RESUMEN
The development of robust and reliable methods for the construction of C(sp2)-C(sp3) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocatalysts based on precious-metals due to their efficient redox processes and tuneable properties. However, due to the cost, scarcity, and toxicity of these metals, the search for suitable replacements should be a priority. Here, we show the use of commercially available heterogeneous semiconductor graphitic carbon nitride (gCN) as a photocatalyst, combined with nickel catalysis, for the cross-coupling between aryl halide and carboxylic acid coupling partners. gCN has been shown to engage in single-electron-transfer (SET) and energy-transfer (EnT) processes for the formation of C-X bonds, and in this manuscript we overcome previous limitations to furnish C-C over C-O bonds using carboxylic acids. A broad scope of both aryl halides and carboxylic acids is presented, and recycling of the photocatalyst demonstrated. The mechanism of the reaction is also investigated.
RESUMEN
A synthesis of all four stereoisomers of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid has been developed, thereby significantly shortening the known literature procedures for the syntheses of these unnatural amino acids. With a simple adjustment of the reaction conditions, we were able to obtain either pure cis or trans acid. Optical resolution was accomplished via diastereomeric salt formation or alternatively via chromatography on a chiral stationary phase. Finally, ab initio calculations gave an explanation for the observed cis selectivity in the initial step.
Asunto(s)
Aminoácidos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Ciclohexanos/síntesis química , Aminoácidos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Ciclohexanos/química , Estructura Molecular , Teoría Cuántica , EstereoisomerismoRESUMEN
High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat.
Asunto(s)
Acetatos/química , Antiinflamatorios/química , Piridinas/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Acetatos/síntesis química , Acetatos/farmacocinética , Administración Oral , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Humanos , Microsomas Hepáticos/metabolismo , Permeabilidad , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relación Estructura-ActividadRESUMEN
Resistance in Gram-negative bacteria to ß-lactam drugs is mediated primarily by the expression of ß-lactamases, and co-dosing of ß-lactams with a ß-lactamase inhibitor (BLI) is a clinically proven strategy to address resistance. New ß-lactamases that are not impacted by existing BLIs are spreading and creating the need for development of novel broader spectrum BLIs. IID572 is a novel broad spectrum BLI of the diazabicyclooctane (DBO) class that is able to restore the antibacterial activity of piperacillin against piperacillin/tazobactam-resistant clinical isolates. IID572 is differentiated from other DBOs by its broad inhibition of ß-lactamases and the lack of intrinsic antibacterial activity.
Asunto(s)
Compuestos de Azabiciclo/síntesis química , Bacterias Gramnegativas/efectos de los fármacos , Inhibidores de beta-Lactamasas/síntesis química , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Farmacorresistencia Microbiana/efectos de los fármacos , Estabilidad de Medicamentos , Bacterias Gramnegativas/enzimología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacologíaRESUMEN
Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary studies were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbamate, or MC-VC-PABC cleavable linker. However, the resulting ADCs lacked antigen-specificity in vivo, probably from premature release of the payload. Second-generation ADCs were then developed, using noncleavable linkers, and the resulting conjugates (ADC-4 and ADC-10) led to in vivo efficacy in an HER-2 expressing (SK-OV-3ip) mouse xenograft model while ADC-11 led to in vivo efficacy in an anti-c-KIT (NCI-H526) mouse xenograft model in a target-dependent manner.
RESUMEN
Bicycloalkyl groups have been previously described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction into complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.1.1]pentane-1,3-diyl (BCP) group improves aqueous solubility by at least 50-fold, and markedly decreases nonspecific binding (NSB) as measured by CHI(IAM), the chromatographic hydrophobicity index on immobilized artificial membranes. Structural variations with the bicyclo[2.2.2]octane-1,4-diyl group led to more lipophilic molecules and did not show the same benefits regarding NSB or solubility, whereas substitutions with cubane-1,4-diyl showed improvements for both parameters. These results confirm the potential advantages of both BCP and cubane motifs as bioisosteric replacements for optimizing para-phenyl-substituted molecules.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Membranas Artificiales , Compuestos de Anilina/química , Compuestos Bicíclicos con Puentes/síntesis química , Ácidos Carboxílicos/química , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , SolubilidadRESUMEN
[reaction: see text] The synthesis of the highly strained 3-aza-[7]-paracyclophane core of haouamines A and B is based on a macrocyclization-aromatization protocol, allowing for a stepwise increase in ring strain and establishing the oxygenation pattern of the natural products.
Asunto(s)
Compuestos Aza/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Aza/química , Cristalografía por Rayos X , Compuestos Heterocíclicos de 4 o más Anillos/química , Conformación Molecular , Estructura MolecularRESUMEN
Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Ciclofilinas/antagonistas & inhibidores , Ciclosporinas/farmacología , Transportadores de Anión Orgánico/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Técnicas de Química Sintética , Cristalografía por Rayos X , Peptidil-Prolil Isomerasa F , Ciclofilinas/química , Ciclofilinas/metabolismo , Ciclosporina/química , Ciclosporina/farmacología , Ciclosporinas/química , Perros , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Inmunosupresores/química , Inmunosupresores/farmacología , Transportador 1 de Anión Orgánico Específico del Hígado , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Ratas , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
The title compounds, C(20)H(24)O(7) and C(40)H(32)O, respectively, are racemic oxepines, the molecules of which contain a chiral axis. Both molecules possess crystallographic C(2) symmetry and the seven-membered ring adopts a twisted-boat conformation.