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Abstract: The synthesis of 1,2,3-triazolo-3′-deoxy-4′-hydroxymethyl carbanucleosides with different reaction conditions and diverse modulations on the heterocycle residues was developed. Heterocycle moieties were efficiently introduced on the pseudo-sugar either via nucleophilic substitution or via 1,3-dipolar Huisgen cycloaddition. With this latter approach, 1,4-disubstituted and 1,4,5-trisubstituted-(±)-[1,2,3]-triazolo-3′-deoxy-4′-hydroxymethyl carbanucleosides were prepared from the corresponding azido-carbocycle and various terminal or internal alkynes. Antiviral activities and cellular toxicities of the final compounds were evaluated as smallpox inhibitors. Unfortunately, at concentrations up to 100mM, none of them inhibited production of vaccinia virus (Lister strain) or cowpox virus (Brighton strain) in vero cells. [Copyright &y& Elsevier]

Studies directed toward the oxidative and reductive desulfurization of readily available 2′- S -aryl-2′-thiouridine derivatives were investigated with the prospect to functionalize the C2′-position of nucleosides. The oxidative desulfurization-difluorination strategy was successful on 2-(arylthio)alkanoate surrogates, while extension of the combination of oxidants and fluoride sources was not an efficient fluorination protocol when applied to 2′- S -aryl-2′-thiouridine derivatives, resulting mainly in C5-halogenation of the pyrimidine ring and C2′-monofluorination without desulfurization. Cyclic voltammetry of 2′-arylsulfonyl-2′-deoxyuridines and their 2′-fluorinated analogues showed that cleavage of the arylsulfone moiety could occur, although at relatively high cathodic potentials. While reductive-desulfonylation of 2′-arylsulfonyl-2′-deoxyuridines with organic electron donors (OEDs) gave predominantly base-induced furan type products, chemical (OED) and electrochemical reductive-desulfonylation of the α-fluorosulfone derivatives yielded the 2′-deoxy-2′-fluorouridine and 2′,3′-didehydro-2′,3′-dideoxy-2′-fluorouridine derivatives. These results provided good evidence of the generation of a C2′-anion through carbon-sulfur bond cleavage, opening new horizons for the reductive-functionalization approaches in nucleosides. [ABSTRACT FROM AUTHOR]

The regioselective selenocyanation of imidazoheterocycles using triselenodicyanide at room temperature is reported. The electrophilic aromatic substitution of a broad range of substrates is promoted by the triselenodicyanide obtained by oxidative coupling of malononitrile and selenium dioxide, under an air atmosphere. The major advantages of the presented method are an easy set-up, excellent yields, short reaction times, use of odorless and inexpensive reagents and easy purification of the final products. [ABSTRACT FROM AUTHOR]

Abstract: In our on-going program targeting anti-pox activity, we report here the synthesis of hitherto unknown acyclic nucleoside phosphonates using olefin cross-metathesis (CM) as a key assembly step. Modification at the C-5 position of the uracil moiety was performed under optimized Pd(0)-catalyzed Stille cross-coupling conditions. None of the obtained compounds were active against poxviruses, nor do they exhibit any toxicity. [Copyright &y& Elsevier]

Thanks to a preliminary in vitro screening of several CCl3-substituted-nitrogen containing heterocycles belonging to our chemical library, the 2-trichloromethylquinoxaline scaffold appeared to be of potential interest for developing new antiplasmodial agents. Then, combining these experimental results to the antimalarial properties reported for various pyrrolo[1,2-a]quinoxaline derivatives, an original series of fifteen 7-substituted-4-trichoromethylpyrrolo[1,2-a]quinoxalines was synthesized in a 4 to 5 reaction steps pathway. All molecules were evaluated in vitro toward both their antiplasmodial activity on the K1 multi-resistant Plasmodium falciparum strain and their cytotoxicity on the HepG2 human cell line. Thus, 3 hit molecules were identified, displaying IC50 values in the micromolar range and low cytotoxicity values, reaching good selectivity indexes, in comparison with the reference drugs chloroquine and doxycycline. Structure-activity relationship studies showed that the pyrrolo[1,2-a]quinoxaline scaffold can support selective antiplasmodial activity when substituted at position 4 by a CCl3 group. However, substitution at position 7 of the same scaffold is neither beneficial for cytotoxicity nor favourable for the solubility in the biological media. [ABSTRACT FROM AUTHOR]