中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Design, Synthesis, and Structure-Activity Relationship Studies of Bisamide Derivatives of Amphotericin B with Potent Efficacy and Low Toxicity

文献类型：期刊论文

作者Ma, Huijun1,2; Qian, Anran1,2; Zheng, Yazhou3; Meng, Xin1; Wang, Ting4; Zhang, Yinyong1; Sun, Lulu1; Zou, Feng4; Zhao, Bomei4; Zhang, Shuhua4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-07-04
页码17
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c02227
通讯作者Zhang, Dan(zhangdan3@simm.ac.cn) ; Yang, Yushe(ysyang@mail.shcnc.ac.cn)
英文摘要ABSTRACT: Amphotericin B (AMB, 1) is the most powerful antibiotic in treating potentially life-threatening invasive fungal infections (IFIs), though severe toxicity derived from self-aggregation greatly limits its clinical application. Herein, we applied a bisamidation strategy at the C16COOH and C3 '-NH2 to improve the therapeutic properties by suppressing self-aggregation. It was found that basic amino groups at the residue of C16 amide were beneficial to activity, while lipophilic fragments contributed to toxicity reduction. Additionally, N-methyl-amino acetyl and amino acetyl moieties at C3 ' amide could help keep the fungistatic effectiveness. The modification work culminated in the discovery of 36 (ED50 = 0.21 mg/kg), which exerted a 1.5-fold stronger antifungal efficacy than amphamide, the optimal derivative theretofore, in mice, low selfaggregation propensity, and thus low acute toxicity. With the improvement in therapeutic index and good PK profile, 36 is promising for further development as a second-generation polyene antifungal agent.
WOS关键词POLYENE MACROLIDE ANTIBIOTICS ; METHYL-ESTER ; CHEMICAL-MODIFICATION ; ANTIFUNGAL AGENTS ; FORMULATIONS ; AGGREGATION ; COMPLEX
资助项目Youth Innovation Promotion Association of Chinese Academy of Sciences and technical ; Cyro-Electron Microscopy Research Center
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000825083000001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/303534]  
专题新药研究国家重点实验室
通讯作者Zhang, Dan; Yang, Yushe
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Shanghai Univ, Coll Sci, Dept Chem, Shanghai 200444, Peoples R China
4.Sichuan Primed Biotech Grp Co Ltd, Dept Microbiol, Chengdu 610041, Sichuan, Peoples R China
推荐引用方式
GB/T 7714		 Ma, Huijun,Qian, Anran,Zheng, Yazhou,et al. Design, Synthesis, and Structure-Activity Relationship Studies of Bisamide Derivatives of Amphotericin B with Potent Efficacy and Low Toxicity[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022:17.
APA Ma, Huijun.,Qian, Anran.,Zheng, Yazhou.,Meng, Xin.,Wang, Ting.,...&Yang, Yushe.(2022).Design, Synthesis, and Structure-Activity Relationship Studies of Bisamide Derivatives of Amphotericin B with Potent Efficacy and Low Toxicity.JOURNAL OF MEDICINAL CHEMISTRY,17.
MLA Ma, Huijun,et al."Design, Synthesis, and Structure-Activity Relationship Studies of Bisamide Derivatives of Amphotericin B with Potent Efficacy and Low Toxicity".JOURNAL OF MEDICINAL CHEMISTRY (2022):17.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。