Jean M. J. Tronchet

Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase: from the Biology of Reverse Transcription to Molecular Design

Replication of human immunodeficiency virus 1 (HIV-1) uses a viral reverse transcriptase (RT) to convert its positive-strand RNA into double stranded DNA, which is then integrated into host genome. Reverse transcription is a complex event involving p66 and p51 RT subunits but also several viral proteins including Nef, Tat, Vif, IN, NCp7 and p55gag. Viral RNA itself forms a primer/template complex by association with a cellular tRNA(Lys3) which is already present in mature virions. A RT initiation complex (RTIC) is thus formed which may also involve cellular protein upon viral entry. X rays diffraction and NMR studies of free or inhibitor-bound RT have led to the recognition of RT 3D structure, and allowed a thorough understanding of the mode of action of classical competitive nucleoside RT inhibitors (NRTIs) and of the binding of allosteric, non NRTIs (NNRTIs) inhibitors. This also opened an access to computer-aided drug design and modeling. Current NNRTIs represent, in terms of chemical structures, a heterogeneous class of inhibitors currently undergoing extensive development. By contrast with NRTIs, they seem to block initiation steps of reverse transcription. Molecular dynamics, detailed analysis of their interaction with RT as well as the incidence, in the series, of cases of non classical biological behavior, as illustrated here for a new family of compounds, suggest mechanisms of action which are not understandable without considering the involvement of the RTIC as a whole. This opens the exciting perspective of developing new compounds based on this integrated knowledge. Key Words: Nonnucleoside reverse transcriptase inhibitors (NNRTIs); Reverse transcriptase initiation complex (RTIC); Human immunodeficiency virus (HIV); Non classical nonnucleoside reverse transcriptase inhibitors; Molecular modeling; Docking; QSAR; Natural endogenous reverse transcription (NERT).

α-Deoxy-α-hydroxyamino sugar phosphonates and the corresponding nitroxide free-radicals☆

Abstract Treatment of sugar aldonitrones with dialkyl phosphites gave sugar α-deoxy-α-( N -hydroxy- N -methylamino)phosphonates, often highly stereoselectively. Repeated nucleophilic addition to a nitrone followed by oxidation of the resulting hydroxylamine allows the “first generation” nitrone, 1,2- O -isopropylidene-α- d - xylo -pentodialdo-1,4-furanose 5-( N -methyloxime), to be converted into the “third generation” cyclic nitrone, [(4 R )-4-diethoxyphosphoryl-5 H ,6 H -1,3-oxazino][6,5- c ](1,2- O -isopropylidene-α- d - xylo -tetrofuranose) N -oxide. The configurational and conformational assignments for all the new compounds prepared were based on short and long-range H,H, H,P, and P,C couplings, and new empirical rules regarding long-range H,P couplings are proposed. The sugar α-deoxy-α-hydroxyamino-phosphonates spontaneously oxidised in the air to give the corresponding nitroxide free-radicals, which afforded good e.s.r. spectra that allowed epimers at the α-carbon atom to be discriminated.

A QSAR study confirming the heterogeneity of the HEPT derivative series regarding their interaction with HIV reverse transcriptase

Summary QSAR concerning the anti-HIV and cytotoxic activities of a series of HEPT analogues has been established using a Hansch-type approach (TSAR™), a neural network approach (TSAR) and a pharmacophore search method (CATALYST™). The techniques employed allowed reliable activity predictions and confirmed the heterogeneity of this series of compounds, which was previously established in biochemical experiments.

Influence des effets orbitalaires sur l'équilibre conformationnel des sucres à insaturation terminale de configuration E

Abstract The glycenoses and alkenes bearing an alkoxy group on the allylic carbon atom and having the general formula RCH(OR)′CHCHX ( E configuration) preferentially adopt, in solution, a conformation in which the alkoxylgroup eclipses the double bond. This conformation is particularly favored when X is an electron-withdrawing group by resonance; it becomes less favored or totally unfavored when X is electron-donating by resonance. This phenomenon, which cannot be attributed to steric hindrance, is explained by inter-orbital interactions.

3-C-(Acylméthylène)-3-désoxy-1,2:5,6-di-O-isopropylidène-α-d-ribo- et -xylo-hexofuranoses

Abstract 1,2:5,6-Di-O-isopropylidene-α- d -ribo- and -xylo-hexofuranos-3-uloses (1 and 2) were treated with the following stabilized phosphorus ylides: (ethoxycarbonylmethylene)triphenylphosphorane, (acetylmethylene)triphenylphosphorane, and (benzoylmethylene)triphenylphosphorane. With the keto sugar having a xylo configuration, a mixture of the geometrical isomers of expected α,β-unsaturated esters or of the enones was obtained in excellent yield. In addition to the usual compounds, the keto sugar 1 gave side-products originating from an epimerization at C-4 or from an allylic prototropy. When 1 and 2 were treated with an excess of (formylmethylene)-triphenylphosphorane, they not only gave monoalkylidenation products, but they also underwent a dialkylidenation. During the course of these reactions, epimerization at C-4 in the unusual direction xylo to ribo, as well as in the more common direction, ribo to xylo, was observed. In dimethyl sulfoxide solution, the cis-3-C-(acetylmethylene)-3-deoxy-1,2:5,6-di-O-isopropylidene-α- d -ribo- and -xylo-hexofuranoses underwent, at an appreciable speed at temperatures above 100°, an allylic prototropic reaction leading to the formation of 3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-(2-oxopropyl)-α- d -erythro-hex-3-enofuranose. The kinetic parameters of the allylic transposition reactions of these two compounds are very similar.

A QSAR study of the antimalarial activity of some synthetic 1,2,4-trioxanes

The antimalarial activity of a series of synthetic 1,2,4-trioxanes is correlated with molecular structure by using a pharmacophore search method (CATALYST). The technique is shown to have predictive accuracy and confirms that docking between an active trioxane and the receptor, heme, is the crucial step for drug action.

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.

3′-Deoxy-3′-Hydroxyamino-β-D-Xylofuranosyluracil and Derivatives Thereof

Abstract The title compound was prepared by reduction of the oxime of the 3′-ketouridine. Condensation with aldehydes gave a series of nitrones whose reduction afforded “second generation” hydroxylamines, some of which showing antiviral activity. The nitroxide free radicals formed upon oxidation of hydroxylamines gave good e.s.r. spectra useful for configurational and conformational assignments.

Terminal Deoxy Hydroxyamino Sugars

Abstract Reduction of sugar aldoximes gave in good yield the corresponding terminal deoxy hydroxyamino sugars. These compounds were found to be reasonably stable (they could be kept for some weeks at 4° C). On standing in the air, these compounds in solution were spontaneously oxidized to the corresponding nitroxide free radicals whose ESR spectra gave useful structural information.

1,2-O-Isopropylide`ne-pentodialdofuranoses

Abstract 1,2- O -Isopropylidenepentodialdofuranoses having ribo , lyxo , and arabino configurations, as well as analogs having one (C-3) or two (C-3 and C-4) hybrid sp 2 carbon atoms were synthesized. The orientation of these compounds at the C-4 C-5 bond is practically independent of the modifications of the substitution at C-3. It seems to be directed by orbital factors favoring a conformer having a carbonyl group and an O-C-4 bond nearly eclipsed.