Carboxylesterase 1 (CES1), a member of the serine hydrolase superfamily, is involved in a wide range of xenobiotic and endogenous substances metabolic reactions in mammals. The inhibition of CES1 could not only alter the metabolism and disposition of related drugs, but also be benefit for treatment of metabolic disorders, such as obesity and fatty liver disease. In the present study, we aim to develop potential inhibitors of CES1 and reveal the preferred inhibitor structure from a series of synthetic pyrazolones (compounds 1-27). By in vitro high-throughput screening method, we found compounds 25 and 27 had non-competitive inhibition on CES1-mediated N-alkylated d-luciferin methyl ester (NLMe) hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. Additionally, Compounds 25, 26 and 27 can inhibit CES1-mediated fluorescent probe hydrolysis in live HepG2 cells with effect. Besides, compounds 25, 26 and 27 could effectively inhibit the accumulation of lipid droplets in mouse adipocytes cells. These data not only provided study basis for the design of newly CES1 inhibitors. The present study not only provided the basis for the development of lead compounds for novel CES1 inhibitors with better performance, but also offered a new direction for the explore of candidate compounds for the treatment of hyperlipidemia and related diseases.

28 Aug 2024·Journal of the American Chemical Society

Pyrazolone-Protein Interaction Enables Long-Term Retention Staining and Facile Artificial Biorecognition on Cell Membranes

Article

Author: Chen, Xiaoqiang ; Xiong, Tao ; Wang, Lei ; Li, Mingle ; Fan, Jiangli ; Peng, Xiaojun ; Lu, Sheng ; Peng, Qiang ; Chen, Yingchao

Cell membrane genetic engineering has been utilized to confer cell membranes with functionalities for diagnostic and therapeutic purposes but concerns over cost and variable modification results. Although nongenetic chemical modification and phospholipid insertion strategies are more convenient, they still face bottlenecks in either biosafety or stability of the modifications. Herein, we show that pyrazolone-bearing molecules can bind to proteins with high stability, which is mainly contributed to by the multiple interactions between pyrazolone and basic amino acids. This new binding model offers a simple and versatile noncovalent approach for cell membrane functionalization. By binding to cell membrane proteins, pyrazolone-bearing dyes enabled precise cell tracking in vitro (>96 h) and in vivo (>21 days) without interfering with the protein function or causing cell death. Furthermore, the convenient anchor of pyrazolone-bearing biotin on cell membranes rendered the biorecognition to avidin, showing the potential for artificially creating cell targetability.

01 Apr 2022·Chemical Biology & Drug DesignQ4 · MEDICINE

1,3‐diarylpyrazolones as potential anticancer agents for non‐small cell lung cancer: Synthesis and antiproliferative activity evaluation

Q4 · MEDICINE

Article

Author: Dahal, Achyut ; Jois, Seetharama D. ; Murru, Siva ; Singh, Sitanshu ; Vo, Huu ; ElHage, Denzel ; Lo, Mary

AbstractA series of pyrazolone compounds with different substitution patterns have been synthesized using microwave‐assisted methods and evaluated their in vitro antiproliferative activity against human lung adenocarcinoma cell lines (A549 and NCI‐H522). Among the tested compounds, the pyrazolone P7 exhibited high antiproliferative activity against both A549 and NCIH522 cancer cell lines while being 10 times less cytotoxic to non‐cancerous cells. Moreover, our compounds P7 and P11 exhibited higher antiproliferative activity and selectivity against A549 and NCIH522 cells compared with the clinically approved drugs Afatinib and Gefitinib. The cell cycle analysis showed that the compound P7 and P11 arrests the cell cycle at G0/G1 phase, whereas the compounds P13 and P14 involved in G2/M phase arrest. The results from antiproliferative activity screening, cell cycle analysis, and kinase profiling indicate that the suitably substituted 1,3‐diarylpyrazolones exhibit high antiproliferative activity against non‐small cell lung cancer cells.

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Indication	Highest Phase	Country/Location	Organization	Date
Analgesia	Preclinical	JP	Hiroshima University	23 Dec 2010

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