RESUMO
Herein, we disclose a palladium-catalyzed cross-coupling of aryl bromides and chlorides with trimethylsilylalkynes under mild reaction conditions. This method utilizes commercially available and air stable palladium precatalysts and avoids the use of copper cocatalysts. Moreover, it allows for the synthesis of a wide range of disubstituted alkynes in high yields with excellent functional group tolerance. The utility of the developed method was further demonstrated via the late-stage alkynylation of pharmaceuticals and natural bioactive compounds.
RESUMO
While developing boron-catalyzed glycosylations using glycosyl fluoride donors and trialkylsilyl ether acceptors, competing pathways involving productive glycosylation or glycosyl exchange were observed. Experimental and computational mechanistic studies suggest a novel mode of reactivity where a dioxolenium ion is a key intermediate that promotes both pathways through addition to either a silyl ether or to the acetal of an existing glycosidic linkage. Modifications in catalyst structure enable either pathway to be favored, and with this understanding, improved multicomponent iterative couplings and glycosyl exchange processes were demonstrated.
Assuntos
Éteres , Glicosídeos , Catálise , Glicosídeos/química , Glicosilação , EstereoisomerismoRESUMO
Challenges in the assembly of glycosidic bonds in oligosaccharides and glycoconjugates pose a bottleneck in enabling the remarkable promise of advances in the glycosciences. Here, we report a strategy that applies unique features of highly electrophilic boron catalysts, such as tris(pentafluorophenyl)borane, in addressing a number of the current limitations of methods in glycoside synthesis. This approach utilizes glycosyl fluoride donors and silyl ether acceptors while tolerating the Lewis basic environment found in carbohydrates. The method can be carried out at room temperature using air- and moisture-stable forms of the catalyst, with loadings as low as 0.5 mol %. These characteristics enable a wide array of glycosylation patterns to be accessed, including all C1-C2 stereochemical relationships in the glucose, mannose, and rhamnose series. This method allows one-pot, iterative glycosylations to generate oligosaccharides directly from monosaccharide building blocks. These advances enable the rapid and experimentally straightforward preparation of complex oligosaccharide units from simple building blocks.
Assuntos
Fluoretos/química , Catálise , Glicosilação , EstereoisomerismoRESUMO
GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.
Assuntos
Compostos Aza/química , Inibidores Enzimáticos/química , Quinolinas/química , Animais , Sítios de Ligação , Encéfalo/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Estabilidade de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/metabolismo , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Infectious diseases due to multidrug-resistant pathogens, particularly carbapenem-resistant Enterobacteriaceae (CREs), present a major and growing threat to human health and society, providing an urgent need for the development of improved potent antibiotics for their treatment. We describe the design and development of a new class of aminoglycoside antibiotics culminating in the discovery of propylamycin. Propylamycin is a 4'-deoxy-4'-alkyl paromomycin whose alkyl substituent conveys excellent activity against a broad spectrum of ESKAPE pathogens and other Gram-negative infections, including CREs, in the presence of numerous common resistance determinants, be they aminoglycoside modifying enzymes or rRNA methyl transferases. Importantly, propylamycin is demonstrated not to be susceptible to the action of the ArmA resistance determinant whose presence severely compromises the action of plazomicin and all other 4,6-disubstituted 2-deoxystreptamine aminoglycosides. The lack of susceptibility to ArmA, which is frequently encoded on the same plasmid as carbapenemase genes, ensures that propylamycin will not suffer from problems of cross-resistance when used in combination with carbapenems. Cell-free translation assays, quantitative ribosome footprinting, and X-ray crystallography support a model in which propylamycin functions by interference with bacterial protein synthesis. Cell-free translation assays with humanized bacterial ribosomes were used to optimize the selectivity of propylamycin, resulting in reduced ototoxicity in guinea pigs. In mouse thigh and septicemia models of Escherichia coli, propylamycin shows excellent efficacy, which is better than paromomycin. Overall, a simple novel deoxy alkyl modification of a readily available aminoglycoside antibiotic increases the inherent antibacterial activity, effectively combats multiple mechanisms of aminoglycoside resistance, and minimizes one of the major side effects of aminoglycoside therapy.
