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
  • 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: [email protected].
  • 4. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: [email protected].
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.