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Biomedical subjects

C Mathé

Publications and source records attributed to C Mathé.

At least 19 recordsLinked to original sources
PubMed2001

Stereospecific synthesis and biological evaluations of beta-L-pentofuranonucleoside derivatives of 5-fluorouracil and 5-fluorocytosine.

In the search for new chemotherapeutic agents, we have focused our work on the synthesis and the study of several unnatural beta-L-nucleoside analogues. In this paper, we report on the synthesis of beta-L-pentofuranonucleosides (and their 2'-deoxy derivatives) of 5-fluorouracil and their inhibitory effects on the proliferation of several murine and human tumor cells. The corresponding 5-fluorocytosine derivatives were also synthesized and their anti-HIV and anti-HBV activities have been evaluated.

Animals↗
PubMed2001

5-(Trifluoromethyl)-beta-l-2'-deoxyuridine, the L-enantiomer of trifluorothymidine: stereospecific synthesis and antiherpetic evaluations.

As a part of our ongoing work on beta-L-nucleoside analogues as potential antiviral drugs, we have synthesized 5-(trifluoromethyl)-beta-L-2'-deoxyuridine (L-TFT), the hitherto unknown L-enantiomer of trifluorothymidine (CF(3)dUrd, TFT). We have also studied the effect of L-TFT on human and herpes simplex virus (HSV) type 1 and 2 thymidine kinases, and human thymidine phosphorylase, as well as its anti-HSV-1 and anti-HSV-2 activities in cell cultures. L-TFT has been found: (i) to inhibit HSV-1 TK with activity comparable to TFT, with no effect on human TK, (ii) to be phosphorylated by the viral enzyme with similar efficiency to TFT, (iii) to be resistant, in contrast to TFT, to hydrolysis by human thymidine phosphorylase. Unfortunately, when evaluated in cell cultures, L-TFT did not show any anti-HSV-1 and anti-HSV-2 activities.

Antiviral Agents↗
PubMed2000

Inhibition of the ras-dependent mitogenic pathway by phosphopeptide prodrugs with antiproliferative properties.

Phosphopeptide prodrugs bearing two S-acyl-2-thioethyl (SATE) biolabile phosphate protections were developed. They are capable to inhibit the Shc/Grb2 interaction and MAP kinases (ERK1 and ERK2) phosphorylation in cellular assay. The S-acetyl-2-thioethyl (MeSATE) analogue showed an IC50 of 1 microM in the inhibition of the colony formation of tumor cell line NIH3T3/HER2.

3T3 Cells↗
PubMed2000

Gene prediction and gene classes in Arabidopsis thaliana.

Gene prediction methods for eukaryotic genomes still are not fully satisfying. One way to improve gene prediction accuracy, proven to be relevant for prokaryotes, is to consider more than one model of genes. Thus, we used our classification of Arabidopsis thaliana genes in two classes (CU(1) and CU(2)), previously delineated according to statistical features, in the GeneMark gene identification program. For each gene class, as well as for the two classes combined, a Markov model was developed (respectively, GM-CU(1), GM-CU(2) and GM-all) and then used on a test set of 168 genes to compare their respective efficiency. We concluded from this analysis that GM-CU(1) is more sensitive than GM-CU(2) which seems to be more specific to a gene type. Besides, GM-all does not give better results than GM-CU(1) and combining results from GM-CU(1) and GM-CU(2) greatly improve prediction efficiency in comparison with predictions made with GM-all only. Thus, this work confirms the necessity to consider more than one gene model for gene prediction in eukaryotic genomes, and to look for gene classes in order to build these models.

Arabidopsis↗
PubMed2000

1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-L-erythro-pentofuran ose, a convenient precursor for the stereospecific synthesis of nucleoside analogues with the unnatural beta-L-configuration.

The title compound 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-L-erythro-pentofuranose (5), a useful precursor for the stereospecific synthesis of beta-L-nucleoside analogues as potential antiviral agents, has been synthesised by a multi-step reaction sequence from L-xylose with a 38% overall yield. The preparation involved conversion of L-xylose to 1,2-O-isopropylidene-alpha-L-xylofuranose which, upon selective 5-O-benzoylation and subsequent radical deoxygenation, provided the protected 3-deoxy sugar derivative. Finally, cleavage of the acetonide group gave the resulting 5-O-benzoyl-3-deoxy-L-erythro-pentose which was acetylated to afford crystalline alpha,beta-5.

