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作者:

Zuo, Zongchao (Zuo, Zongchao.) | Wang, Limei (Wang, Limei.) | Wang, Shaozheng (Wang, Shaozheng.) | Liu, Xinyu (Liu, Xinyu.) | Wu, Dandan (Wu, Dandan.) | Ouyang, Zhangyi (Ouyang, Zhangyi.) | Meng, Ruoxi (Meng, Ruoxi.) | Shan, Yajun (Shan, Yajun.) | Zhang, Shouguo (Zhang, Shouguo.) | Peng, Tao (Peng, Tao.) | Wang, Lin (Wang, Lin.) | Li, Zhongtang (Li, Zhongtang.) | Cong, Yuwen (Cong, Yuwen.)

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Scopus SCIE

摘要:

Considering the increasing risk of nuclear attacks worldwide, the development of develop potent and safe radioprotective agents for nuclear emergencies is urgently needed. gamma-tocotrienol (GT3) and delta-tocotrienol (DT3) have demonstrated a potent radioprotective effect by inducing the production of granulocyte-colony stimulating factor (G-CSF) in vivo. However, their application is limited because of their low bioavailability. The utilization of ester prodrugs can be an effective strategy for modifying the pharmacokinetic properties of drug molecules. In this study, we initially confirmed that DT3 exhibited the most significant potential for inducing G-CSF effects among eight natural vitamin E homologs. Consequently, we designed and synthesized a series of DT3 ester and ether derivatives, leading to improved radioprotective effects. The metabolic study conducted in vitro and in vivo has identified DT3 succinate 5b as a prodrug of DT3 with an approximately seven-fold higher bioavailability compared to DT3 alone. And DT3 ether derivative 8a were relatively stable and approximately 4 times more bioavailable than DT3 prototype. Furthermore, 5b exhibited superior ability to mitigate radiation-induced pancytopenia, enhance the recovery of bone marrow hematopoietic stem and progenitor cells, and promote splenic extramedullary hematopoiesis in sublethal irradiated mice. Similarly, 8a shown potential radiation protection, but its radiation protection is less than DT3. Based on these findings, we identified 5b as a DT3 prodrug, and providing an attractive candidate for further drug development.

关键词:

delta-Tocotrienol Hematopoietic injury Vitamin E Radiation countermeasures Prodrug G-CSF Acute radiation syndrome Radioprotector

作者机构:

  • [ 1 ] [Zuo, Zongchao]Beijing Univ Technol, Fac Environm & Life, Beijing 100124, Peoples R China
  • [ 2 ] [Wang, Lin]Beijing Univ Technol, Fac Environm & Life, Beijing 100124, Peoples R China
  • [ 3 ] [Zuo, Zongchao]Beijing Inst Radiat Med, Beijing 100850, Peoples R China
  • [ 4 ] [Wang, Limei]Beijing Inst Radiat Med, Beijing 100850, Peoples R China
  • [ 5 ] [Wang, Shaozheng]Beijing Inst Radiat Med, Beijing 100850, Peoples R China
  • [ 6 ] [Liu, Xinyu]Beijing Inst Radiat Med, Beijing 100850, Peoples R China
  • [ 7 ] [Ouyang, Zhangyi]Beijing Inst Radiat Med, Beijing 100850, Peoples R China
  • [ 8 ] [Meng, Ruoxi]Beijing Inst Radiat Med, Beijing 100850, Peoples R China
  • [ 9 ] [Shan, Yajun]Beijing Inst Radiat Med, Beijing 100850, Peoples R China
  • [ 10 ] [Zhang, Shouguo]Beijing Inst Radiat Med, Beijing 100850, Peoples R China
  • [ 11 ] [Peng, Tao]Beijing Inst Radiat Med, Beijing 100850, Peoples R China
  • [ 12 ] [Wang, Lin]Beijing Inst Radiat Med, Beijing 100850, Peoples R China
  • [ 13 ] [Cong, Yuwen]Beijing Inst Radiat Med, Beijing 100850, Peoples R China
  • [ 14 ] [Li, Zhongtang]Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, 38 Xue Yuan Rd, Beijing 100191, Peoples R China
  • [ 15 ] [Wu, Dandan]Nanjing Univ, Coll Life Sci, State Key Lab Pharmaceut Biotechnol SKLPB, Xianlin Campus, Nanjing 210046, Peoples R China
  • [ 16 ] [Wang, Lin]27 Taiping Rd, Beijing, Peoples R China
  • [ 17 ] [Cong, Yuwen]27 Taiping Rd, Beijing, Peoples R China
  • [ 18 ] [Li, Zhongtang]38 Xueyuan Rd, Beijing, Peoples R China

通讯作者信息:

  • [Wang, Lin]27 Taiping Rd, Beijing, Peoples R China;;[Cong, Yuwen]27 Taiping Rd, Beijing, Peoples R China;;[Li, Zhongtang]38 Xueyuan Rd, Beijing, Peoples R China;;

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来源 :

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

ISSN: 0223-5234

年份: 2024

卷: 269

6 . 7 0 0

JCR@2022

被引次数:

WoS核心集被引频次:

SCOPUS被引频次: 3

ESI高被引论文在榜: 0 展开所有

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