RESUMO
Parasitic protozoa employ a salvage pathway to synthesize purines and generate essential active nucleotides, whereas mammals are capable of their de novo biosynthesis. This difference provides opportunity for the design of potential new antiprotozoan compounds. A series of 47 adenosine analogues was prepared with modifications at the 2-, 6- and 5'-positions, based on the hypothesis that such compounds would serve as substrates for protozoan nucleoside salvage enzymes, while remaining refractory in mammalian cells. The nucleosides were designed to produce toxic metabolites upon cleavage to the corresponding purine base by the parasite. Three 7-deazaguanosine derivatives were prepared with similar objectives. All of these compounds were tested in vitro against T. brucei (African sleeping sickness), T. cruzi (Chagas' disease), L. donovani (leishmaniasis) and P. falciparum (malaria). In order to determine the therapeutic selectivity indices (SI) of the antiprotozoan nucleosides, their cytotoxicities toward a rat myoblast cell line were also determined. One adenosine derivative proved highly effective against P. falciparum (IC50=110nM and SI=1010, while a modified guanosine displayed potent activities against L. donovani (IC50=60nM, SI=2720) and T. brucei (IC50=130nM, SI=1250), as well as moderate activity against T. cruzi (IC50=3.4µM, SI=48). These results provide proof of concept for the nucleoside-based antiprotozoan strategy, as well as potential lead compounds for further optimization and validation.
Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Animais , Antiprotozoários/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Concentração Inibidora 50 , Leishmania donovani/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Espectrofotometria Infravermelho , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacosRESUMO
The malaria-causing parasite Plasmodium falciparum employs a salvage pathway for the biosynthesis of nucleotides, in contrast to de novo biosynthesis that is utilized by the human host. A series of twenty-two 2-, 6- and 5'-modified adenosine ribonucleosides was synthesized, with the expectation that these compounds would generate toxic metabolites instead of active nucleotides by the pathogen, while remaining inert in host cells. Bioassays with P. falciparum (K1 strain) indicated IC50 values as low as 110nM and a selectivity index with respect to cytotoxicity toward an L6 rat myoblast cell line of >1000 for the most potent analogue.
Assuntos
Antimaláricos/farmacologia , Malária/tratamento farmacológico , Mioblastos/efeitos dos fármacos , Nucleosídeos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Antimaláricos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Mioblastos/parasitologia , Nucleosídeos/síntese química , Nucleosídeos/química , Testes de Sensibilidade Parasitária , Ratos , Relação Estrutura-AtividadeRESUMO
Copovidone, a copolymer of vinyl acetate and N-vinyl-2-pyrrolidone, was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and after deacetylation the polymer was functionalized by introduction of amino, azide, and alkyne pendant groups to allow attachment of glycans and peptide. Candida albicans ß-mannan trisaccharides 1 and 2 and M. tuberculosis arabinan hexasaccharide 3 with appropriate tethers were conjugated to the polymers by squarate or click chemistry. C. albicans T-cell peptide 4 bearing a C-terminal ε-azidolysine was also conjugated to copovidone by click chemistry. The resulting conjugates provide convenient non-protein-based antigens that are readily adsorbed on ELISA plates, and display excellent characteristics for assay of antibody binding to the haptenic group of interest. Copovidone and BSA glycoconjugates exhibited similar adsorption characteristics when used to coat ELISA plates, and both conjugates were optimal when used as coating solutions at low nanogram/mL concentrations. Provided that the copovidone conjugated glycan is stable to acid, assay plates can be easily processed for reuse at least three times without detectable variation or degradation in ELISA readout.
