2. Academic Validation
  3. Discovery of seven-membered ring berberine analogues as highly potent and specific hCES2A inhibitors

Discovery of seven-membered ring berberine analogues as highly potent and specific hCES2A inhibitors

  • Chem Biol Interact. 2023 Apr 18;110501. doi: 10.1016/j.cbi.2023.110501.
Yun Yang 1,  Yuan Xiong 2,  Guanghao Zhu 2,  Mengru Sun 2,  Kun Zou 2,  Yitian Zhao 2,  Yong Zhang 3,  Zhijian Xu 4,  Yiming Li 2,  Weiliang Zhu 4,  Qi Jia 5,  Bo Li 6,  Guangbo Ge 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 2 School of Pharmacy, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 3 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 4 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 5 School of Pharmacy, 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: q_jia@126.com.
  • 6 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: boli@simm.ac.cn.
  • 7 School of Pharmacy, 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.
PMID: 37080375 DOI: 10.1016/j.cbi.2023.110501
Abstract

Human carboxylesterase 2A (hCES2A) is a key serine hydrolase responsible for the metabolic clearance of large number of compounds bearing the ester- or amide-bond(s). Inhibition of hCES2A can relieve the chemotherapy-induced toxicity and alter the pharmacokinetic bahaviors of some orally administrate esters-containing agents. However, most of the hCES2A inhibitors show poor cell-membrane permeability and poor specificity. Herein, guided by the structure activity relationships (SAR) of fifteen natural Alkaloids against hCES2A, fifteen new seven-membered ring berberine analogues were designed and synthesized, and their anti-hCES2A activities were evaluated. Among all tested compounds, compound 28 showed potent anti-hCES2A effect (IC50 = 1.66 μM) and excellent selectivity over hCES1A (IC50 > 100 μM). The SAR analysis revealed that the seven-membered ring of these berberine analogues was a crucial moiety for hCES2A inhibition, while the secondary amine group of the ring-C is important for improving their specificity over other serine hydrolases. Inhibition kinetic analyses and molecular dynamic simulation demonstrated that 28 strongly inhibited hCES2A in a mixed-inhibition manner, with an estimated Ki value of 1.035 μM. Moreover, 28 could inhibit intracellular hCES2A in living HepG2 cells and exhibited suitable metabolic stability. Collectively, the SAR of seven-membered ring berberine analogues as hCES2A inhibitors were studied, while compound 28 acted as a promising candidate for developing highly selective hCES2A inhibitors.

Keywords

Berberine analogues; Human carboxylesterase 2 (hCES2A); Inhibition kinetics; Selectivity; Structure-activity relationships (SAR).

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