Martina Zsély

New types of spin-labelled sugar and nucleoside analogs: Pyrrolidine, morpholine and piperidine N-Oxyls

Abstract Analogs of blocked furanose ( 20 ) or pyranose sugars (i.e. 15 ) and of nucleosides (i.e. 23 ) in which the ring oxygen has been replaced with a -N(OH)-bridge have been prepared in generally good yields by a general reductive cyclization procedure preserving the configuration of the preexistant asymetric centers and proceedings stereoselectively (in more favorable cases stereospecifically) when creating a new asymetric center. The title compounds oxidized to nitroxide free radicals affording usable ESR spectra.

Spin-labelled glycolipid analogues" D-glucose series

Abstract Neoglycolipids bearing a paramagnetic probe in their lipophilic aglycon have been prepared. All belong to the d -glucose series, both anomers for the glucoside representatives, respectively β and α anomers in the S - and C -glucosyl series. Two different types of radical sites have been used, a relatively short-lived imino N -oxyl group for glucosides and a more stable N -acylamino N -oxyl moiety in the other cases. EPR spectra of these radical species afforded information on the conformation of the lipophilic chain in the vicinity of the paramagnetic probe.

Anti-HIV Derivatives of 1-(2,3-Dideoxy-3-N-hydroxyamino-β-D-threo-pentofuranosyl)thymine

Abstract Representative examples of the title compounds including bicyclic analogs (7–9) in which a perhydro-1,3-oxazine is ortho-fused to the furanose ring, have been prepared in good to excellent yields. Compounds 5 and 7 showed marked activity against HIV-1 and HIV-2 replication in CEM cells (50% inhibitory concentration: 0.80–4.3μg/mL). Their di-O-acetylated (6) and mono-O-acetylated (8) derivatives were considerably less effective. To the best of our knowledge, these β-D-threo anti-HIV nucleoside analogs constitute the first examples of anti-HIV active nucleosides bearing this configuration.

Synthesis and anti-HIV activity of 3′-deoxy-3′-(N-hydroxyamino) analogues of nucleosides

Abstract 3′-Deoxy analogues of thymidine and uridine bearing a 3′-N-alkyl-(or N-aralkyl) -N-hydroxyamino group either on the α or the β face of the furanose ring have been prepared. One of these (13), exhibited a moderate anti-HIV activity.

Spin labeled nucleoside analogues: 4'-Hydroxymorpholin-2'-ylpurines and pyrimidines

Abstract Upon borane-pyridine reduction, a series of nucleoside dialdehyde dioximes 2 underwent cyclization to the corresponding 4′-hydroxymorpholin-2′-ylpurines or pyrimidines 3 from which the peracetyl derivatives 4 were prepared. At room temperature, compounds 3 and 4 exist as a mixture of invertomers in which the 4′S (equatorial 4′-OH or 4′-OAc) predominates. A 14 kcal/mol, nitrogen inversion barrier was estimated from variable temperature experiments. N.O.E. and 3JCH measurements established the anti conformation of the base-“sugar” bond. Compounds 3 spontaneously oxidized to the corresponding aminoxyl free radicals, EPR spectra of which showed that they existed in a chair conformation.

Deoxyhydroxyamino analogs of sugars : derivatives of methyl 2,3-dideoxy-2-hydroxyamino-α-D-arabino-and -lyxo-hexopyranosides

Abstract N -Substituted hydroxylamines reacted both regio- and stereo-specifically with ethyl 2,3-dideoxy-α- d - glycero -hex-2-enopyranosid-4-ulose ( 1 ) to give N -substituted ethyl 2,3-dideoxy-2-hydroxyamino-α- d - threo -hexopyranosid-4-uloses ( 2 – 7 ), whereas O -methylhydroxylamine gave a mixture of O -methyloximes ( 8 – 10 ), including the product of both stereospecific conjugate addition and oximation ( 10 ). Sodium borohydride reduction of ethyl 2,3-dideoxy-2-( N -hydroxy- N -methylamino)- and 2,3-dideoxy-2-( N -hydroxy- N -isopropylamino)α- d - threo -hexopyranosid-4-uloses proceeded stereoselectively, and the major product had the α- d - arabino configuration. The conformations of these compounds were established using n.m.r. spectroscopy and X-ray diffraction for 3 and 19 . The major interest of these deoxyhydroxyamino sugars was their easy oxidation into spin-labelled sugar analogs whose conformation could be studied by e.s.r. spectroscopy.

Spin-labelled sulfur containing neoglycolipids

A neoglycolipid of structure beta-D-Glcp-S-(CH2)3N(OH)(CH2)4-O-cholest-5-en-3 beta-yl has been prepared in fair overall yield by reduction of the nitrone obtained by condensation of beta-D-Glcp-S-(CH2)3NHOH and OCH-(CH2)3-O-cholest-5-en-3 beta-yl. This synthetic procedure is very flexible, allowing a large range of lengths for the spacer arm, different positions for the NOH group along the spacer arm chain and the replacement of the sulfur by other bio-isosteric groups. The new neoglycolipid spontaneously oxidized to the corresponding nitroxide free radical whose EPR spectrum gave information on its conformational equilibrium which was further studied by molecular mechanics.

BICYCLONUCLEOSIDES AND RING-CHAIN INTERCONVERSION

Four types of bicyclonucleosides differing in the easiness of their ring-chain interconversion have been prepared, some exhibited anti-HIV activity and the ratio of their cyclic and open-chain forms could have some bearing on their biological activity.

Synthesis and Anti-HIV Activity of Further Examples of 1-[3-Deoxy-3-(N-hydroxyamino)-β-d-threo-(and β-d-erythro)-pentofuranosyl]thymine Derivatives1

Abstract Upon sodium cyanoborohydride reduction followed by de-O-silylation, the O-methyloxime and N-benzylnitrone of 5′-TBDMS-3′-ketothymidine gave resolvable epimeric mixtures of 1-[2,3-dideoxy-3-(N-methoxyamino)-β-d-threo-and β-d-erythro-pentofuranosyl]thymine and 1-[3-(N-benzyl-N-hydroxyamino)-2,3-dideoxy-β-d-threo- and β-d-erythro-pentofuranosyl]thymine respectively. These compounds were inactive against HIV. On the other hand, 1-[2,3-dideoxy-3-(N-hydroxyamino)-5-O-TBDMS-β-d-threo-pentofuranosyl]thymine, upon treatment with acetone, then de-O-silylation, gave the bicyclonucleoside analogue 15, slightly more active against HIV in vitro than DDI.

Novel Types of Spin Labelled Nucleoside Analogues

Abstract A variety of modified nucleosides or dinucleosides bearing one of the following functions have been prepared: N-hydroxyureas, N-hydroxyamines, N-hydroxycarbamates, α-(N-hydroxyamino)phosphonates. Upon oxidation, these compounds afford the corresponding aminoxyl free radicals which have been studied by EPR spectroscopy. Some of these compounds exhibited antiviral properties.