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

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机构： [1]Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China [2]The Second Clinical Medical College of North Sichuan Medical College⋅Department of Pharmacy, Nanchong Central Hospital⋅Nanchong Key Laboratory of [3]Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, ChongQing, 400038, China [4]Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, 110016, China [5]Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China

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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 EC50 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 Aβ25-35 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.Copyright © 2022 Elsevier Masson SAS. All rights reserved.

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出版当年[2022]版：

大类 | 1 区

医学

小类 | 1 区药物化学

最新[2023]版：

大类 | 2 区

医学

小类 | 1 区药物化学

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第一作者机构： [2]The Second Clinical Medical College of North Sichuan Medical College⋅Department of Pharmacy, Nanchong Central Hospital⋅Nanchong Key Laboratory of [3]Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, ChongQing, 400038, China

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