RESUMEN
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Administración Oral , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Haplorrinos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine), a nucleoside reverse transcriptase inhibitor with extremely potent anti-HIV activity, was concisely synthesized from (R)-glyceraldehyde acetonide in an 18% overall yield by a 12-step sequence involving highly diastereoselective ethynylation of an α-alkoxy ketone intermediate. The present synthesis is superior, both in overall yield and in the number of steps, to the previous one which required 18 steps from an expensive starting material and resulted in a modest overall yield of 2.5%.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Desoxiadenosinas/síntesis química , Gliceraldehído/análogos & derivados , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Inhibidores de la Transcriptasa Inversa/síntesis química , Gliceraldehído/química , VIH/enzimología , Transcriptasa Inversa del VIH/química , Humanos , Espectroscopía de Resonancia Magnética , EstereoisomerismoRESUMEN
9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.
Asunto(s)
Antineoplásicos/síntesis química , Carbazoles/síntesis química , Piperazinas/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Carbazoles/farmacocinética , Carbazoles/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Ratones , Ratones SCID , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacología , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
A concise synthesis of di-O-methyl-beta,gamma-dehydrocurvularin, the di-O-methylated derivative of the naturally occurring nematicidal macrolide, beta,gamma-dehydrocurvuralin, was accomplished by starting from a commercially available aromatic carboxylic acid in a three-step sequence consisting of esterification, Friedel-Crafts acylation, and microwave-promoted ring-closing metathesis.