In vitro and in vivo biological evaluation of newly synthesized multi-target 20(R)-panaxadiol derivatives for treating Alzheimer's disease.
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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DOI：
10.1016/j.ejmech.2022.114825
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发表时间：
2022-10
影响因子：
6.7
通讯作者：
Lei Pang;Jin Li;Zheng-Fang Liu;Yin Shen Quan;He-huan Sui;Y. Jia;Fen‐er Chen;Jung Joon Lee;Peng Liu;Zhe-Shan Quan;Qing-Kun Shen;Hong-yan Guo
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文献类型：
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作者：
Lei Pang;Jin Li;Zheng-Fang Liu;Yin Shen Quan;He-huan Sui;Y. Jia;Fen‐er Chen;Jung Joon Lee;Peng Liu;Zhe-Shan Quan;Qing-Kun Shen;Hong-yan Guo
本论文对一系列3-羟基取代的新型20（R）-人参二醇衍生物进行了深入研究，发现其中一个苄基取代氨基甲酸酯化合物（化合物14 a）具有最强的神经保护活性，其EC_（50）为13.17 μM。化合物14 a的神经保护作用比多奈哌齐略强，比20（R）-人参二醇强得多。化合物14 a在7.5-120 μM下在各种细胞系中表现出低毒性。此外，化合物14 a还具有抑制细胞凋亡、诱导tau蛋白过度磷酸化、影响β-淀粉样蛋白（Aβ）、β-分泌酶、活性氧、肿瘤坏死因子-α、环氧合酶-2和白细胞介素-1 β的产生以及促进Aβ25- 35解聚等多种生物活性。化合物14 a穿过血脑屏障的有效渗透率为26.13 × 10−6cm/s，表明它可以在中枢神经系统中提供足够的暴露。此外，化合物14 a改善了小鼠的学习、记忆和新物体识别，并且体内毒性实验证实了良好的治疗安全范围。因此，化合物14是治疗阿尔茨海默病的有希望的多功能先导物，并为天然产物衍生的抗阿尔茨海默病药物提供了新的途径。
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 vitroanalysis revealed that a compound bearing benzyl-substituted carbamate, which we denoted compound14a, exhibited the most potent neuroprotective activity, with an EC50of 13.17 μM. The neuroprotective effect of compound14awas slightly more potent than that of donepezil and much more potent than that of 20(R)-panaxadiol. Compound14aat 7.5–120 μM exhibited low toxicity in various cell lines. In addition, compound14aexhibited 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 Aβ25-35disaggregation. The effective permeability of compound14aacross the blood-brain barrier was 26.13 × 10−6cm/s, indicating that it can provide adequate exposure in the central nervous system. Further, compound14aimproved learning, memory, and novel object recognition in mice, andin vivotoxicity experiments confirmed a good therapeutic safety range. Thus, compound14ais a promising multifunctional lead for treating Alzheimer's disease and offers new avenues for natural product-derived anti-Alzheimer's disease drugs.