title: Novel multi-substituted benzyl acridone derivatives as survivin inhibitors for hepatocellular carcinoma treatment.
abstract: Sorafenib was the only small-molecule drug approved by FDA for treatment of the advanced hepatocellular carcinoma (HCC). Recent study indicated that YM155 was a promising agent for HCC cells with high survivin expression, however, the antitumor activity needs to be further improved. Based on molecular docking and rational design method, a series of multi-substituted benzyl acridone derivatives were designed and synthesized. MTT assay indicated that some of the synthesized compounds displayed better antiproliferative activity against HepG2 cells than YM155. Later study indicated that the representive compound 8u may directly interact with survivin protein and induce HepG2 cells apoptosis, which is different from YM155. In addition, ADME property was predicted in silico, and it performed well. Moreover, in vivo preliminary experiments showed that 8u may be a good lead compound in the treatment of HCC.
authors.affiliation: Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China; Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen, 518057, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen, 518057, PR China.
authors.forename: Cunlong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China. Electronic address: chunmeigao@sz.tsinghua.edu.cn.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Gao
authors.affiliation: National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China.
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China; Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen, 518057, PR China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Wu
authors.affiliation: Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen, 518057, PR China; Bioinformatics and Drug Design Group, Department of Pharmacy, Centre for Computational Science and Engineering, National University of Singapore, 117543, Singapore.
authors.forename: Yuzong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tan
authors.affiliation: National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D054831:Acridones / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008113:Liver Neoplasms / Q000188:drug therapy*; D000077022:Survivin
chemical_list: D054831:Acridones; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin
keywords: Acridones; Antitumor; Molecular docking; Survivin; YM155