RESUMEN
In this report, the strategy and outcome of expanding SAR exploration to improve solubility and metabolic stability are discussed. Compound 35 exhibited excellent potency, selectivity over A(1) and improved solubility of >4 mg/mL at pH 8.0. In addition, compound 35 had good metabolic stability with a scaled intrinsic clearance of 3 mL/min/kg (HLM) and demonstrated efficacy in the haloperidol induced catalepsy model.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Aminopiridinas/química , Química Farmacéutica/métodos , Pirimidinas/síntesis química , Diseño de Fármacos , Haloperidol/química , Humanos , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Enfermedad de Parkinson/terapia , Unión Proteica , Pirimidinas/química , Pirimidinas/farmacología , Receptor de Adenosina A1/química , Receptor de Adenosina A2A/química , Solubilidad , Relación Estructura-ActividadRESUMEN
The synthesis and the biological evaluation of a new family diterpenes are presented. The synthetic studies were inspired by the structural framework of acanthoic acid (1) and yielded a family of compounds that were evaluated as anti-inflammatory agents. Among them, compounds 2, 10, 12, and 16 exhibited a very low nonspecific cytotoxicity and inhibited the synthesis of TNF-alpha with greater than 65 % efficacy at low micromolar concentrations. Cytokine-specificity studies revealed that these compounds also inhibited the synthesis of the proinflammatory cytokines IL-1beta and IL-6, while inhibition of IL-1ra and IL-8 synthesis was marginal and only occurred at high concentrations. Further studies, through EMSA and Western blot analyses, indicated that these compounds decreased the extent of phosphorylation of IkappaBalpha; this suggests that they exert their anti-inflammatory profile by inhibiting NF-kappaB-mediated cytokine synthesis. These findings imply that these diterpenes represent promising leads for the development of novel anti-inflammatory agents.
Asunto(s)
Citocinas/biosíntesis , Diterpenos/síntesis química , Diterpenos/farmacología , Proteínas I-kappa B/antagonistas & inhibidores , Diterpenos/química , Humanos , Proteínas I-kappa B/metabolismo , Inhibidor NF-kappaB alfa , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Fosforilación , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
[structure: see text] An efficient, enantioselective synthesis of the C1-C12 fragment 2 of borrelidin is presented. Construction of the "skipped" polymethylene chain of 2 was accomplished by iteration of Myers' alkylation, while formation of the C3 stereocenter was achieved by Roush's asymmetric allylboration methodology.
Asunto(s)
Antibacterianos/síntesis química , Alcoholes Grasos/síntesis química , Alquilación , Antibacterianos/química , Alcoholes Grasos/química , Indicadores y Reactivos , Macrólidos , EstereoisomerismoRESUMEN
An efficient synthetic approach to the tricyclic core 8 of lateriflorone is described. Essential to the synthesis was the implementation of a biomimetic tandem Claisen/Diels-Alder reaction that produced the desired tricyclic scaffold as a single isomer. A rationalization of the excellent regio and stereoselectivity of this transformation is also proposed. [reaction: see text]
Asunto(s)
Compuestos Policíclicos/síntesis química , Compuestos de Espiro/síntesis química , Espironolactona/síntesis química , Xantonas , Ciclización , Garcinia/química , Conformación Molecular , Estereoisomerismo , Xantenos/químicaRESUMEN
[reaction: see text] Two different routes to the tricyclic core of Garcinia-derived natural products are described. The first approach is based on a tandem Claisen/Diels-Alder rearrangement and delivers the desired lactone 14. The second approach, employing a Wessely oxidation/Diels-Alder protocol, leads to the same caged heterocycle, albeit with modified constitution.