RESUMEN
Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2.
Asunto(s)
Descubrimiento de Drogas , Imidazoles/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazinas/farmacología , Pirimidinas/farmacología , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Imidazoles/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazinas/síntesis química , Pirazinas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
[structure: see text] A second generation total synthesis of the potent antitumor agent (+)-phorboxazole A (1) has been achieved. The cornerstone of this approach comprises a more convergent strategy, involving late-stage Stille union of a fully elaborated C(1-28) macrocycle with a C(29-46) side chain. The second generation synthesis entails the longest linear sequence of 24 steps, with an overall yield of 4.2%.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Oxazoles/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Estructura Molecular , Oxazoles/químicaRESUMEN
[reaction: see text] A linear but concise synthetic approach toward the structurally related natural products myriaporone and tedanolide is reported. The route is highlighted by a stereoselective homoallenylboration and a regio- and chemoselective nitrile oxide cycloaddition. Installation of the (Z)-olefin completed the carbon skeleton of myriaporone 1.
Asunto(s)
Alquenos/síntesis química , Compuestos Epoxi/síntesis química , Lactonas/síntesis química , Alquenos/química , Animales , Antineoplásicos/síntesis química , Compuestos de Boro/química , Macrólidos/síntesis química , Nitrilos/química , Poríferos/química , EstereoisomerismoRESUMEN
A highly convergent second-generation synthesis of (+)-phorboxazole A has been achieved. Highlights of the synthetic approach include improved Petasis-Ferrier union/rearrangement conditions on a scale to assemble multigram quantities of the C(11-15) and C(22-26) cis-tetrahydropyrans inscribed with the phorboxazole architecture, a convenient method to prepare E- and Z-vinyl bromides from TMS-protected alkynes utilizing radical isomerization of Z-vinylsilanes, and a convergent late-stage Stille union to couple a fully elaborated C(1-28) macrocyclic iodide with a C(29-46) oxazole stannane side chain to establish the complete phorboxazole skeleton. The synthesis, achieved with a longest linear sequence of 24 steps, proceeded in 4.6% overall yield.