Acetic Anhydrides↗
PubMed2000

Unnatural enantiomers of 5-azacytidine analogues: syntheses and enzymatic properties.

Although 2'-deoxy-beta-D-5-azacytidine (Decitabine) and beta-D-5-azacytidine display potent antileukemic properties, their therapeutic use is hampered by their sensitivity to nucleophiles and to deamination catalysed by cytidine deaminase. As shown earlier [Shafiee M., Griffon J.-F., Gosselin G., Cambi A., Vincenzetti S., Vita A., Erikson S., Imbach J.-L., Maury G., Biochem. Pharmacol. 56 (1998) 1237-1242], beta-L-enantiomers of cytidine derivatives are resistant to cytidine deaminase. We thus synthesized several 5-azacytosine beta-L-nucleoside analogues to evaluate their enzymatic and biological properties. 2'-Deoxy-beta-L-5-azacytidine (L-Decitabine), beta-L-5-azacytidine, 1-(beta-L-xylo-furanosyl)5-azacytosine, and 1-(2-deoxy-beta-L-threo-pentofuranosyl)5-azacytosine were stereospecifically prepared starting from L-ribose and L-xylose. D- and L-enantiomers of 2'-deoxy-beta-5-azacytidine were weak substrates of human recombinant deoxycytidine kinase (dCK) compared to beta-D-deoxycytidine, whereas both enantiomers of beta-5-azacytidine or the L-xylo-analogues were not substrates of the enzyme. As expected, none of the presently reported derivatives of beta-L-5-azacytidine was a substrate of human recombinant cytidine deaminase (CDA). The prepared compounds were tested for their activity against HIV and HBV and they did not show any significant activity or cytotoxicity. In the case of L-Decitabine, this suggests that the enantioselectivities of concerned enzymes other than dCK and CDA might not be favourable.

Antiviral Agents↗
PubMed1999

Molecular basis for the enantioselectivity of HIV-1 reverse transcriptase: role of the 3'-hydroxyl group of the L-(beta)-ribose in chiral discrimination between D- and L-enantiomers of deoxy- and dideoxy-nucleoside triphosphate analogs.

In order to identify the basis for the relaxed enantio-selectivity of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and to evaluate possible cross-resistance patterns between L-nucleoside-, D-nucleoside- and non-nucleoside RT inhibitors, to be utilised in anti-HIV-1 combination therapy, we applied an in vitro approach based on the utilisation of six recom-binant HIV-1 RT mutants containing single amino acid substitutions known to confer Nevirapine resistance in treated patients. The mutants were compared on different RNA/DNA and DNA/DNA substrates to the wild type (wt) enzyme for their sensitivity towards inhibition by the D- and L-enantiomers of 2'-deoxy- and 2',3'-dideoxynucleoside triphosphate analogs. The results showed that the 3'-hydroxyl group of the L-(beta)-2'-deoxyribose moiety caused an unfavourable steric hindrance with critic residues in the HIV-1 RT active site and this steric barrier was increased by the Y181I mutation. Elimination of the 3'-hydroxyl group removed this hindrance and significantly improved binding to the HIV-1 RT wt and to the mutants. These results demonstrate the critical role of both the tyrosine 181 of RT and the 3'-position of the sugar ring, in chiral discrimination between D- and L-nucleoside triphosphates. Moreover, they provide an important rationale for the combination of D- and L-(beta)-dideoxynucleoside analogs with non-nucleoside RT inhibitors in anti-HIV chemotherapy, since non-nucleosideinhibitors resistance mutations did not confer cross-resistance to dideoxynucleoside analogs.

Anti-HIV Agents↗
PubMed1999

Classification of Arabidopsis thaliana gene sequences: clustering of coding sequences into two groups according to codon usage improves gene prediction.

