The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its therapy. One hopeful approach is to develop multifuntional ligands. Here, a total of 23 compounds based on nobiletin structure were designed and synthesized. The neuroprotective activities were evaluated for their antioxidant, anti-inflammatory and anti-Aβ 42 (Amyloid βprotein 42) neurotoxicity properties by MTT assays. The results demonstrated compound A12 was the most promising derivative against inflammatory (14.6 � 0.6 %) and cell damages induced by hydrogen peroxide (47.2 � 1.1 %), oxygen glucose deprivation (36.2 � 1.1 %) and Aβ 42 (40.7 � 2.1 %). Molecular docking study revealed A12 formed a greater area of interactions with Aβ 42 to prevent it from acquiring a beta sheet conformation for aggregation. Structure-activity relationships revealed the introduction of hydroxyl on ring B and aurone skeleton with a five-membered ring C could be benefit to increase their neuroprotective activities. In summary, A12 might represent a promising multifunctional neuroprotective agent against AD.
Objective:
In this study, the synthesis of a series of derivatives had been carried out by
bioisosterism design on the basis of dimethyl cardamonin (DMC). Subsequently, we evaluated their
reversal activities as potential P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) agents.
Methods:
Dimethyl cardamonin derivatives were synthesized from acetophenones and the
corresponding benzaldehydes in the presence of 40% KOH by Claisen-Schmidt reaction. And their
cytotoxicity and reversal activities in vitro were assessed with MTT. Moreover, the compound B4 were
evaluated by doxorubicin (DOX) accumulation, Western blot and wound-healing assays deeply.
Results:
The results showed that compounds B2, B4 and B6 had potency of MDR reversers with little
intrinsic cytotoxicity. Meanwhile, these compounds also demonstrated the capability to inhibit MCF-7
and MCF-7/DOX cells migration. Besides, the most compound B4 was selected for further study, which
promoted the accumulation of DOX in MCF-7/DOX cells and inhibited the expression of P-gp at protein
levels.
Conclusion:
The above findings may provide new insights for the research and development of
P-gp-mediated MDR reversal agents.
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