Assuntos
Anticorpos/análise , Especificidade de Anticorpos , Haptenos/imunologia , Oligossacarídeos/imunologia , Peptídeos/imunologia , Pirrolidinas/imunologia , Tensoativos/química , Compostos de Vinila/imunologia , Adsorção , Anticorpos/imunologia , Candida albicans/química , Candida albicans/imunologia , Química Click , Ensaio de Imunoadsorção Enzimática , Reutilização de Equipamento , Haptenos/química , Conformação Molecular , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/imunologia , Oligossacarídeos/química , Peptídeos/química , Polímeros/química , Pirrolidinas/química , Compostos de Vinila/químicaRESUMO
Structural pre-organization of the multivalent ligands is important for successful interaction with multimeric proteins. Polymer-based heterobifunctional ligands that contain pendant groups prearranged into heterodimers can be used to probe the active site and surrounding area of the receptor. Here we describe the synthesis and activities of a series of galactose conjugates on polyacrylamide and dextran. Conjugation of a second fragment resulted in nanomolar inhibitors of cholera toxin, while the galactose-only progenitors showed no detectable activity.
Assuntos
Toxina da Cólera/antagonistas & inibidores , Polímeros/química , Polímeros/farmacologia , Resinas Acrílicas/química , Aminação , Sítios de Ligação , Toxina da Cólera/metabolismo , Dextranos/química , Descoberta de Drogas , Ensaio de Imunoadsorção Enzimática , Gangliosídeo G(M1)/metabolismo , Galactose/química , Ligantes , Polímeros/síntese química , Polímeros/metabolismoRESUMO
Various tribenzotriquinacenes (TBTQs), most of which incorporate six functional groups at the periphery of their C3v-symmetrical, rigid and convex-concave molecular framework, have been studied with respect to their ability to form supramolecular complexes with the C60 and C70 fullerenes, either in the solid state or in solution. The hexabromo derivative Br6-TBTQ was cocrystallized with C60 as [Br6-TBTQ
RESUMO
An array of homogeneous glycans representing all the major carbohydrate structures present in the cell wall of the human pathogen Mycobacterium tuberculosis and other mycobacteria has been probed with a panel of glycan-binding receptors expressed on cells of the mammalian innate immune system. The results provide an overview of interactions between mycobacterial glycans and receptors that mediate uptake and survival in macrophages, dendritic cells, and sinusoidal endothelial cells. A subset of the wide variety of glycan structures present on mycobacterial surfaces interact with cells of the innate immune system through the receptors tested. Endocytic receptors, including the mannose receptor, DC-SIGN, langerin, and DC-SIGNR (L-SIGN), interact predominantly with mannose-containing caps found on the mycobacterial polysaccharide lipoarabinomannan. Some of these receptors also interact with phosphatidyl-myo-inositol mannosides and mannose-containing phenolic glycolipids. Many glycans are ligands for overlapping sets of receptors, suggesting multiple, redundant routes by which mycobacteria can enter cells. Receptors with signaling capability interact with two distinct sets of mycobacterial glycans: targets for dectin-2 overlap with ligands for the mannose-binding endocytic receptors, while mincle binds exclusively to trehalose-containing structures such as trehalose dimycolate. None of the receptors surveyed bind furanose residues, which often form part of the epitopes recognized by antibodies to mycobacteria. Thus, the innate and adaptive immune systems can target different sets of mycobacterial glycans. This array, the first of its kind, represents an important new tool for probing, at a molecular level, biological roles of a broad range of mycobacterial glycans, a task that has not previously been possible.
Assuntos
Mycobacterium/química , Polissacarídeos/química , Polissacarídeos/imunologia , Imunidade Inata , Análise em Microsséries/métodos , Mycobacterium/metabolismo , Soroalbumina BovinaRESUMO
The first X-ray structural determinations of pristine fullerene C(60), cocrystallized 1:1 with corannulene and with its pentaalkyl-substituted derivative, 1,3,5,7,9-penta-tert-butyl-corannulene, have now been achieved.
RESUMO
The combination of a modular assembly of enantiopure triynes and a powerful rhodium-catalyzed [2 + 2 + 2] alkyne cyclotrimerization reaction opens new and efficient entries to a set of alcyopterosins, including the first total synthesis of the alcyopterosins L, M, and C.