title: Development of amino- and dimethylcarbamate-substituted resorcinol as programmed cell death-1 (PD-1) inhibitor.
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.
authors.affiliation: School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
authors.forename: An
authors.initials: A
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China; First Affiliated Hospital of Jilin University, Changchun 130021, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Dong
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Wei
authors.affiliation: School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China. Electronic address: yangxiaoh@jlu.edu.cn.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Yang
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: xiaojunhai@139.com.
authors.forename: Jun-Hai
authors.initials: JH
authors.lastname: Xiao
authors.affiliation: Department of Organic Chemistry, College of Chemistry, Jilin University, Changchun 130021, China. Electronic address: zaiqun-liu@jlu.edu.cn.
authors.forename: Zai-Qun
authors.initials: ZQ
authors.lastname: Liu
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D015394:Molecular Structure; D061848:Optical Imaging; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D012118:Resorcinols / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013419:Sulfamethizole / Q000737:chemistry / Q000494:pharmacology; D013421:Sulfamethoxypyridazine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D061026:Programmed Cell Death 1 Receptor; D012118:Resorcinols; D013419:Sulfamethizole; D013421:Sulfamethoxypyridazine; C031389:resorcinol
keywords: 3-Hydroxythiophenol; Inhibitor; Programmed cell death-1 (PD-1); Resorcinol