Assuntos
Aminoglicosídeos/síntese química , Aminoglicosídeos/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterobacteriaceae/efeitos dos fármacos , Aminoglicosídeos/química , Animais , Antibacterianos/química , Técnicas de Química Sintética , Cobaias , Hexosaminas/síntese química , Hexosaminas/química , Hexosaminas/farmacologia , Hexosaminas/toxicidade , Camundongos , Testes de Sensibilidade Microbiana , Células NIH 3T3 , Relação Estrutura-AtividadeRESUMO
The off-target binding of aminoglycosides (AGs) to the A site of human mitochondrial ribosomes in addition to bacterial ribosomes causes ototoxicity and limits their potential as antibiotics. A fluorescence assay was employed to determine relative binding affinities of classical and improved AG compounds to synthetic RNA constructs representing the bacterial and mitochondrial A sites. Results compared well with previously reported in vitro translation assays with engineered ribosomes. Therefore, the minimal RNA motifs and fluorescence assay are shown here to be useful for assessing the selectivity of new compounds.
Assuntos
Aminoglicosídeos/química , Bactérias/metabolismo , Mitocôndrias/metabolismo , RNA/metabolismo , Sítios de Ligação , Fluorescência , HumanosRESUMO
Mephedrone (MEPH) is a ß-ketoamphetamine stimulant drug of abuse that is often a constituent of illicit bath salts formulations. Although MEPH bears remarkable similarities to methamphetamine (METH) in terms of chemical structure, as well as its neurochemical and behavioral effects, it has been shown to have a reduced neurotoxic profile compared with METH. The addition of a ß-keto moiety and a 4-methyl ring substituent to METH yields MEPH, and a loss of direct neurotoxic potential. In the present study, two analogs of METH, methcathinone (MeCa) and 4-methylmethamphetamine (4MM), were assessed for their effects on mouse dopamine (DA) nerve endings to determine the relative contribution of each individual moiety to the loss of direct neurotoxicity in MEPH. Both MeCa and 4MM caused significant alterations in core body temperature as well as locomotor activity and stereotypy, but 4MM was found to elicit minimal dopaminergic toxicity only at the highest dose. By contrast, MeCa caused significant reductions in all markers of DA nerve-ending damage over a range of doses. These results lead to the conclusion that ring substitution at the 4-position profoundly reduces the neurotoxicity of METH, whereas the ß-keto group has much less influence on this property. Although the mechanism(s) by which the 4-methyl substituent reduces METH-induced neurotoxicity remains unclear, it is speculated that this effect is mediated by a loss of DA-releasing action in MEPH and 4MM at the synaptic vesicle monoamine transporter, an effect that is thought to be critical for METH-induced neurotoxicity.
Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Metanfetamina/análogos & derivados , Terminações Nervosas/efeitos dos fármacos , Síndromes Neurotóxicas , Propiofenonas , Animais , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacologia , Relação Dose-Resposta a Droga , Drogas Ilícitas/química , Drogas Ilícitas/farmacologia , Metanfetamina/química , Metanfetamina/farmacologia , Camundongos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Propiofenonas/química , Propiofenonas/farmacologiaRESUMO
Modification at the 5''-position of 4,5-disubstituted aminoglycoside antibiotics (AGAs) to circumvent inactivation by aminoglycoside modifying enzymes (AMEs) is well known. Such modifications, however, unpredictably impact activity and affect target selectivity thereby hindering drug development. A survey of 5''-modifications of the 4,5-AGAs and the related 5-O-furanosyl apramycin derivatives is presented. In the neomycin and the apralog series, all modifications were well-tolerated, but other 4,5-AGAs require a hydrogen bonding group at the 5''-position for maintenance of antibacterial activity. The 5''-amino modification resulted in parent-like activity, but reduced selectivity against the human cytosolic decoding A site rendering this modification unfavorable in paromomycin, propylamycin, and ribostamycin. Installation of a 5''-formamido group and, to a lesser degree, a 5''-ureido group resulted in parent-like activity without loss of selectivity. These lessons will aid the design of next-generation AGAs capable of circumventing AME action while maintaining high antibacterial activity and target selectivity.
