RESUMEN
A five-step synthesis of the natural product angelicoin A using a late stage highly regioselective palladium(0)-catalyzed decarboxylative prenyl migration and aromatization sequence as the key step is reported. The method was extended with geranyl migration in eight-step total syntheses of hericenone J and hericenol A from geraniol.
Asunto(s)
Neopreno/química , Fenoles/química , Fenoles/síntesis química , Terpenos/química , Terpenos/síntesis química , Monoterpenos Acíclicos , Catálisis , Estructura Molecular , Paladio/química , EstereoisomerismoRESUMEN
The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Interferones/agonistas , Receptor Toll-Like 7/agonistas , Aldehído Oxidasa/metabolismo , Animales , Antivirales/química , Antivirales/farmacocinética , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Hepacivirus/fisiología , Hepatitis C/virología , Humanos , Inyecciones Intravenosas , Inductores de Interferón/síntesis química , Inductores de Interferón/química , Inductores de Interferón/farmacocinética , Inductores de Interferón/farmacología , Microsomas Hepáticos/metabolismo , Terapia Molecular Dirigida , Peso Molecular , Purinas/síntesis química , Purinas/metabolismo , Ratas , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.
Asunto(s)
Antivirales/química , Hepacivirus/efectos de los fármacos , Purinas/química , Infecciones por Virus ARN/tratamiento farmacológico , Receptor Toll-Like 7/agonistas , Administración Oral , Animales , Antivirales/síntesis química , Antivirales/uso terapéutico , Diseño de Fármacos , Ratones , Modelos Animales , Purinas/farmacocinética , Purinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Receptor Toll-Like 7/metabolismoRESUMEN
The synthesis and structure-activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound 36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.
Asunto(s)
Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Inhibidores de Fusión de VIH/química , Isoquinolinas/química , Ácidos Nicotínicos/química , Animales , Células Cultivadas , Diseño de Fármacos , Proteína gp120 de Envoltorio del VIH/metabolismo , Inhibidores de Fusión de VIH/síntesis química , Inhibidores de Fusión de VIH/farmacocinética , VIH-1/efectos de los fármacos , Semivida , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Ácidos Nicotínicos/síntesis química , Ácidos Nicotínicos/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The antifungal natural product citrafungin A was synthesized using, as key steps, an asymmetric aldol reaction of a chiral oxazolidinone, diastereoselective alkylation of a chiral 1,3-dioxolan-2-one, semihydrogenation of an enyne, and selective methyl ester deprotection.
Asunto(s)
Alquenos/síntesis química , Antifúngicos/síntesis química , Lactonas/síntesis química , Aldehídos/química , Alquilación , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , EstereoisomerismoRESUMEN
A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein-ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK.
RESUMEN
Five-step total syntheses of angelicoin A and B from 2,2,6-trimethyl-4-dioxinone are reported using late stage biomimetic aromatization reactions via diketo-dioxinones as intermediates. In addition, with angelicoin A, this aromatization was coupled with a palladium-catalyzed decarboxylative prenylation in a one-pot sequence as the key step.
Asunto(s)
Materiales Biomiméticos/síntesis química , Cumarinas/síntesis química , Paladio/química , Catálisis , Estructura Molecular , PrenilaciónRESUMEN
The total synthesis of aigialomycin D, without the need for phenol protection, was carried out using the C-acylation of a keto-dioxinone dianion, a cascade sequence consisting of ketene generation, alcohol trapping and aromatization, and ring-closing metathesis.