While genomic sequences are accumulating, finding the location of the genes remains a major issue that can be solved only for about a half of them by homology searches. Prediction methods are thus required, but unfortunately are not fully satisfying. Most prediction methods implicitly assume a unique model for genes. This is an oversimplification as demonstrated by the possibility to group coding sequences into several classes in Escherichia coli and other genomes. As no classification existed for Arabidopsis thaliana, we classified genes according to the statistical features of their coding sequences. A clustering algorithm using a codon usage model was developed and applied to coding sequences from A. thaliana, E. coli, and a mixture of both. By using it, Arabidopsis sequences were clustered into two classes. The CU1 and CU2 classes differed essentially by the choice of pyrimidine bases at the codon silent sites: CU2 genes often use C whereas CU1 genes prefer T. This classification discriminated the Arabidopsis genes according to their expressiveness, highly expressed genes being clustered in CU2 and genes expected to have a lower expression, such as the regulatory genes, in CU1. The algorithm separated the sequences of the Escherichia-Arabidopsis mixed data set into five classes according to the species, except for one class. This mixed class contained 89 % Arabidopsis genes from CU1 and 11 % E. coli genes, mostly horizontally transferred. Interestingly, most genes encoding organelle-targeted proteins, except the photosynthetic and photoassimilatory ones, were clustered in CU1. By tailoring the GeneMark CDS prediction algorithm to the observed coding sequence classes, its quality of prediction was greatly improved. Similar improvement can be expected with other prediction systems.

Algorithms↗
PubMed1999

Evaluation of gene prediction software using a genomic data set: application to Arabidopsis thaliana sequences.

MOTIVATION: The annotation of the Arabidopsis thaliana genome remains a problem in terms of time and quality. To improve the annotation process, we want to choose the most appropriate tools to use inside a computer-assisted annotation platform. We therefore need evaluation of prediction programs with Arabidopsis sequences containing multiple genes. RESULTS: We have developed AraSet, a data set of contigs of validated genes, enabling the evaluation of multi-gene models for the Arabidopsis genome. Besides conventional metrics to evaluate gene prediction at the site and the exon levels, new measures were introduced for the prediction at the protein sequence level as well as for the evaluation of gene models. This evaluation method is of general interest and could apply to any new gene prediction software and to any eukaryotic genome. The GeneMark.hmm program appears to be the most accurate software at all three levels for the Arabidopsis genomic sequences. Gene modeling could be further improved by combination of prediction software. AVAILABILITY: The AraSet sequence set, the Perl programs and complementary results and notes are available at http://sphinx.rug.ac.be:8080/biocomp/napav/. CONTACT: Pierre.Rouze@gengenp.rug.ac.be.

Alternative Splicing↗
PubMed1994

Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro.

The L enantiomer of 2',3'-dideoxycytidine (DDC) was recently shown to inhibit selectively human immunodeficiency virus type 1 (HIV-1) in vitro. In the current study, the potent anti-HIV activity of L-DDC was confirmed and extended to several HIV-1 and HIV-2 strains in various cell culture systems, including primary human lymphocytes and macrophages. Furthermore, its 5-fluoro congener, beta-L-2',3'-dideoxy-5-fluorocytidine (L-FDDC), was found to have more potent anti-HIV activity and a higher therapeutic index in acutely infected human peripheral blood mononuclear cells. These compounds had no marked activity against HIV-1 isolates resistant to the oxathiolane pyrimidine nucleosides (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine, but 3'-azido-3'-deoxythymidine (AZT)-resistant viruses were susceptible to L-DDC and L-FDDC. Cytotoxicity studies with human myeloid progenitor cells indicated that L-DDC and L-FDDC had median inhibitory concentrations comparable to those of AZT, DDC, and FDDC, but L-DDC and L-FDDC were significantly less toxic than AZT, DDC, and FDDC when erythroid progenitor cells were used. L-FDDC had the highest selectivity indices (6,000 and 9,000 for erythroid and myeloid progenitor cells, respectively) of all the compounds evaluated. Further preclinical development of L-FDDC is warranted in order to determine its potential usefulness in the treatment of HIV infections.

Antiviral Agents↗
PubMed1994

Pure nucleoside enantiomers of beta-2',3'-dideoxycytidine analogs are selective inhibitors of hepatitis B virus in vitro.

