title: Design, Synthesis and Structure-Activity Relationship Optimization of Lycorine Derivatives for HCV Inhibition.
abstract: Lycorine is reported to be a multifunctional compound. We previously showed that lycorine is an HCV inhibitor with strong activity. Further research on the antivirus mechanism indicated that lycorine does not affect the enzymes that are indispensable to HCV replication but suppresses the expression of Hsc70 in the host cell to limit HCV replication. However, due to the cytotoxicity and apoptosis induction of lycorine, lycorine is unsafe to be a anti-HCV agent for clinical application. As a result of increasing interest, its structure was optimized for the first time and a novel series of lycorine derivatives was synthesized, all of which lost their cytotoxicity to different degrees. Structure-activity analysis of these compounds revealed that disubstitution on the free hydroxyl groups at C1 and C2 and/or degradation of the benzodioxole group would markedly reduce the cytotoxicity. Furthermore, an α, β-unsaturated ketone would improve the HCV inhibitory activity of lycorine. The C3-C4 double bond is crucial to the anti-HCV activity because hydrogenation of this double bond clearly weakened HCV inhibition.
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Duozhi
authors.initials: D
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Jieyun
authors.initials: J
authors.lastname: Cai
authors.affiliation: Laboratory of Antiviral Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100050, China.
authors.forename: Junjun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.|College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming 650500, Yunnan, China.
authors.forename: Chenxu
authors.initials: C
authors.lastname: Jing
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Junlin
authors.initials: J
authors.lastname: Yin
authors.affiliation: Laboratory of Antiviral Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100050, China.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Laboratory of Antiviral Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100050, China.
authors.forename: Zonggen
authors.initials: Z
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Hao
mesh_terms: D047151:Amaryllidaceae Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D005786:Gene Expression Regulation; D050883:HSC70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D006865:Hydrogenation; D007659:Ketones / Q000737:chemistry; D010617:Phenanthridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014758:Viral Core Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D047151:Amaryllidaceae Alkaloids; D000998:Antiviral Agents; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D007659:Ketones; D010617:Phenanthridines; D014758:Viral Core Proteins; C015330:lycorine