RESUMO
Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aß-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aß toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aß deposition in Aß1-42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Cinamatos , Triazóis , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Cinamatos/química , Cinamatos/farmacologia , Cinamatos/síntese química , Humanos , Camundongos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Relação Estrutura-Atividade , Estrutura Molecular , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Relação Dose-Resposta a Droga , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Descoberta de Drogas , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , MasculinoRESUMO
An efficient one-pot reaction for the synthesis of oxoaporphine alkaloids has been developed. Twenty-three compounds of oxoaporphine alkaloids were prepared and assessed for their antitumor activities. Most compounds inhibited the growth of T-24 tumor cells in vitro. Particularly, 4B displayed the most potent activity with an IC50 value of 0.5 µM, which was 19-fold more potent than the parent compound 4. The substitution at C3-position of oxoaporphine core by -NO2 significantly enhanced the anticancer activity. Mechanism studies indicated that 4 and 4B induced cell cycle arrest at G2/M phase; in contrast, 4V induced cell cycle arrest at the S phase. Increase of mitochondrial ROS/Ca2+ and decrease of MMP, accompanied by activation of caspase-3/9, were observed in T-24 cells after exposure to compounds 4, 4B and 4V, suggesting that the mitochondrial pathway was involved in the induced apoptosis. Moreover, compound 4B effectively inhibited tumor growth in a mouse xenograft model bearing T-24.