A novel hydroxytyrosol derivative HT-3 enhances antioxidant and neuroprotective activity through efficient molecular conjugation

  • Bioorg Chem. 2025 Jul 1:161:108484. doi: 10.1016/j.bioorg.2025.108484.
Linjie Zhang  1 ,  Haopai Wei  1 ,  Taihe Han  1 ,  Suntao Shi  1 ,  Xiaopeng Zhang  2 ,  Xuezhao Shi  1 ,  Haixia Zhang  1 ,  Baoxin Zhang  3
Affiliations
  • 1. State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
  • 2. School of Information Science and Engineering, Lanzhou University, Lanzhou 730000, China.
  • 3. State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China. Electronic address: [email protected].
PMID: 40300447 DOI: 10.1016/j.bioorg.2025.108484
Abstract

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.

Keywords
HT-3; Hydroxytyrosol; Nanoparticles; Neuroprotection; Nrf2; Parkinson's disease.
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