Subject(s)
Drug Discovery/methods , Immune System Diseases/drug therapy , Inflammation/drug therapy , Small Molecule Libraries/chemistry , Small Molecule Libraries/therapeutic use , Th17 Cells/drug effects , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Humans , Immune System Diseases/immunology , Inflammation/immunology , Small Molecule Libraries/pharmacology , Th17 Cells/immunologyABSTRACT
A series of darunavir analogues featuring a substituted bis-THF ring as P2 ligand have been synthesized and evaluated. High affinity protease inhibitors (PIs) with an interesting activity on wild-type HIV and a panel of multi-PI resistant HIV-1 mutants containing clinically observed, primary mutations were identified using a cell-based assay. A number of PIs have been synthesized that show equivalent and greater activity for HIV-1 mutant strains as compared to wild-type HIV-1. The activity on the purified enzyme was confirmed for a selection of analogues.
ABSTRACT
The synthesis of 2',2'-difluoro KRN7000 is described. In vivo evaluation demonstrates that this fluorinated glycolipid induces CD1d-dependent TCR activation of NKT cells, with a bias towards Th2 cytokine production.
Subject(s)
Antigens, CD1/immunology , Galactosylceramides/chemical synthesis , Galactosylceramides/pharmacology , Lymphocyte Activation/drug effects , Animals , Cytokines/blood , Cytokines/immunology , Mice , Mice, Inbred C57BL , Natural Killer T-Cells , Receptors, Natural Killer Cell/immunologyABSTRACT
The synthesis of 4-deoxy-4,4-difluoro-KRN7000 starting from phytosphingosine is described. Key steps include a regioselective benzylation of azidophytosphingosine and a deoxofluor-mediated fluorination of the corresponding 4-ketone. This fluorination failed completely when the adjacent 3-OH was protected as benzyl ether but proceeded well when a benzoyl group was used. The biological evaluation reveals a bias toward Th1 cytokine induction upon Natural Killer T cell activation.
Subject(s)
Galactosylceramides/chemical synthesis , Galactosylceramides/pharmacology , Animals , Benzene/chemistry , Cytokines/metabolism , Galactosylceramides/chemistry , Killer Cells, Natural/drug effects , Killer Cells, Natural/metabolism , Mice , Mice, Inbred C57BL , Molecular StructureABSTRACT
Aza TSAO-T derivatives bearing a substituted dihydroisothiazole dioxide ring with a phenyl group at 5'' position were prepared. Biological evaluation showed that phenyl group gives rise to a dramatical decrease of the inhibitory effect.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Aza Compounds/chemical synthesis , HIV-1/drug effects , Spiro Compounds/chemical synthesis , Anti-HIV Agents/chemistry , Aza Compounds/chemistry , Aza Compounds/pharmacology , Molecular Structure , Nucleosides/chemical synthesis , Nucleosides/chemistry , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis and the biological evaluation of the anti-HIV-1 activity of TSAO-Boc(3)T (8) are described. The computational analysis showed that the N-3 Boc group promotes new interactions in the binding site of the enzyme leading to a good inhibitory activity.
Subject(s)
Anti-HIV Agents/pharmacology , HIV-1/drug effects , HIV-2/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Spiro Compounds/chemistry , Virus Replication/drug effects , Anti-HIV Agents/chemical synthesis , Binding Sites , Cell Line , Models, Chemical , Reverse Transcriptase Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
An efficient, enantioselective synthesis of a disubstituted bis-THF scaffold 5 is described, as well as an efficient differentiation of the 1,3-diol unit. [reaction: see text]
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Lactones/chemical synthesis , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Darunavir , Furans/chemistry , Indicators and Reagents , Oxidation-Reduction , Stereoisomerism , Sulfonamides/chemical synthesis , Sulfonamides/chemistryABSTRACT
We have carried out a theoretical analysis of aza analogues of [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide) by a variety of computational tools, aimed to account for the effect of the endocyclic amino moiety N-2" on the inhibitory activity against HIV-1. Docking studies suggest that compounds substituted at the N-3 and N-2' ' positions present the same binding mode to the [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide)thymine prototype, where the endocyclic amino group remains mostly exposed to the solvent. A careful conformational analysis performed through different theoretical levels, from molecular mechanics to high-level quantum mechanical calculations, provides a rationalization based on conformational preferences, which appears as strongly determined by the substitution at N-2", and on electrostatic effects from the bulk water.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , Reverse Transcriptase Inhibitors/chemistry , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Thymidine/analogs & derivatives , Models, Molecular , Molecular Conformation , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , Thymidine/chemistry , Thymidine/pharmacologyABSTRACT
Aza TSAO-T derivatives bearing a dihydroisothiazole dioxide ring instead of an oxathiole dioxide ring at the C-3' position on the sugar moiety were prepared. We have synthesized four families of compounds depending on substitution at both N-3 and N-2' '. Biological evaluation showed that these compounds are HIV-1(III(B))-specific and potent reverse transcriptase inhibitors with EC(50) values between 0.13 and 3.5 microM in cell culture.
Subject(s)
Aza Compounds/pharmacology , HIV-1/physiology , Reverse Transcriptase Inhibitors/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Thymidine/analogs & derivatives , Thymidine/chemical synthesis , Thymidine/pharmacology , Virus Replication/drug effects , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Cell Line , HIV-1/drug effects , HIV-2/drug effects , HIV-2/physiology , Humans , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Uridine/analogs & derivativesABSTRACT
The carbanion-mediated sulfonate intramolecular cyclizations (CSIC protocols) of glyco-alpha-sulfonamidonitriles derived from readily available monosaccharides have been extensively investigated using potassium carbonate, cesium carbonate, n-BuLi, and LDA as bases. As a result, a series of enantiomerically pure spiro(4-amino-5-H-2,3-dihydroisothiazole-1,1-dioxide) derivatives have been prepared efficiently and isolated in good yield. The synthesis of these new bicyclic systems is key to accessing a novel range of aza analogues of TSAO nucleosides (ATSAOs).
Subject(s)
Nitriles/chemistry , Ribose/analogs & derivatives , Sulfonamides/chemistry , Thiazoles/chemical synthesis , Xylose/analogs & derivatives , Carbonates/chemistry , Cyclization , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Nucleosides/chemistry , Thiazoles/chemistryABSTRACT
TSAO derivatives which were first synthesized in 1992 have shown strong inhibitory effect and selectivity against HIV-1 (Camarasa, M.J.; Pérez-Pérez, M.J.; San-Félix, A.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992, 35, 2721-2727). The structure-activity relationship of these derivatives has shown strong binding between the amino acids constituting the reverse transcriptase and the different pharmacophore (tert-butyldimethylsilyl group, amino and sulfonate groups of the TSAO derivatives) (Camarasa, M.J.; San-Félix, A.; Pérez-Pérez, M.J.; Velázquez, S., Alvarez, R.; Chamorro, C.; Jimeno, M.L.; Pérez, C.; Gago, F.; De Clercq, E.; Balzarini, J. J. Carbohydr. Chem. 2000, 19, 6403-6406). We described the synthesis of an original TSAO analogue where, basically, the O-1'' atom is replaced by a nitrogen atom.