Assuntos
Aminoglicosídeos , Ribossomos , Aminoglicosídeos/farmacologia , Antibacterianos/farmacologia , Humanos , Neomicina/farmacologia , Inibidores da Síntese de Proteínas , Relação Estrutura-AtividadeRESUMO
Propylamycin (4'-deoxy-4'-propylparomomycin) is a next generation aminoglycoside antibiotic that displays increased antibacterial potency over the parent, coupled with reduced susceptibility to resistance determinants and reduced ototoxicity in the guinea pig model. Propylamycin nevertheless is inactivated by APH(3')-Ia, a specific aminoglycoside phosphotransferase isozyme that acts on the primary hydroxy group of the ribofuranosyl moiety (at the 5''-position). To overcome this problem, we have prepared and studied the antibacterial and antiribosomal activity of various propylamycin derivatives carrying amino or substituted amino groups at the 5''-position in place of the vulnerable hydroxy group. We find that the introduction of an additional basic amino group at this position, while overcoming the action of the aminoglycoside phosphoryltransferase isozymes acting at the 5''-position as anticipated, results in a significant drop in selectivity for the bacterial over the eukaryotic ribosomes that is predictive of increased ototoxicity. In contrast, 5''-deoxy-5''-formamidopropylamycin retains the excellent across-the-board levels of antibacterial activity of propylamycin itself, while circumventing the action of the offending aminoglycoside phosphotransferase isozymes and affording even greater selectivity for the bacterial over the eukaryotic ribosomes. Other modifications to address the susceptibility of propylamycin to the APH(3')-Ia isozyme including deoxygenation at the 3'-position and incorporation of a 6',5''-bis(hydroxyethylamino) modification offer no particular advantage.
Assuntos
Aminoglicosídeos , Antibacterianos , Animais , Antibacterianos/toxicidade , Cobaias , Testes de Sensibilidade Microbiana , RibossomosRESUMO
RATIONALE: Mephedrone is a commonly abused constituent of "bath salts" and has many pharmacological effects in common with methamphetamine. Despite their structural similarity, mephedrone differs significantly from methamphetamine in its effects on core body temperature and dopamine nerve endings. The reasons for these differences remain unclear. OBJECTIVES: Mephedrone elicits a transient hypothermia which may provide intrinsic neuroprotection against methamphetamine-like toxicity to dopamine nerve endings. Furthermore, evidence in the literature suggests that this hypothermia is mediated by serotonin. By utilizing transgenic mice devoid of brain serotonin, we determined the contribution of this neurotransmitter to changes in core body temperature as well as its possible role in protecting against neurotoxicity. The effects of methcathinone and 4-methyl-methamphetamine, two structural analogs of mephedrone and methamphetamine, were also evaluated in these mice. RESULTS: The hypothermia induced by mephedrone and methcathinone in wild-type mice was not observed in mice lacking brain serotonin. Despite preventing drug-induced hypothermia, the lack of serotonin did not alter the neurotoxic profiles of the test drugs. CONCLUSIONS: Serotonin is a key mediator of pharmacological hypothermia induced by mephedrone and methcathinone, but these body temperature effects do not contribute to dopamine nerve ending damage observed in mice following treatment with mephedrone, methcathinone or 4-methyl-methamphetamine. Thus, the key component of methamphetamine neurotoxicity lacking in mephedrone remains to be elucidated.
Assuntos
Hipotermia/metabolismo , Drogas Ilícitas/toxicidade , Metanfetamina/análogos & derivados , Síndromes Neurotóxicas/metabolismo , Propiofenonas/toxicidade , Triptofano Hidroxilase/deficiência , Animais , Feminino , Hipotermia/induzido quimicamente , Hipotermia/fisiopatologia , Metanfetamina/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terminações Nervosas/efeitos dos fármacos , Terminações Nervosas/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/fisiopatologia , Triptofano Hidroxilase/genéticaRESUMO
A series of derivatives of the 4,5-disubstituted class of 2-deoxystreptamine aminoglycoside antibiotics neomycin, paromomycin, and ribostamycin was prepared and assayed for (i) their ability to inhibit protein synthesis by bacterial ribosomes and by engineered bacterial ribosomes carrying eukaryotic decoding A sites, (ii) antibacterial activity against wild type Gram negative and positive pathogens, and (iii) overcoming resistance due to the presence of aminoacyl transferases acting at the 2'-position. The presence of five suitably positioned residual basic amino groups was found to be necessary for activity to be retained upon removal or alkylation of the 2'-position amine. As alkylation of the 2'-amino group overcomes the action of resistance determinants acting at that position and in addition results in increased selectivity for the prokaryotic over eukaryotic ribosomes, it constitutes an attractive modification for introduction into next generation aminoglycosides. In the neomycin series, the installation of small (formamide) or basic (glycinamide) amido groups on the 2'-amino group is tolerated.
