RESUMO

Neuroendocrine prostate cancer (NEPC) is a highly aggressive cancer that is resistant to hormone therapy and characterized by poor prognosis, as well as limited therapeutic options. Since the natural product lycobetaine was reported to exhibit good antitumor activities against various types of cancers, we initially simplified the scaffold of lycobetaine to obtain the active compound 1, an isoquinoline derivative with an aryl moiety substitution at the 4-position, which showed apparent antiproliferative activities against NPEC cell line LASCPC-01 in vitro. Subsequently, we carried out structural optimization and systematic structure-activity relationship (SAR) studies on compound 1, leading to the discovery of compound 46, which demonstrated potent inhibitory activities against the LASCPC-01 cell line with an IC50 value of 0.47 µM. Moreover, compound 46 displayed remarkable selectivity over prostate cancer cell line PC-3 with a selectivity index greater than 190-fold. Further cell-based mechanism studies revealed that compound 46 and lycobetaine can effectively induce G1 cell cycle arrest and apoptosis dose dependently. However, lycobetaine inhibited the expression of neuroendocrine markers, while compound 46 slightly upregulated these proteins. This suggested that compound 46 might exert its antitumor activities through a different mechanism than lycobetaine, warranting further study.

Assuntos

Antineoplásicos , Apoptose , Proliferação de Células , Isoquinolinas , Neoplasias da Próstata , Humanos , Isoquinolinas/farmacologia , Isoquinolinas/química , Isoquinolinas/síntese química , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Masculino , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia

RESUMO

Deep learning is a type of high-level learning that has received widespread attention in research on higher education; however, learning scenarios as an important variable have been ignored to some extent in past studies. This study aimed to explore the learning state of engineering students in three learning scenarios: theoretical learning, experimental learning, and engineering practice. Samples of engineering university students in China were recruited online and offline; the students filled in the engineering Education-Study Process Questionnaire, which was revised from the R-SPQ-2F. The results of clustering analysis showed four types of learning approaches in the three scenarios: typical deep learning, typical shallow learning, deep-shallow learning, and free learning. Engineering learners in different learning scenarios tended to adopt different learning approaches and showed gender differences. Due to factors such as differences in culture and choice of learning opportunities, the deep and shallow learners demonstrated excellent learning performance, which is in sharp contrast with the "learning failure" exhibited by such students abroad.