5-N-methylated quindoline derivatives as telomeric g-quadruplex stabilizing ligands: effects of 5-N positive charge on quadruplex binding affinity and cell proliferation.
A series of 5-N-methyl quindoline (cryptolepine) derivatives (2a- x) as telomeric quadruplex ligands was synthesized and evaluated. The designed ligands possess a positive charge at the 5- N position of the aromatic quindoline scaffold. The quadruplex binding of these compounds was evaluated by circular dichroism (CD) spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, nuclear magnetic resonance (NMR), and molecular modeling studies. Introduction of a positive charge not only significantly improved the binding ability but also induced the selectivity toward antiparallel quadruplex, whereas the nonmethylated derivatives tended to stabilize hybrid-type quadruplexes. NMR and molecular modeling studies revealed that the ligands stacked on the external G-quartets and the positively charged 5- N atom could contribute to the stabilizing ability. Long-term exposure of human cancer cells to 2r showed a remarkable cessation in population growth and cellular senescence phenotype and accompanied by a shortening of the telomere length.
Lu
Yu-Jing
YJ
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Ou
Tian-Miao
TM
Tan
Jia-Heng
JH
Hou
Jin-Qiang
JQ
Shao
Wei-Yan
WY
Peng
Dan
D
Sun
Ning
N
Wang
Xiao-Dong
XD
Wu
Wei-Bin
WB
Bu
Xian-Zhang
XZ
Huang
Zhi-Shu
ZS
Ma
Dik-Lung
DL
Wong
Kwok-Yin
KY
Gu
Lian-Quan
LQ
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002474:Cell-Free System; D002942:Circular Dichroism; D003956:Dialysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054856:G-Quadruplexes; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008745:Methylation; D008958:Models, Molecular; D011188:Potassium / Q000737:chemistry; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016615:Telomere / Q000737:chemistry* / Q000235:genetics; D013816:Thermodynamics
D000470:Alkaloids; D004791:Enzyme Inhibitors; D007211:Indoles; D008024:Ligands; D011804:Quinolines; C016712:quindoline; D019098:Telomerase; D011188:Potassium