Zhang Linjie, Wei Haopai, Han Taihe, Shi Suntao, Zhang Xiaopeng, Shi Xuezhao, Zhang Haixia, Zhang Baoxin
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
School of Information Science and Engineering, Lanzhou University, Lanzhou 730000, China.
Bioorg Chem. 2025 Jul 1;161:108484. doi: 10.1016/j.bioorg.2025.108484. Epub 2025 Apr 23.
Molecular conjugation is a promising strategy for drug development, which could enhance the efficacy, selectivity, and bioavailability of high-potency compounds through precise structural modifications. Our previous studies demonstrated that hydroxytyrosol (HT) provides excellent neuroprotection in PC12 cells, which is derived from olive oil, and now widely used as a natural food additive. In this study, we rationally designed and synthesized a string of HT derivations by coupling caffeic acid skeletons, and found that HT-3 exhibited the strongest antioxidant activity and superior neuroprotective efficacy via the Keap1/Nrf2/ARE pathway among the HT analogue. Additionally, nanoparticles of HT-3 (HT-3 NPs) were constructed for reducing toxicity and enhancing efficacy, which could enhance blood-brain barrier penetration, accelerate metabolism, and prolong brain retention in mice model of Parkinson's disease. This work would open a new avenue for further investigation of HT analogue.
分子共轭是药物开发的一种有前景的策略，它可以通过精确的结构修饰来提高高效能化合物的疗效、选择性和生物利用度。我们之前的研究表明，羟基酪醇（HT）在PC12细胞中具有出色的神经保护作用，它源自橄榄油，现在被广泛用作天然食品添加剂。在本研究中，我们通过偶联咖啡酸骨架合理设计并合成了一系列HT衍生物，发现HT-3在HT类似物中通过Keap1/Nrf2/ARE途径表现出最强的抗氧化活性和卓越的神经保护功效。此外，构建了HT-3纳米颗粒（HT-3 NPs）以降低毒性并提高疗效，其可以增强血脑屏障穿透性、加速新陈代谢并延长在帕金森病小鼠模型中的脑内滞留时间。这项工作将为进一步研究HT类似物开辟一条新途径。
