scientifiques
scientifiques
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Recherches scientifiques |
Publications scientifiques |
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| NUCLEOSIDES |
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4'-Hydroxymorpholin-2'-ylpurines and Pyrimidines12,19
We synthetized nucleoside analogues in which the ring ribofuranose was replaced by an N-hydroxy-morpholino cycle. Unfortunately none of the products of these series was active against the virus HIV. |
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Thymidine Analogues : Deoxy-(N-hydroxyamino) Nucleosides 11,10,24,28 Modified nucleosides still represent the most useful chemical series for the treatment of HIV infections (AZT, ddI). Such compounds, both endowed with anti HIV activity and bearing a paramagnetic probe, could constitute tools for the study of the mode of action of antiviral molecules. We prepared a series of deoxy-(N-hydroxyamino) analogues of the nucleosides. Some of these compounds showed marked activity against HIV-1 and HIV-2 replication in CEM cells. These products are not actives in cells that lack thymidine kinase, so their mode of action probably corresponds to the AZT, inhibitor of reverse transcriptase. In addition one of them was found to be more active against small-cell lung cancer then Ara-C or 5-FU. We were encouraged by these results and we prepared a lot of molecules having structures similar to the active products, for example O-alkylated oximes, and O- and N-alkyl hydroxylamines. None of them had interesting biological activity, just one compound was found to be active against the Hepatitis B virus in submicromolar concentrations. |
Nucleosides and Acyclonucleosides Bearing a N-Hydroxyureido Group27,30
 Hydroxyurea (HU), a ribonucleotide reductase inhibitor has been used in the treatment of some malignant and viral diseases and seems now to be promising, in association with 2,3dideoxynucleosides, for the management of AIDS. In an attempt to increase the specificity of action of this radical scavenger, or at least, to study the topological aspects of its reactivity, we introduced the N-hydroxyureido group into nucleosides by using Mitsunobu reaction or by reacting a nucleoside nitrogen nucleophile with a carbonyl electrophile. From the currently available antiviral testing results, concerning the nucleoside analogues it appears that the most noticable activity exert against Varicella Zoster virus (VZV). One acyclonucleoside derivative was found to be very active against the virus HIV-1, its therapeutic index is better than 100.000. We prepared peptid-like dinucleotide analogues33,36 also in which the internucleosidic bridge consists of a spacer of approximately the same length as in the natural compounds. These compounds could be tested as inhibitors of nucleotide-protein interactions, we supposed that they are able to disrupt zinc finger parts of nucleocapsid. Antiviral activity of these dinucleotides were tested in vitro against HIV-1, HIV-2, HSV-1, HSV-2, CMV, VZV and EBV but in no case EC50 values inferior to 10 µM was found. |
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Seconucleosides29 and neonucleosides
From the known dioxoseconucleosides a series of mono- and dihydroxylamine was prepared using a large variety of R groups of increasing lipophilicity. Antiviral properties of these novel compounds were also tested, unfortunately they didn't show any interesting activity. Neonucleosides were formed by ring-closure of a dimesyl derivative. |
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Bicyclonucleosides
Three different types of bicyclonucleosides were prepared: Isoxazolidinofuranosylthymines21 by using intramolecular Mitsunobu reactions. Pyrrolidino- or piperidinofuranosylnucleosides by reverse Cope elimination reaction25,32. Neither the isoxazolidinofuranosylthymines nor the pyrrolidino or the pyperidinofuranosylnucleosides showed activity against the virus HIV. Pyrrolidino- and piperidinofuranosyl analogues of the uridine are actually tested against the virus of the Hepatitis C. Perhydro-1,3-oxazinofuranosyl nucleosides23,31,35,37 by intramolecular nucleophilic addition of the 5'-OH group to the nitrone at the 3' position of the nucleoside.  Many of these compounds with unusual β-D-threo configuration had significant activity against HIV-1 and HIV-2, (IC50 in the 0.3-3.0 µM range). As this series is particularly interesting we prepared more than 50 of bicyclo compounds to study their structure-activity relationsships. |
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Spironucleosides
TSAO derivatives constitute useful models of HIV reverse transcriptase non-nucleoside site inhibitors. They can attain high levels of antiviral activity but the virus develops resistance to these compounds extremely rapidly. The sequence of the mutated enzyme provides useful information about interactions between the enzyme and its inhibitor. We prepared a series of spironucleosides bearing an 1,3-oxazidine or a perhydro-1,3oxazine rings. Unfortunately they are not active against the HIV. We are currently having them tested against other viruses like: HBV, HCV and Herpesviruses. |
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NEOGLYCOPROTEINS13 AND NEOGLYCOLIPIDS14,22
