RESUMEN
A novel series of N(1)-(3-fluoro-4-(6,7-disubstituted-quinolin-4-yloxy)phenyl)-N(4)-arylidenesemicarbazide derivatives were synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against A549, HT-29, MKN-45 and MDA-MB-231 cancer cell lines in vitro. Several potent compounds were further evaluated against three other cancer cell lines (U87MG, NCI-H460 and SMMC7721). Most of compounds tested exhibited moderate to excellent activity. The studies of SARs identified the most promising compound 28 (c-Met IC50=1.4nM) as a c-Met kinase inhibitor. In this study, a promising compound 28 was identified, which displayed 2.1-, 3.3-, 48.4- and 3.6-fold increase against A549, HT-29, U87MG and NCI-H460 cell lines, respectively, compared with that of Foretinib.
Asunto(s)
Antineoplásicos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Quinolinas/química , Semicarbacidas/síntesis química , Semicarbazonas/química , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Células HT29 , Humanos , Simulación del Acoplamiento Molecular , Fosforilación/efectos de los fármacos , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/toxicidad , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-met/metabolismo , Quinolinas/síntesis química , Quinolinas/toxicidad , Semicarbacidas/química , Semicarbacidas/toxicidad , Semicarbazonas/síntesis química , Semicarbazonas/toxicidad , Relación Estructura-ActividadRESUMEN
The manuscript describes the synthesis of 10-substituted dihydroartemisinin derivatives containing N-aryl phenylethenesulfonamide groups and their in vitro anti-tumor activities against the HT-29, MDA-MB-231, U87MG, H460, A549 and HL-60 cancer cell lines and the normal WI-38 cell line. Most tested compounds showed enhanced cytotoxic activities and good selectivity toward the MDA-MB-231, HT-29 and HL-60 cell lines, with IC50 values in the single-digit µM range as compared with dihydroartemisinin (DHA), and all of them displayed less toxicity towards WI-38 cells. Among them, compounds 3c and 6c with trifluoromethoxy groups on the N-phenyl ring were found to be most active compounds against the six tested cancer cell lines.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/toxicidad , Artemisininas/química , Artemisininas/toxicidad , Antineoplásicos/síntesis química , Artemisininas/síntesis química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Células HT29 , Humanos , Concentración 50 InhibidoraRESUMEN
Langerhans cell histiocytosis (LCH) is a clonal neoplasm of myeloid dendritic cells, rarely involving the thyroid gland. Papillary thyroid carcinoma (PTC) is the most common histological subtype of thyroid cancer. We report a rare case of a 34-year-old Chinese woman who has LCH with PTC and cervical lymph node metastasis of LCH, with a review of the literature. The patient has thyroid nodules and cervical lymph node enlargement detected by neck ultrasound during physical examination. Fine needle aspiration cytology (FNAC) showed PTC with Hashimoto's thyroiditis and BRAF V600E mutation after thyroidectomy and lymph node dissection. Histopathological examination suggests that LCH was concurrent with classical PTC, accompanied by LCH cervical lymph node metastasis. No BRAF, HRAS, and TERT promoter mutations were detected in LCH metastatic lesions. The patient is in stable clinical condition currently.