2. Academic Validation
  3. Structure-activity relationship studies of (E)-3,4-dihydroxystyryl alkyl sulfones as novel neuroprotective agents based on improved antioxidant, anti-inflammatory activities and BBB permeability

Structure-activity relationship studies of (E)-3,4-dihydroxystyryl alkyl sulfones as novel neuroprotective agents based on improved antioxidant, anti-inflammatory activities and BBB permeability

  • Eur J Med Chem. 2019 Jun 1:171:420-433. doi: 10.1016/j.ejmech.2019.03.044.
Ying Chen 1,  Bolin Wu 1,  Yameng Hao 1,  Yunqi Liu 1,  Zhili Zhang 1,  Chao Tian 1,  Xianling Ning 2,  Ying Guo 1,  Junyi Liu 3,  Xiaowei Wang 4
Affiliations

Affiliations

  • 1 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
  • 2 Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, 100191, China.
  • 3 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China. Electronic address: jyliu@bjmu.edu.cn.
  • 4 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: xiaoweiwang@bjmu.edu.cn.
PMID: 30928712 DOI: 10.1016/j.ejmech.2019.03.044
Abstract

(E)-3,4-dihydroxystyryl alkyl sulfones, as new analogues of neurodegenerative agents, were designed and synthesized. The biological results demonstrated that most of the target compounds preserved antioxidant and anti-inflammatory potency in scavenging reactive free radicals, protecting neuronal cells against neurotoxins such as H2O2, 6-hydroxydopamine and inhibiting lipopolysaccharide (LPS)-induced over-production of NO. Among these compounds, 6.22 with cyclopentyl propyl exhibited prominent antioxidant activity at low concentration (2.5 μM) in H2O2 model (cell viability = 94.5%). In addition, 6.22 (IC50 = 1.6 μM) displayed better anti-inflammatory activity than that of lead compound 1 (IC50 = 13.4 μM). In view of the outstanding performance of 6.22, the apoptotic rates of H2O2-damaged PC12 cells were detected by Annexin V-FITC/PI assay. 6.22 showed higher potency in inhibition of Apoptosis than 1 at low concentration (2.5 μM), consisting with the antioxidant and anti-inflammatory models. Furthermore, with the predicted CNS (+) blood-brain barrier (BBB) permeability (Pe = 6.84 × 10-6 cm s-1), low cytotoxicity and favorable physiochemical properties based on calculation, compound 6.22 can be further developed as a potential multifunctional neuroprotective agent.

Keywords

Annexin V-PI apoptosis stain; Anti-inflammatory; Antioxidant; BBB permeability; Neurodegenerative diseases.

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