Novel synthetic 2-amino-10-(3,5-dimethoxy)benzyl-9(10H)-acridinone derivatives as potent DNA-binding antiproliferative agents.
A series of novel 9(10H)-acridinone derivatives with terminal amino substituents at C2 position on the acridinone ring were synthesized and studied for their antiproliferative activity and underlying mechanisms. These compounds demonstrated promising cytotoxicity to leukemia cells CCRF-CEM, displaying IC(50) values in the low micromolar range. Structure-activity relationships (SAR) indicated that the compound 6d bearing a pyrrolidine substituent and 8a with a methyl ammonium side chain displayed higher cytotoxicity to CCRF-CEM cells and also solid tumor cells A549, HepG2, and MCF7. Furthermore, the compounds 6d and 8a had strong binding activity to calf thymus DNA (ct DNA), as detected by UV absorption and fluorescence quenching assays, but limited inhibitory activity to human topoisomerase 1 (topo 1). Taken together, this study discovered a series of new synthetic 9(10H)-acridinone derivatives with potent DNA binding and anticancer activity.
Gao
Chunmei
C
The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
Liu
Feng
F
Luan
Xudong
X
Tan
Chunyan
C
Liu
Hongxia
H
Xie
Yonghua
Y
Jin
Yibao
Y
Jiang
Yuyang
Y
D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity
D000166:Acridines; D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I