Synthesis and antiproliferative activity of 2,7-diamino l0-(3,5-dimethoxy)benzyl-9(10H)-acridone derivatives as potent telomeric G-quadruplex DNA ligands.
A novel series of l0-(3,5-dimethoxy)benzyl-9(10H)-acridone derivatives with terminal ammonium substituents at C2 and C7 positions on the acridone ring were successfully synthesized as antiproliferation agents. The biologic activity of the acridone compounds against leukemia CCRF-CEM cells demonstrated that some of the compounds displayed good antiproliferative activity, among which compound 6a containing dimethylamine substituents at the terminal C2 and C7 positions exhibited the highest cytotoxicity with IC50 at 0.3μM. In addition compound 6a showed little toxicity against normal 293T cells proliferation with IC50 more than 100μM. Further study indicated that compound 6a had strong binding activity to human telomeric G-quadruplex DNA, as detected by mass spectrometry, CD spectroscopy, UV absorption, FRET and fluorescence quenching assays. Our data suggested that the activity of 6a might be associated with its stabilization of G-quadruplex DNA, which can be developed as potent antitumor agent.
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; 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.
Chunmei
C
Gao
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; National & Local United Engineering Lab for Personalized Anti-Tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Department of Chemistry, Tsinghua University, Beijing 100084, PR China.
Wei
W
Zhang
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; National & Local United Engineering Lab for Personalized Anti-Tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Department of Chemistry, Tsinghua University, Beijing 100084, PR China.
Shengnan
S
He
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.
Shangfu
S
Li
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; National & Local United Engineering Lab for Personalized Anti-Tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: liu.feng@sz.tsinghua.edu.cn.
Feng
F
Liu
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; 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.
Yuyang
Y
Jiang
D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054831:Acridones; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D003959:Diamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004123:Dimethylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008024:Ligands
D000166:Acridines; D054831:Acridones; D000970:Antineoplastic Agents; D003959:Diamines; D004123:Dimethylamines; D008024:Ligands; C041300:acridone; D004247:DNA; C034516:dimethylamine
Acridone derivatives; Antiproliferative activity; G-quadruplex DNA; Synthesis