Roger Condom

Cyclic PNA hexamer-based compound: modelling, synthesis and inhibition of the HIV-1 RNA dimerization process

Abstract A cyclic molecule constituted by (i) a hexameric PNA moiety complementary to six among the nine residues of the dimerization initiation site loop of HIV-1 and (ii) a spacer tethering the N- to the C-extremities of the PNA, has been elaborated to inhibit the dimerization process of HIV-1 genome. This compound has been synthesized following a liquid-phase procedure (fully protected backbone approach). Preliminary agarose gel electrophoresis analyses have shown that the cyclic PNA conjugate is able to inhibit the HIV-1 dimerization.

Liquid phase synthesis of a peptidic nucleic acid dimer

Abstract The first liquid phase synthesis of a peptidic nucleic acid (PNA_) dimer containing guinine and adenine has been achieved in good yields. A new strategy was elaborated in order to circumvent difficult coupling of the protected PNA.

New synthetic routes to β-fluoro β-phenyllactic acid derivatives and β-fluorocyanohydrins

Abstract Alkyl phenyl 2,3-epoxycarboxylates from the well-known Darzens glycidic esters synthesis react under very mild conditions with pyridinium-poly-hydrogen fluoride to give corresponding 3-fluoro 3-phenyllactates in almost quantitative yields with a high regio and stereoselectivity. This method can be applied successfully to other glycidic derivatives : glycidoamides, glycidonitriles, glycidoiminoesters… The spectrometric propertities (IR, NMR) are presented.

Short peptide nucleic acids (PNA) inhibit hepatitis C virus internal ribosome entry site (IRES) dependent translation in vitro.

The internal ribosome entry site (IRES) of hepatitis C virus (HCV) which governs the initiation of protein synthesis from viral RNA represents an ideal target for antisense approaches. Using an original bicistronic plasmid, we first established that sequence and translational activity of HCV IRESs cloned from six patients, whether responders or not to combination therapy, were conserved. We then tested the hypothesis that antisense molecules, i.e. short peptide nucleic acids (PNA), could inhibit HCV translation by binding to the highly conserved IIId or IV loop regions of the IRES. Five 6-10mer PNAs were designed. They strongly inhibit HCV IRES-driven translation in a rabbit reticulocyte lysate assay. This inhibition was highly specific since corresponding PNAs with only one mismatch were inactive. Short phosphorothioate oligonucleotides of same sequence were unable to inhibit HCV translation. PNA molecule was shown to have anti-HCV activity in Huh-7.5 cells when electroporated with a full-length HCV genome construct. Using oligonucleotide as carrier, PNA was also transfected in HCV replicon-harboring cells and in JFH1 infected Huh-7.5 cells.

A short and highly stereoselective synthesis of α-(2-aminothiazolyl)-C-nucleosides

Abstract A short route to novel α-(2-aminothiazolyl)-C-nucleosides has been developed. The key step was the high diastereoselective reduction of the hemiacetal intermediates using L-Selectride, which afforded the corresponding R -diols in quantitative yields. These diols were converted, after C4–C1 ring closure and protecting groups cleavage, to their corresponding free α-C-nucleosides.

LIQUID-PHASE SYNTHESIS OF POLYAMIDE NUCLEIC ACIDS (PNA)

Abstract Three liquid-phase processes for the elaboration of short orthogonally protected PNA have been devised. Two of these methods are similar to the convergent and divergent approaches in peptide synthesis. The third process consists in building a fully protected polyamide backbone, by using as many different and orthogonal protecting groups as there are different types of nucleic bases in the targeted polyPNA. Simultaneous and selective cleavage of one kind of protecting group allows the simultaneous attachment of several identical nucleobase units.

Liquid-phase synthesis of a cyclic hexameric peptide nucleic acid

Abstract A cyclic fully N-protected hexameric (aminoethylglycinamide) can be readily obtained by using a divergent approach in liquid phase and consists of coupling orthogonal fragments of suitable oligomers. This cyclic N-protected backbone is then converted into a peptide nucleic acid by a series of selective deprotection–coupling steps affording the desired structure in good overall yields. Such a procedure could provide a general approach for targeting any short cyclic peptide nucleic acids (containing every kind of nucleobase).

Formation d'aziridines dans KF/acetonitrile - obtention de 3-fluoro amino-acides par ouverture avec HF/Py

Abstract Synthesis of 1-trityl-2-phenylaziridine, 1-trityl-2-methylaziridine and 2-methylcarboxylates of 1-tritylaziridine,1-trityl-3-methylaziridine, 1-trityl-3-phenylaziridine by reacting N-triphenylmethyl-α-chloroamines and methyl esters of N-triphenylmethyl-O-mesylsulfonyl-α-aminoacids with KF in acetonitrile under reflux is described. Functionalized aziridines opened with hydrogen fluoride in pyridine (70 %) give isobutyl 3-fluoroalanine, methyl 3-fluorophenylalanine and methyl 2-amino-3-fluorobutyrate.

Fluorinated peptides incorporating a 4-fluoroproline residue as potential inhibitors of HIV protease

Abstract N-Fmoc-4-fluoro-L-proline methyl ester was prepared as an attractive synthon for both solid and solution phase peptide synthesis. Its use for the synthesis of Fmoc-Phe-Pro(F)-OMe and Fmoc-Pro(F)-Val-Val-OMe is presented. Direct fluorination with DASTof a 4-hydroxy proline residue incorporated into a peptide and elongation from the terminal amino group allowed preparation of the hexapeptide Boc-AlaAla-Phe-Pro (F) -Val-Val-OMe, analogous to the p 17-p24 gag junction of structural HIV proteins. None of the fluoropeptides in the paper displayed anti-protease or anti-HIV activity.

Monofluoration quantitative par le phenyltetrafluorophosphorane influence de la température

Abstract The monofluorination by substitution of the hydroxyl group of the β-hydroxyesters of (o, m, p) Z - C 6 H 4 - C(OH)R - CH R′ - COOR″ structure (where Z = halogen, methyl, methoxy, nitro and H) of 2,2,2 trichloroarylcarbinols by the phenyl tetrafluorophosphorane is described. The temperature at which the alkoxytrifluorophosphorane is decomposed, determines the nature (alkene alkoxytrifluorophosphorane, monofluorinated compounds) of the products and their yield. Knowledge of this temperature for erythro and threo isomers permits the selective fluorination of one them in a mixture.