2. Academic Validation
  3. New bysspectin A derivatives as potent inhibitors of human carboxylesterase 2A

New bysspectin A derivatives as potent inhibitors of human carboxylesterase 2A

  • Eur J Med Chem. 2023 Nov 5;259:115708. doi: 10.1016/j.ejmech.2023.115708.
Wenxuan Li 1,  Ya Zhang 2,  Yuanyuan Wu 1,  Guanghao Zhu 2,  Xiaoyu Liu 1,  Yunqing Song 2,  Bo Ma 1,  Sheng Lin 3,  Guangbo Ge 4,  Xiaozhen Jiao 5,  Ping Xie 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 3 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100029, China.
  • 4 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: geguangbo@shutcm.edu.cn.
  • 5 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: jiaoxz@imm.ac.cn.
PMID: 37544184 DOI: 10.1016/j.ejmech.2023.115708
Abstract

Human Carboxylesterase 2A (hCES2A), the most abundant Carboxylesterase in the human gut, plays a crucial role in the metabolic clearance and activation of various ester-bearing drugs, environmental toxins and carcinogens. Inhibition of intestinal hCES2A can alleviate irinotecan-induced gut toxicity and modulate the oral bioavailability of hCES2A-substrate drugs. Bysspectin A, a natural product isolated from the endophytic fungus Byssochlamys spectabilis, has been identified as a highly selective hCES2A inhibitor. Herein, two sets of bysspectin A derivatives have been designed and synthesized, utilizing a Cu-catalyzed domino Sonogashira-cyclization as the key step. Following two rounds of structure activity relationship (SAR) studies and structural optimizations, compound 20w was identified as the most potent hCES2A inhibitor, with an IC50 value of 1.6 nM, an approximately 1000-fold improvement over bysspectin A. Further investigation showed that 20w potently inhibited hCES2A in a mixed inhibition manner, while this agent could also potently inhibit intracellular hCES2A in living cells and exhibited suitable metabolic stability. In summary, our findings demonstrate that a new bysspectin A derivative (20w) is a promising candidate for the development of clinically used hCES2A inhibitor.

Keywords

Bysspectin A; Derivatives; Human carboxylesterase 2A (hCES2A); Selective inhibitors; Structure-activity relationships (SARs).

Figures
Products