RESUMEN
Wee1 inhibition has received great attention in the past decade as a promising therapy for cancer treatment. Therefore, a potent and selective Wee1 inhibitor is highly desirable. Our efforts to make safer and more efficacious Wee1 inhibitors led to the discovery of compound 16, a highly selective Wee1 inhibitor with balanced potency, ADME, and pharmacokinetic properties. The chiral ethyl moiety of compound 16 provided an unexpected improvement of Wee1 potency. Compound 16, known as ZN-c3, showed excellent in vivo efficacy and is currently being evaluated in phase 2 clinical trials.
Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Descubrimiento de Drogas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Área Bajo la Curva , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Perros , Diseño de Fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Semivida , Humanos , Masculino , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The total synthesis of the Lycopodium alkaloid lyconadin A was accomplished and it was applied to the total syntheses of the related congeners, lyconadins B and C. Lyconadin A has attracted attention as a challenging target for total synthesis due to the unprecedented pentacyclic skeleton. Our synthesis of lyconadin A features a facile construction of the highly fused tetracyclic skeleton through a combination of an aza-Prins reaction and an electrocyclic ring opening, followed by formation of a C-N bond. Transformation of the bromoalkene moiety of the tetracycle to a key enone intermediate was extensively investigated, and three methods via sulfide, oxime, or azide intermediates were established. A pyridone ring was constructed from the key enone intermediate to complete the synthesis of lyconadin A. A dihydropyridone ring could also be formed from the same enone intermediate, leading to a synthesis of lyconadin B. Establishment of the conditions for an electrocyclic ring opening without formation of the C-N bond resulted in completion of the total synthesis of lyconadin C.
Asunto(s)
Compuestos Policíclicos/síntesis química , Ciclización , Compuestos Policíclicos/químicaRESUMEN
The total synthesis of lyconadin A from (R)-5-methylcyclohex-2-enone was accomplished. Our synthesis features the facile construction of a highly fused tetracyclic compound through a combination of an aza-Prins reaction and an electrocyclic ring opening. Transformation of the bromoalkene moiety in the tetracycle could be achieved by either a vinylogous Pummerer rearrangement or the formation and subsequent isomerization of the nitrosoalkene to furnish an α,ß-unsaturated ketone, from which the pyridone ring was constructed.
Asunto(s)
Compuestos Policíclicos/síntesis química , Estructura Molecular , Compuestos Policíclicos/química , EstereoisomerismoRESUMEN
Axially chiral 1,1'-biaryl-2,2'-dimethanol (3, BAMOL) family of diols are highly effective catalysts for enantioselective hetero-Diels-Alder reactions between aminosiloxydiene 1 and a wide variety of unactivated aldehydes. The reactions proceed in useful yields and excellent enantioselectivities. The diols function in the same capacity as Lewis acids, by activating the aldehyde carbonyl group through hydrogen bonding.