RESUMO
We synthesized an oxidation-responsive polycaprolactone (O-PCL) bearing pendant arylboronic esters as H2O2-responsive motifs. H2O2 induces fast depolymerization of O-PCL within days. Nanoparticles formulated from O-PCL disintegrate and release payload in response to concentrations of H2O2 (50 µM) that are relevant to human disease.
Assuntos
Peróxido de Hidrogênio/química , Nanopartículas/química , Poliésteres/química , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanopartículas/administração & dosagem , Oxirredução , Poliésteres/administração & dosagemRESUMO
An 8-oxopurine-6-carboxamide compound (1a) was previously identified as an inhibitor of non-small cell lung cancer (NSCLC). In this study, more than 30 purine-6-carboxamide derivatives with variations at the C2, N7, C8, and N9 positions were synthesized to investigate the structure-activity relationship as a basis for the construction of an advanced pharmacophore model. This model suggests that purine-6-hydroxamate and purine-6-amidoxime analogs could form more hydrogen bonds with a target protein to enhance the inhibitory activities against H1975â¯cells. Among the series of analogs, hydroxamate 17 and amidoxime 19a exhibited excellent potency against H1975â¯cells (IC50â¯<â¯1.5⯵M) and other lung cancer cells with either wild-type or mutated epidermal growth factor receptor (EGFR). Mouse experiments indicated that compounds 17 and 19a were efficient anticancer agents with no appreciable toxicity. The mechanisms of action for the induction of cell apoptosis were determined to involve microtubule fragmentation and p53-mediated signaling pathways.
Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ácidos Hidroxâmicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Oximas/farmacologia , Purinas/farmacologia , Amidas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ácidos Hidroxâmicos/química , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Oximas/química , Purinas/química , Relação Estrutura-AtividadeRESUMO
Microtubule targeting agents (MTAs) constitute a class of drugs for cancer treatment. Despite many MTAs have been proven to significantly improve the treatment outcomes of various malignancies, resistance has usually occurred. By selection from a two million entry chemical library based on the efficacy and safety, we identified purine-type compounds that were active against lung small cell lung cancer (NSCLC). The purine compound 5a (GRC0321) was an MTA with good effects against NSCLC. Lung cancer cells H1975 treated with 5a could induce microtubule fragmentation, leading to G2/M cell cycle arrest and intrinsic apoptosis. Compound 5a directly targeted katanin and regulated the severing activity of katanin, which cut the cellular microtubules into short pieces and activated c-Jun N-terminal kinases (JNK). The microtubule fragmenting effect of 5a is a unique mechanism in MTAs. It might overcome the resistance problems that most of the MTAs have faced.