2. Academic Validation
  3. Development of amino- and dimethylcarbamate-substituted resorcinol as programmed cell death-1 (PD-1) inhibitor

Development of amino- and dimethylcarbamate-substituted resorcinol as programmed cell death-1 (PD-1) inhibitor

  • Eur J Pharm Sci. 2016 Jun 10:88:50-8. doi: 10.1016/j.ejps.2016.03.023.
An Liu 1,  Lei Dong 2,  Xiao-Li Wei 3,  Xiao-Hong Yang 4,  Jun-Hai Xiao 5,  Zai-Qun Liu 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
  • 2 School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China; First Affiliated Hospital of Jilin University, Changchun 130021, China.
  • 3 Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • 4 School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China. Electronic address: yangxiaoh@jlu.edu.cn.
  • 5 Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: xiaojunhai@139.com.
  • 6 Department of Organic Chemistry, College of Chemistry, Jilin University, Changchun 130021, China. Electronic address: zaiqun-liu@jlu.edu.cn.
PMID: 27063329 DOI: 10.1016/j.ejps.2016.03.023
Abstract

Blockading the interaction of programmed death-1 (PD-1) protein with its ligands (PD-Ls, such as PD-L1) was proved to be a pathway for suppressing the development of tumors and Other degradations of biological species. Thus, finding PD-1 inhibitors situated at the convergence point of drug discovery. In addition to some monoclonal antibodies applied to treat cancers clinically, the screening of organic molecules for hindering the interaction of PD-1 with PD-L1 became an efficient strategy in the development of PD-1 inhibitors. We herein applied resorcinol and 3-hydroxythiophenol as the core to link with N,N-dimethylcarbamate and Other alkyl-substituted amines to afford 13 amine-appended phenyl dimethylcarbamates (AAPDs). The test for blockading the combination of PD-1 with PD-L1 revealed that abilities of 13 AAPDs were higher than that of sulfamethizole, a successful PD-1 inhibitor. In particular, large hydrophobic substituents at amine moiety or a nitro at resorcinol skeleton enhanced the inhibitory effect of AAPD even higher than that of sulfamethoxypyridazine, another successful PD-1 inhibitor. The present results may provide valuable information for further investigation on synthetic PD-1 inhibitors.

Keywords

3-Hydroxythiophenol; Inhibitor; Programmed cell death-1 (PD-1); Resorcinol.

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