RESUMO
A novel method for preparation of a new class of dihydropyridine thioglycosides and their corresponding dehydrogenated forms, via reaction of piperidinium salts of dihydropyridinethiones with 2,3,4,6-tetra-O-acetyl-α-D-gluco- and galactopyranosyl bromides has been studied. The evaluation of antiproliferative activity against HepG-2 cell lines (liver carcinoma cell lines) of the dihydropyridine thioglycosides and pyridine thioglycosides revealed that many of the thioglycosides have interesting antitumor activities specifically 5c, 5g, 5l, 5o, 5p, 7a, 7i, 7p, 8b, 8f, 8s, and 8v.
Assuntos
Antineoplásicos/síntese química , Carcinoma Hepatocelular/tratamento farmacológico , Di-Hidropiridinas/síntese química , Neoplasias Hepáticas/tratamento farmacológico , Tioglicosídeos/síntese química , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Di-Hidropiridinas/uso terapêutico , Desenho de Fármacos , Células Hep G2 , Humanos , Estrutura Molecular , Oxirredução , Relação Estrutura-Atividade , Tioglicosídeos/uso terapêuticoRESUMO
A novel series of acyclic pyridine thioglycosides has been synthesized. Evaluation of the anti proliferative activity of these compounds against HEPG-2 cell lines (liver carcinoma cell lines) shows that most of the compounds have high anti-tumor activities especially 6b, 6c, 7b and 7c. Furthermore, in the modeling study, these compounds showed that they have high binding affinity with thymidylate synthase dihydrofolate reductase (TS-DHFR).
Assuntos
Antineoplásicos/síntese química , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Piridinas/síntese química , Tioglicosídeos/síntese química , Antineoplásicos/uso terapêutico , Sítios de Ligação , Carcinoma Hepatocelular/patologia , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Complexos Multienzimáticos/metabolismo , Ligação Proteica , Piridinas/uso terapêutico , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/metabolismo , Tioglicosídeos/uso terapêutico , Timidilato Sintase/metabolismoRESUMO
Although most patients with papillary thyroid cancer (PTC) have favorable outcomes, some have advanced PTC that is refractory to external beam radiation and systemic chemotherapy. Galectin-3 (Gal-3) is a beta-galactoside-binding protein with antiapoptotic activity that is consistently overexpressed in PTC. The purpose of this study is to determine if Gal-3 inhibition promotes apoptosis, chemosensitivity, and radiosensitivity in PTC. PTC cell lines (8505-C and TPC-1) and human ex vivo PTC were treated with a highly specific small molecule inhibitor of Gal-3 (Td131_1). Apoptotic activity was determined by flow cytometric analysis as well as caspase-3 and PARP cleavage. The minimum inhibitory concentrations of Td131_1 and doxorubicin were determined, and their combined effects were measured to test for synergistic activity. The effects of Td131_1 on radiosensitivity were determined by a clonogenic assay. Td131_1 promoted apoptosis, improved radiosensitivity, and synergistically enhanced chemosensitivity to doxorubicin in PTC cell lines. In PTC ex vivo, Td131_1 treatment alone induced the cleavage of caspase-3 and PARP. Td131_1 and doxorubicin together activated apoptosis in PTC ex vivo to a greater degree than their combined individual effects. Td131_1 activated apoptosis and had synergistic activity with doxorubicin in PTC. We conclude that Gal-3 targeted therapy is a promising therapeutic strategy for advanced PTC that is refractory to surgery and radioactive iodine therapy.