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The Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferons in response to sensing viral or bacterial cytosolic DNA. Cyclic dinucleotides (CDNs) are known to activate STING. Here, we describe the synthesis and biological evaluation of two new 3',3'‐CDN, in which the internucleotide linkages were replaced, respectively, by a 1,2,3‐triazole moiety (as more stable isosteres of phosphate linkers) and an unsaturated carbon chain (as flexibility can led to crucial binding affinity and specificity). Thus, CuAAC and macrocyclization by RCM are the two key steps. [ABSTRACT FROM AUTHOR]

Nucleoside analogues are at the forefront of antiviral therapy for last decades. To circumvent some of their limitations, based on their metabolism, and in order to improve their anti‐viral potency and selectivity, several families of nucleoside analogues have been described through structural modifications at the sugar and heterocycles. The replacement of the oxygen of the nucleoside by a methylene has led to the family of carbocyclic (or cyclopentane) nucleoside analogues. Various potent anti‐HIV and anti‐HBV drugs belong to this family. Main syntheses of carbocyclic analogues of nucleosides used Diels‐Alder reactions (in racemic or asymmetric series), but also started from carbohydrates (ribose, glucose), as a source of optically active compounds, which then had to be transformed into carbacycles under various conditions. The growing interest in carbocyclic nucleosides has led several groups, including ours, to develop new analogues and to explore novel routes. This article will review some of the recent chemistry developed on selected five‐membered ring carbocyclic nucleosides. [ABSTRACT FROM AUTHOR]

The convenient preparation of three imidazo[1,2‐a]pyridine‐2‐carboxamide intermediates is reported through known Strecker–Ugi type multicomponent reactions, Tschitschibabin type condensations, and further synthetic sequences. The derivatives were then efficiently converted to novel 4‐chloro‐2‐(trifluoromethyl)pyrido[1,2‐e]purines by their original reactions with 2,2,2‐trifluoroacetamide, followed by subsequent dehydroxychlorination reactions. These compounds were cross‐coupled under microwave irradiation through SuzukiMiyaura and Sonogashira palladium(0) catalysis to various aromatic and alkynyl reagents, thus providing the related C‐4 substituted pyrido[1,2‐e]purines of biological interest in good yields. [ABSTRACT FROM AUTHOR]

Access to fluoroalkylidene-oxetanes and -azetidines was realized from 3-oxetanone, 3-azetidinone, and fluorosulfones through the Julia-Kocienski reaction. This approach allows the preparation of new precursors of fluorinated four-membered rings that contain a nucleic base, an ester or aryl sulfone function, and a pyrrolidine ring. Benzothiazolyl-sulfone-mediated aza-Michael addition reaction of nitrogen nucleophiles enables access to 3,3-disubstituted oxetanes. [ABSTRACT FROM AUTHOR]

Methylanthraniloyl derivatives of ATP and CDP were used in vitro as fluorescent probes for the donor-binding and acceptor-binding sites of human UMP-CMP kinase, a nucleoside salvage pathway kinase. Like all NMP kinases, UMP-CMP kinase binds the phosphodonor, usually ATP, and the NMP at different binding sites. The reaction results from an in-line phosphotransfer from the donor to the acceptor. The probe for the donor site was displaced by the bisubstrate analogs of the Ap5X series (where X = U, dT, A, G), indicating the broad specificity of the acceptor site. Both CMP and dCMP were competitors for the acceptor site probe. To find antimetabolites for antivirus and anticancer therapies, we have developed a method of screening acyclic phosphonate analogs that is based on the affinity of the acceptor-binding site of the human UMP-CMP kinase. Several uracil vinylphosphonate derivatives had affinities for human UMP-CMP kinase similar to those of dUMP and dCMP and better than that of cidofovir, an acyclic nucleoside phosphonate with a broad spectrum of antiviral activities. The uracil derivatives were inhibitors rather than substrates of human UMP-CMP kinase. Also, the 5-halogen-substituted analogs inhibited the human TMP kinase less efficiently. The broad specificity of the enzyme acceptor-binding site is in agreement with a large substrate-binding pocket, as shown by the 2.1 Å crystal structure. [ABSTRACT FROM AUTHOR]

3′-Azido-3′-deoxythymidilyl-(5′,5′)-2′,3′-dideoxy-5′-inosinic acid (AZT-P-ddI, IVX-E-59, Scriptene) is a heterodimer composed of one molecule of 3′-azido-3′-deoxythymidine (zidovudine or AZT) and one molecule of 2′,3′-dideoxyinosine (didanosine or ddI) linked through their 5′ positions by a phosphate bond. AZT-P-ddI exhibits enhanced antiviral activity and selectivity in vitro compared with AZT and ddI alone. The pharmacokinetics of AZT-P-ddI were studied in 12 patients with human immunodeficiency virus (HIV) who had CD4+ cell counts higher than 200 cells/mm3. Isotopic preparations of (14C)-AZT-P-(3H)-ddI were administered intravenously (50 mg and 100 mg) to eight patients; 1 month later these patients were crossed over to oral administration (100 mg and 200 mg). A second group of patients (n = 4) received only a 450-mg oral dose of AZT-P-ddI. Plasma levels of unchanged AZT-P-ddI after intravenous infusion declined rapidly and were undetectable 0.75 hours after the end of infusion, whereas the parent compound was not detected after oral administration, indicative of a very rapid metabolism. The parent entity was enzymatically cleaved in vivo yielding the two constituent drugs AZT and ddI, which were subsequently subjected to their respective pharmacokinetic and metabolic processes. The β-glucuronide derivative of AZT (GAZT) represented the major metabolite of AZT, but there were no detectable levels of the toxic metabolite 3′-amino-3′-deoxythymidine (AMT). A major and previously unrecognized in vivo metabolite of ddI, referred as ddI-M, was detected in plasma and urine. Analysis by high-field proton nuclear magnetic resonance and mass spectrometry led to the identification of ddI-M as being R(-)- dihydro-5-(hydroxymethyl)-2(3H)-furanone. The formation of AZT and ddI metabolites was increased after oral administration of AZT-P-ddI compared with the intravenous infusion, with an area under the concentration-time curve (AUC) ratio of metabolite to AZT and metabolite to ddI being 7.7 and 5.7 (oral) and 3.8 and 1.1 (intravenous), respectively. The newly identified ddI-M exhibited sustained plasma levels for extended time periods with an apparent elimination half-life (t1/2) of approximately 10 hours after oral administration of AZT-P-ddI. Recovery of radioactivity associated with 3H and 14C in urine was essentially complete within 48 hours after oral and intravenous administration of AZT-P-ddI. The oral bioavailability of AZT (64.7-67.3%) and ddI (33.6-42.9%) and the other pharmacokinetic parameters were consistent with previous data reported with each nucleoside analog alone or in combination therapy. [ABSTRACT FROM AUTHOR]

The synthesis of a broad range of drugs bearing a (E)-but-2-enyl aliphatic side chain is described including an olefin acyclic olefin cross metathesis as key step. [ABSTRACT FROM AUTHOR]