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  3. Green synthesis of neuroprotective spirocyclic chalcone derivatives and their role in protecting against traumatic optic nerve injury

Green synthesis of neuroprotective spirocyclic chalcone derivatives and their role in protecting against traumatic optic nerve injury

  • Eur J Med Chem. 2024 Oct 1:280:116933. doi: 10.1016/j.ejmech.2024.116933.
Jianzhang Wu 1,  Meiting Han 2,  Xiangpeng Tan 3,  Ling Zeng 4,  Zhenzhen Yang 5,  Hongliang Zhong 6,  Xiaohui Jiang 4,  Shuang Yao 4,  Weibin Liu 4,  Wulan Li 6,  Xin Liu 7,  Wencan Wu 8
Affiliations

Affiliations

  • 1 The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, 325027, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China. Electronic address: wjzwzmu@163.com.
  • 2 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 3 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China.
  • 4 The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, 325027, China.
  • 5 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 6 The 1st Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 7 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China. Electronic address: liuxin0711lx@163.com.
  • 8 The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, 325027, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China. Electronic address: wuwencan@wmu.edu.cn.
PMID: 39368262 DOI: 10.1016/j.ejmech.2024.116933
Abstract

For clinically prevalent traumatic optic neuropathy (TON) and other retinal and optic nerve injuries lacking effective therapeutic agents, there is an urgent clinical demand for developing highly efficient and safe neuroprotective agents. Here, we have integrated naturally sourced chalcone with isatin through a catalyst-free green synthesis method, reporting a series of spirocyclic chalcone derivatives with significantly lower cytotoxicity than chalcone itself. Following in vitro cell protection assays in models of hydrogen peroxide and glutamic acid-induced damage, multiple active compounds capable of combating both forms of damage were identified. Among these, candidate compound X38 demonstrated promising neuroprotective prospects: in vitro, it attenuated glutamate-induced cell Apoptosis, while in vivo, it effectively ameliorated retinal thinning and loss of optic nerve electrophysiological function induced by optic nerve injury. Preliminary mechanistic studies suggest that X38 exerts its neuroprotective effects by mitigating intracellular ROS accumulation, inhibiting JNK phosphorylation, and alleviating oxidative stress. Additionally, acute toxicity studies (intraperitoneal injection, 500 mg/kg) underscored the favorable in vivo safety profile of X38. Taken together, this study has designed a class of safe, neuroprotective spirocyclic chalcone derivatives that can be synthesized using green methods, offering an attractive candidate for treating retinal and optic nerve injuries.

Keywords

Chalcone; Michael receptor; Optic nerve; Oxidative glutamate toxicity; Oxidative stress; RGCs.

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