(-)-beta-L-2',3'-Dideoxycytidine (beta-L-DDC), (+)-beta-D-2',3'-dideoxycytidine (beta-D-DDC), (-)-beta-L-2',3'-dideoxy-5-fluorocytidine (beta-L-FDDC), (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine (beta-L-FTC), and (+)-beta-D-1,3-dioxolane-5-fluorocytidine (beta-D-FDOC) were evaluated for their anti-hepatitis B virus (anti-HBV) activities in HBV-transfected human liver cells (2.2.15). The order of decreasing potency for the compounds at the 90% effect level was beta-D-FDOC > beta-L-FTC > beta-L-FDDC approximately beta-L-DDC >> beta-D-DDC. Inhibition of HBV in transfected liver cells by the cytosine nucleosides was selective. The beta-L-nucleoside-5'-triphosphates were consistently more potent inhibitors of woodchuck hepatitis virus DNA polymerase than the corresponding natural beta-D-enantiomers.

Antiviral Agents↗
PubMed1994

Enantiomeric 2',3'-dideoxycytidine derivatives are potent human immunodeficiency virus inhibitors in cell cultures.

2',3'-dideoxy-beta-L-cytidine (beta-L-DDC) and its 5-fluoro derivative (beta-L-5-F-DDC) have been stereospecifically synthesized by a multi-step reaction sequence from L-xylose and their anti-HIV properties examined. Among these two L-enantiomers, the hitherto unknown beta-L-5-F-DDC emerged as a potent anti-HIV-1 and HIV-2 compound in different cell culture systems, with selectivity indices similar or superior to those of the currently licensed drug DDC which has the natural beta-D configuration.

Cells, Cultured↗
PubMed1992

[Deep venous thromboses in erysipelas of the leg. A prospective study of 40 cases].

The treatment of lover limb erysipelas rests on antibiotic therapy directed against streptococci, but the necessity of prescribing a concomitant anticoagulant treatment has not yet been established. The incidence of deep vein thrombosis in patients with erysipelas of the leg in unknown. In a prospective study of 40 patients presenting with this type of skin disease, we looked for deep vein thrombosis, using systematically pulsed Doppler vein exploration combined with ultrasonography and, if necessary, a second Doppler examination and a phlebography. Six cases of deep vein thrombosis were diagnosed. This complication was observed in 5 patients at high risk for deep venous thrombosis; it had never been foreseen at clinical examination.

Adult↗
PubMed1989

[Congenital mesoblastic nephroma in the adult].

Congenital mesoblastic nephroma is a benign neoplasm of the kidney which is usually diagnosed during the first three months of life. We report herein a case of mesoblastic nephroma in a 69 year-old man. At this age, diagnosis can only be made by histopathologic examination of the operative specimen. This was the case for our patient and the five other cases reported in the literature. Histogenesis of mesoblastic nephroma is open to debate: mesenchymal origin for some authors, tumor of the blastema for most of the others.

Aged↗
PubMed1984

[The model of French medicine and its structural requirements for the year 2000].

The authors review the quality and defects of the French medicine model regarding its structural, hygienic, human, budgetary, geographic, educational and scientific aspects. They suggest several solutions concerning the necessary separation between hospitals, which should be reserved for patients, and institutions for healthy subjects, because of microbial infection dangers. They recommend the division of the latter into centers for family planning and maternity, centers for the detection, prevention and health education and centers for medical adaptation and education. They stress the advantages and the necessity of maintaining two structures, public and private, and the need for a European health policy to produce medical appliances in the field of imaging and automation, which France lacks so much that the short and long term future of its medicine is threatened.

Budgets↗
PubMedDate not supplied

[Systemic scleroderma and primary bronchopulmonary adenocarcinoma. A new case].

The authors report a case of systemic sclerosis associated with primary lung adenocarcinoma. This association has previously been reported in patients with old scleroderma complicated by extensive fibrosis of the lungs allegedly regarded as a precancerous lesion. The case reported here is of interest owing to the absence of pulmonary fibrosis.

Adenocarcinoma↗