Christophe Mathé

Anti-human immunodeficiency and anti-hepatitis B virus activities of β-l-2′,3′-dideoxy purine nucleosides

Abstract β- l -2′,3′-Dideoxyadenosine, β- l -2′,3′-didehydro-2′,3′-dideoxyadenosine and related compounds were synthesized in a stereoselective manner. These compounds were tested in vitro against HBV in 2.2.15 cell line and against HIV-1 in PBM and CEM cells. It was found that β- l -2′,3′-dideohydro-2′,3′-dideoxyadenosine ( 7 ) exhibited significant anti-HIV (EC 50 0.38 μM in PBM cells) and anti-HBV activity (EC 50 1.2 μM).

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.

Inhibition of Hepatitis B Virus Replication by Nucleoside Enantiomers of β-2′,3′-Dideoxypurine Analogues

Various purine β-L-2′,3′-dideoxynucleoside analogues with both sugar and base modifications including β-L-ddG, β-L-ddl, β-L-ddA, 2′-azido-β-L-araddA, 2′-amino-β-L-araddA, 2′,5′-anhydro-β-L-araddA, 2′-azido-β-L-ddA, 2′-amino-β-L-ddA, 2′-fluoro-β-L-ddA, 3′-azido-β-L-ddA, 3′-amino-β-L-ddA, 3′-fluoro-β-L-ddA, 2,6-diamino-β-L-2′,3′-dideoxyfuranosylpurine, 6-cyclopropylamino-β-L-ddA, 2′-azido-6-N-triphenylphosphine-β-L-araddA, 2-amino-6-methylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopropylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopentylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2′,3′-didehydro-β-L-ddA and 2′,3′-didehydro-6-N-triphenyl phosphine-β-L-ddA were synthesized and evaluated as potential inhibitors of hepatitis B virus (HBV) replication in HBV DNA-transfected human hepatoblastoma-derived Hep-G2 cells (2.2.15 cells). β-L-ddA, 2′-azido-β-L-ddA, 3′-azido-β-L-ddA, 2″,3′-didehydro-β-L-ddA (β-L-D4A) and a modified base of β-L-D4A, inhibited HBV replication in vitro. β-L-D4A was the more potent and selective antiHBV agent with a 50% effective concentration value of 0.1 μM and a selectivity index of 1800. On the basis of this finding, studies are in progress to synthesize new purine derivatives with the β-L unnatural configuration which hopefully will lead to identifying additional potent and highly selective anti-HBV agents.

1,2-Di-O-acetyl-5-O-benzoyl-3-deoxy-l-erythro-pentofuranose, a convenient precursor for the stereospecific synthesis of nucleoside analogues with the unnatural β-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.

SYNTHESIS AND ANTIVIRAL EVALUATION OF 3′-C-TRIFLUOROMETHYL NUCLEOSIDE DERIVATIVES BEARING ADENINE AS THE BASE

3′-deoxy-3′-C-trifluoromethyl- (3), 2′,3′-dideoxy-3′-C-trifluoromethyl- (5) and 2′,3′-dideoxy-2′,3′-didehydro-3′-C-trifluoromethyladenosine (6) derivatives have been synthesized and their antiviral properties examined. All these derivatives were stereospecifically prepared by glycosylation of adenine with a trifluoromethyl sugar precursor (1), followed by appropriate chemical modifications. The prepared compounds were tested for their activity against HIV, but they did not show an antiviral effect.

Probing the reactivity of H-phosphonate derivatives for the hydrophosphonylation of various alkenes and alkynes under free-radical conditions

Hydrophosphonylation is an efficient process to create carbon–phosphorus bonds from unsaturated C–C bonds and to give rise to alkylphosphonate or vinylphosphonate derivatives. In this work, we report on the reactivity of H-phosphonate derivatives for the hydrophosphonylation of various alkenes and alkynes under photoinduced free-radical conditions. The reaction was carried out on activated, unactivated and/or disubstituted alkenes or alkynes with 2,2-dimethoxy-2-phenylacetophenone as a photoinitiator under UV irradiation.

Synthesis and biological evaluation of some 5-nitro- and 5-amino derivatives of 2'-deoxycytidine, 2',3'-dideoxyuridine, and 2',3'-dideoxycytidine.

Abstract In this article, we describe the synthesis of 5-nitro-1-(2-deoxy-α-D-erythro-pentofuranosyl)cytosine (4α), 5-nitro-1-(2-deoxy-β-D-erythro-pentofuranosyl)cytosine (4β), 5-amino-1-(2-deoxy-α-D-erythro-pentofuranosyl)cytosine (5α), 5-nitro-1- (2-deoxy-β-D-erythro-pentofuranosyl)cytosine (5β), 5-nitro-1-(2,3-dideoxy-β- D-ribofuranosyl)uracil (6β), 5-amino-1-(2,3-dideoxy-α,β-D-ribofuranosyl)uracil (7), 5-nitro-1-(2,3-dideoxy-α,β-D-ribofuranosyl)cytosine (8) and 5-amino-1-(2,3-dideoxy-β-D-ribofuranosyl)cytosine (9β). The prepared compounds were tested for their activity against HIV and HBV viruses, but they did not show significant activity.

Stereospecific synthesis of unnatural β-L-enantiomers of 2-chloroadenine pentofuranonucleoside derivatives

2′,3′-Dideoxy- (1), 2′,3′-unsaturated- (2), 2′,3′-dideoxy-3′-fluoro- (3), 3′-azido-2′,3′-dideoxy- (4) and 2′-deoxy- (5) β-L-ribofuranonucleosides of 2-chloroadenine have been synthesised and their antiviral properties examined. All these derivatives were stereospecifically prepared by glycosylation of 2,6-dichloropurine with a suitable peracylated L-xylo-furanose (6). Treatment of the resulting protected β-L-nucleoside with methanolic ammonia followed by appropriate chemical modifications gave the 2-chloro-9-(2-deoxy-β-L-threo-pentofuranosyl)adenine 11. Its 5′-O-benzoyl derivative 12 was then converted to nucleosides 1 and 2 via radical deoxygenation reaction or base-promoted β-elimination of the corresponding mesyl ester. Additionally, compounds 3–5 were obtained from 12 either by reaction with (diethylamino)sulfur trifluoride or via Mitsunobu reactions using diphenylphosphoryl azide or benzoic acid as incoming nucleophiles. The prepared compounds were tested for their activity against HIV and HBV viruses, but they did not show significant antiviral activity nor cytotoxicity.

New carbocyclic nucleoside analogues with a bicyclo[2.2.1]heptane fragment as sugar moiety; synthesis, X-ray crystallography and anticancer activity.

An amine group was synthesized starting from an optically active bicyclo[2.2.1]heptane compound, which was then used to build the 5 atoms ring of a key 6-chloropurine intermediate. This was then reacted with ammonia and selected amines obtaining new adenine- and 6-substituted adenine conformationally constrained carbocyclic nucleoside analogues with a bicyclo[2.2.1]heptane skeleton in the sugar moiety. X-ray crystallography confirmed an exo-coupling of base to the ring and a L configuration of the nucleoside analogues. The compounds were tested for anticancer activity.

Revisited 3′-Deoxy-3′-C-Methyl-β-D-Ribonucleoside Series

The synthesis of some 3′-deoxy-3′-C-methylnucleoside analogues bearing naturally occuring nucleic acid bases was achieved from the preparation of a suitable peracylated 3-deoxy-3-C-methyl sugar using a stereoselective pathway. In addition, examples of chemical modifications at the 2′ position are presented.