The neopglycoproteins are the semisynthetic proteins, prepared by fixation of one unit of glucide onto the native protein. We were the first to try to fix 1-deoxy-l-(N-hydroxyamino)-D-glucitol onto human and bovine serumalbumin through a pentamethylene spacer arm.  Artificial glycolipids exhibit a large spectrum of useful properties, for example: liquid crystals, specific detergents, immunomodulators, recognition markers for targeting drug delivery systems, and antiviral agents. In most of these applications, the usefulness of neoglycolipids should be further increased by spin labelling which would allow the monitoring of the interaction of these compounds with neighbouring molecules. For these reasons, we developed spin-labelling techniques consisting of the replacement of an oxy group (-O-) with the structurally close N-hydroxyamino (-N(OH)-) group. Study of their bilogîcal usefulness (anti-HIV, anti-prion) is under investigation. |
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| DIELS-ALDER REACTION IN CARBOHYDRATE CHEMISTRY |
| HETERO DIELS-ALDER REACTIONS |
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Thio Diels-Alder1,4,5,6,17
Because of their interesting biological effects, saccharides containing sulphur in the pyranose or furanose ring have been the subjects of a great deal of synthetic effort. Generally the ring sulphur atom is introduced by means of nucleophilic substitution reaction. Another possibility is the direct construction of the thiopyranose ring through cycloaddition of a thiodienophile onto a diene. We studied the Diels-Alder reaction of three types of thiodienophiles: pentathiomonoorthooxalates4,17, dithiooxalates5,6,17, and O-thioformates1,6,17. Diels-Alder rection of pentathiomonoorthooxalates with butadiene have yielded unsaturated, open-chain compounds. 1,1-dithiooxalates and O-thioformates gave 3,6-dihydro-2H-thiopyran skeleton, can be used for the synthesis of 5-thiopyranose sugar analogues. For example we found that (4+2) cycloaddition rections of sugar 1,1-dithiooxalates and O-thioformates with asymmetric dienes exhibit an opposite regioselectivity and the diastereoselectivity is poor in general. Ab initio calculations showed that the polarities of the LUMO orbitals are opposite for the two thiodienophiles, thus the opposite regioselectivity can be explained by this fact. From the products of the cycloaddition of O-thioformates we were able to synthetise simple disaccharides bearing sulphur in the pentopyranose unit. |
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Aza Diels-Alder16
Swainsonine is a natural product which has a potent α-mannosidase, immunomodulant, antimetastatic properties. Preparation of its analogues is of considerable importance for the elucidation of structure-biological activity relationships. We synthetized swainsonine analogues from D- and L-arabinose respectively. Configurations of the new stereocenters were deduced from NMR (NOE) measurements and by X-ray crystallography. |
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Intramolecular Diels-Alder reactions (IMDA)3,6,7,8,9,17
Intramolecular Diels-Alder reactions of 1,6,8-nonatrienes and 1,7,9-decatrienes have been used frequently for the construction of chiral ring systems of natural products. Our aim was to study the possibilities of the application of single monosaccharides as tether chains in IMDA reactions and the influence of the three or four chiral centers on the stereochemical outcome of the IMDA reactions. Every time excellent diastereoselectivity was observed. We attempted to explain our results by taking into consideration conformations leading to transition states. In summary it could be established that the stereochemical course of thermal IMDA reactions could be strongly influenced by substituents in the linking chain but not by the nature of the dienophile nor the diene. |
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| SYNTHESIS OF DIFFERENT SUGARS |
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Deoxylhydroxyarnino analogues of sugars11
Sugar derivatives in which one oxygen atom is replaced with a hydroxyamino group are structurally similar to their natural counterparts. The major interest of these deoxyhydroxyamino sugars was their easy oxidation into spin-labelled sugar analogues whose conformation could be studied by e.s.r. spectroscopy. Such compounds were prepared by conjugate addition of N-substituted hydroxylamines to sugar enolones. |
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D- and L-Daunoseamine (Utilisation of "Tartraldehydes")10,15
Tartraldehydes (2,3-dihydroxybutane-1,4-dials) and their derivatives are potential C4 dichiral synthetic units. We elaborated a simple method for their preparation, and we used them as starting materials for the synthesis of 3-amino-2,3,6-trideoxyhexoses, important constituents of several antibiotics and cardiotonic glycosides. |
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3,4-Dideoxy-DL-hex-3-enopyranosides2
Some years ago we elaborated a method for the short conversion of 5-hydroxymethyl-2-furaldehyde into isomeric methyl 3,4-dideoxy-DL-hex-3-enopyranosides from which rare monosaccharides were synthetized. |
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