title: Molecular design, synthesis and biological research of novel pyridyl acridones as potent DNA-binding and apoptosis-inducing agents.
abstract: A series of novel pyridyl acridone derivatives comprised of a pseudo-five-cyclic system to extend the π-conjugated acridone chromophore, were designed and synthesized as potent DNA binding antitumor compounds. Most synthesized compounds displayed good activity against human leukemia K562 cells in MTT tests, with compound 6d exhibiting the highest activity with IC50 value at 0.46 μM. Moreover, 6d showed potent activities against solid tumor cell lines (0.16-3.79 μM). Several experimental studies demonstrated that the antitumor mode of action of compound 6d involves DNA intercalation, topoisomerase I inhibition, and apoptosis induction through the mitochondrial pathway. In summary, compound 6d represents a novel and promising lead structure for the development of new potent anticancer DNA-binding agents.
authors: Tsinghua University, Department of Chemistry, Beijing 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China.
authors: Bin
authors: B
authors: Zhang
authors: Tsinghua University, Department of Chemistry, Beijing 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China.
authors: Kang
authors: K
authors: Chen
authors: Tsinghua University, Department of Chemistry, Beijing 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China.
authors: Ning
authors: N
authors: Wang
authors: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China; Shenzhen Anti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: chunmeigao@sz.tsinghua.edu.cn.
authors: Chunmei
authors: C
authors: Gao
authors: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China.
authors: Qinsheng
authors: Q
authors: Sun
authors: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China.
authors: Lulu
authors: L
authors: Li
authors: Bioinformatics and Drug Design Group, Department of Pharmacy, Centre for Computational Science and Engineering, 117543, Singapore.
authors: Yuzong
authors: Y
authors: Chen
authors: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China; Shenzhen Anti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
authors: Chunyan
authors: C
authors: Tan
authors: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China.
authors: Hongxia
authors: H
authors: Liu
authors: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Shenzhen 518055, PR China; Shenzhen Anti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; School of Medicine, Tsinghua University, Beijing 100084, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
authors: Yuyang
authors: Y
authors: Jiang
mesh_terms: D054831:Acridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D020014:K562 Cells; D008928:Mitochondria / Q000187:drug effects; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology
chemical_list: D054831:Acridones; D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I
keywords: Acridone; Antitumor; DNA; Molecular docking; Pyridyl; Topoisomerase I