitrobenzoyl-3-trifluoroacetamido-L-ribo-hex- 1-enitol, a fully protected glycal of L-ristosamine, in the presence of trimethylsilyl triflate.

Anti-Bacterial Agents↗
PubMed1992

[Synthesis of polydeoxygenated and iodinated disaccharides].

3-Amino-polydeoxy disaccharides have been prepared by condensation of a glycal with methyl 2,3,6-trideoxy-alpha-L-erythro-(or threo)-hex-2-enopyranoside in the presence of N-iodosuccinimide. After acid hydrolysis of the glycoside, 1,4-addition of hydrazoic acid to the corresponding hex-2-enopyranose led to 3-azido-disaccharides which were acetylated. Reduction of the azido group gave 2,2'-dideoxy- or 2,2'-dideoxy-2'-iodo compounds. Condensation of O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-alpha-L-manno-hexopy-rano syl)-(1----4)-1- O-acetyl-2,3,6-trideoxy-3-trifluoroacetamido-alpha-L-arabino-he xopyranose with daunomycinone, followed by 3',4'-O-deacetylation produced the new anthracycline, 7-O-[O-(2,6-dideoxy-2-iodo-alpha-L-manno-hexopyranosyl)-(1----4)-2,3,6- trideoxy-3-trifluoroacetamido-alpha-L-arabino-hexopyranosyl]-da uno-mycinone.

Carbohydrate Sequence↗
PubMed1991

Pharmacological and physicochemical properties of a new anthracycline with potent antileukemic activity.

The antiproliferative effect of F860191, a new anthracycline with high antitumor activity in L1210 leukemia-inoculated mice, was investigated in vitro on different leukemia cell lines. Comparison of the IC50 value of F860191 with that of daunorubicin and doxorubicin disclosed a superior activity for this drug against the three leukemia cell lines tested. Studies on the mechanism of the antiproliferative activity showed that F860191 induced a G2 + M arrest in the cycle of treated cells. Physicochemical properties of this drug suggested that the high cytotoxic effect of F860191 could be related to its capacity to induce free radicals and to generate DNA breaks through its interaction with topoisomerase II.

Animals↗