title: Synthesis and antiproliferative activity of 9-benzylamino-6-chloro-2-methoxy-acridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors.
abstract: A series of 9-benzylamino acridine derivatives were synthesized as an extension of our discovery of acridine antitumor agents. Most of these acridine compounds displayed good antiproliferative activity with IC50 values in low micromole range and structure-activity relationships were studied. Topo I- and II- mediated relaxation studies suggested that all of our compounds displayed strong Topo II inhibitory activity at 100 μM, while only four exhibited moderate Topo I inhibitory activity. The typical compound 8p could penetrate A549 cancer cells efficiently. Compound 8p could intercalate within the double-stranded DNA structure and induce DNA damage. Moreover, compound 8p could induce A549 cells apoptosis through caspase-dependent intrinsic pathway and arrest A549 cells at the G2/M phase.
authors.affiliation: 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, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China; ShenzhenAnti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: ShenzhenAnti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China; ShenzhenAnti-Tumor Drug Development Engineering Laboratory, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Tsinghua University, Department of Chemistry, Beijing 100084, PR China.
authors.forename: Ti
authors.initials: T
authors.lastname: Yang
authors.affiliation: 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, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: 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, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China. Electronic address: chunmeigao@sz.tsinghua.edu.cn.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Gao
authors.affiliation: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tan
authors.affiliation: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, PR China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Liu
authors.affiliation: 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, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518-55, 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: D000166:Acridines / 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; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008024:Ligands; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D008024:Ligands; D059005:Topoisomerase II Inhibitors; D004247:DNA; D004250:DNA Topoisomerases, Type II
keywords: Acridine derivatives; Antiproliferative activity; DNA damage; Topoisomerase II inhibitor