Assuntos
Aminoglicosídeos/síntese química , Aminoglicosídeos/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Ribossomos/efeitos dos fármacos , Sítios de Ligação , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Hexosaminas , Humanos , Testes de Sensibilidade Microbiana , Neomicina/química , Neomicina/farmacologia , Paromomicina/química , Paromomicina/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Ribossomos/metabolismo , Relação Estrutura-AtividadeRESUMO
Methamphetamine and mephedrone are designer drugs with high abuse liability and they share extensive similarities in their chemical structures and neuropharmacological effects. However, these drugs differ in one significant regard: methamphetamine elicits dopamine neurotoxicity and mephedrone does not. From a structural perspective, mephedrone has a ß-keto group and a 4-methyl ring addition, both of which are lacking in methamphetamine. Our previous studies found that methcathinone, which contains only the ß-keto substituent, is neurotoxic, while 4-methylmethamphetamine, which contains only the 4-methyl ring substituent, elicits minimal neurotoxicity. In the present study, it was hypothesized that the varying neurotoxic potential associated with these compounds is mediated by the drug-releasable pool of dopamine, which may be accessed by methamphetamine more readily than mephedrone, methcathinone, and 4-methylmethamphetamine. To test this hypothesis, l-DOPA and pargyline, compounds known to increase both the releasable pool of dopamine and methamphetamine neurotoxicity, were combined with mephedrone, 4-methylmethamphetamine and methcathinone. Methamphetamine was also tested because of its ability to increase releasable dopamine. All three regimens significantly enhanced striatal neurotoxicity and glial reactivity for 4-methylmethamphetamine. Methcathinone neurotoxicity and glial reactivity were enhanced only by l-DOPA. Mephedrone remained non-neurotoxic when combined with either l-DOPA or pargyline. Body temperature effects of each designer drug were not altered by the combined treatments. These results support the conclusion that the neurotoxicity of 4-methylmethamphetamine, methcathinone and methamphetamine may be differentially regulated by the drug-releasable pool of dopamine due to ß-keto and 4-methyl substituents, but that mephedrone remains non-neurotoxic despite large increases in this pool of dopamine. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
Assuntos
Encéfalo/metabolismo , Drogas Desenhadas/toxicidade , Dopamina/metabolismo , Síndromes Neurotóxicas , Análise de Variância , Animais , Temperatura Corporal/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Sinergismo Farmacológico , Feminino , Metanfetamina/análogos & derivados , Metanfetamina/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Propiofenonas/toxicidade , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
The synthesis of a series of neomycin derivatives carrying the 2-hydroxyethyl substituent on N6' and/or N6â´ both alone and in combination with a 4'-O-ethyl group is described. By means of cell-free translation assays with wild-type bacterial ribosomes and their hybrids with eukaryotic decoding A sites, we investigate how individual substituents and their combinations affect activity and selectivity at the target level. In principle, and as shown by cell-free translation assays, modifications of the N6' and N6â´ positions allow enhancement of target selectivity without compromising antibacterial activity. As with the 6'OH aminoglycoside paromomycin, the 4'-O-ethyl modification affects the ribosomal activity, selectivity, and antibacterial profile of neomycin and its 6'-N-(2-hydroxyethyl) derivatives. The modified aminoglycosides show good antibacterial activity against model Gram-positive and Gram-negative microbes including the ESKAPE pathogens Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, and Acinetobacter baumannii.
Assuntos
Antibacterianos/síntese química , Neomicina/análogos & derivados , Paromomicina/análogos & derivados , Biossíntese de Proteínas/efeitos dos fármacos , Ribossomos/efeitos dos fármacos , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/crescimento & desenvolvimento , Antibacterianos/farmacologia , Pareamento de Bases , Sequência de Bases , Configuração de Carboidratos , Enterobacter cloacae/efeitos dos fármacos , Enterobacter cloacae/crescimento & desenvolvimento , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Neomicina/farmacologia , Paromomicina/farmacologia , Ribossomos/genética , Ribossomos/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Relação Estrutura-Atividade , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismoRESUMO
Reaction of variously substituted N-trifluoromethanesulfonyloxy maleimides with primary amines in the presence of potassium carbonate in DMF at room temperature results in the formation of 3-N-alkyl pyrimidin-2,4-diones in good yield.