Synthesis of Paeonol-Ozagrel Conjugate: Structure Characterization and In Vivo Anti-Ischemic Stroke potential

Jing Zhang; Miaomiao Jiang; Hui Zhao; Lan Han; Yu Jin; Weidong Chen; Jianqing Wang; Ziyu Zhang; Can Peng

doi:10.3389/fphar.2020.608221

Synthesis of Paeonol-Ozagrel Conjugate: Structure Characterization and In Vivo Anti-Ischemic Stroke potential

Front Pharmacol. 2021 Feb 1:11:608221. doi: 10.3389/fphar.2020.608221. eCollection 2020.

Authors

Jing Zhang^{1

2

3}, Miaomiao Jiang^{1

2

4}, Hui Zhao⁴, Lan Han^{1

2

3}, Yu Jin⁵, Weidong Chen^{1

2

3}, Jianqing Wang⁴, Ziyu Zhang^{1

2}, Can Peng^{1

2

3}

Affiliations

¹ College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
² Institute of Pharmaceutics, Anhui Academy of Chinese Medicine, Hefei, China.
³ Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei, China.
⁴ Department of Pharmacy, the Fourth Affiliated Hospital of Anhui Medical University, Hefei, China.
⁵ Chaohu Jinchen Pharmacy Co., Ltd., Shanghai Haihong Industrial Group, Chaohu, China.

Abstract

Ischemic stroke is a common neurological disease that can lead to mortality and disability. The current curative effect remains unsatisfactory because drug accumulation in the diseased areas is insufficient as a result of the unique blood-brain barrier. Therefore, much attention has been paid to develop a novel therapeutic compound, paeonol-ozagrel conjugate (POC), for ischemic stroke. Then, POC was successfully synthesized by conjugating of paeonol and ozagrel as mutual prodrug. A series of in vitro characterizations and evaluations, including high - resolution mass spectroscopy, nuclear magnetic resonance spectroscopy, partition coefficient, and assessment of cytotoxicity against PC12 cells, were performed. Pharmacokinetic study demonstrated POC is eliminated quickly (t_1/2 = 53.46 ± 19.64 min), which supported a short dosing interval. The neurological score, infarct volume, histopathological changes, oxidative stress, inflammatory cytokines levels, and TXA₂ levels also were evaluated in vivo in middle cerebral artery occlusion (MCAO) rats. All results showed that POC had a significant curative and therapeutic effect on ischemic stroke, as evaluated by the middle cerebral artery occlusion. Overall, POC can be expected to become a new drug candidate for the treatment of ischemic stroke.

Keywords: chemical structure characterization; cytotoxicity; inflammatory cytokines; ischemic stroke; oxidative stress; paeonol-ozagrel conjugate; partition coefficient; synthesis.