In vitro and in vivo biological evaluation of newly synthesized multi-target 20(R)-panaxadiol derivatives for treating Alzheimer's disease.

An extensive study was performed to discover a series of novel 20(R)-panaxadiol derivatives with various substituents at the 3-OH position as nontoxic, brain-permeable, multi-target leads for treating Alzheimer's disease. In vitro analysis revealed that a compound bearing benzyl-substituted carbamate, which we denoted compound 14a, exhibited the most potent neuroprotective activity, with an EC ₅₀ of 13.17 μM. The neuroprotective effect of compound 14a was slightly more potent than that of donepezil and much more potent than that of 20(R)-panaxadiol. Compound 14a at 7.5-120 μM exhibited low toxicity in various cell lines. In addition, compound 14a exhibited a wide range of biological activities, including inhibiting apoptosis; inducing tau hyperphosphorylation; affecting beta-amyloid (Aβ), β-secretase, reactive oxygen species, tumor necrosis factor-α, cyclooxygenase-2, and interleukin-1β production; and promoting Aβ _25-35 disaggregation. The effective permeability of compound 14a across the blood-brain barrier was 26.13 × 10 ^-6  cm/s, indicating that it can provide adequate exposure in the central nervous system. Further, compound 14a improved learning, memory, and novel object recognition in mice, and in vivo toxicity experiments confirmed a good therapeutic safety range. Thus, compound 14a is a promising multifunctional lead for treating Alzheimer's disease and offers new avenues for natural product-derived anti-Alzheimer's disease drugs.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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