Stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc by quindoline derivatives.
Stabilization of G-quadruplex structures in the promoter region of certain oncogenes is an emerging field in anticancer drug design. Human c-myc gene is one of these oncogenes, and G-quadruplexes have been proven to be the transcriptional controller of this gene. In the present study, the interaction of quindoline derivatives with G-quadruplexes in c-myc was investigated. The experimental results indicated that these derivatives have the ability to induce/stabilize the G-quadruplexes in c-myc, which lead to down-regulation of the c-myc in the Hep G2 cell line. It was found that derivatives with terminal amino groups in their side chains would selectively bind to the isomers with the double nucleotide loops in the absence of K+. Molecular modeling studies revealed the binding mode between the derivatives and the G-quadruplexes is end-stacking at the 3'-position, and the positively charged side chain on the quindoline derivatives may contribute to the selectivity to certain loop isomers of topological quadruplexes as well as the improved stabilization action.
Ou
Tian-Miao
TM
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Lu
Yu-Jing
YJ
Zhang
Chi
C
Huang
Zhi-Shu
ZS
Wang
Xiao-Dong
XD
Tan
Jia-Heng
JH
Chen
Yuan
Y
Ma
Dik-Lung
DL
Wong
Kwok-Yin
KY
Tang
Johnny Cheuk-On
JC
Chan
Albert Sun-Chi
AS
Gu
Lian-Quan
LQ
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000235:genetics*; D003956:Dialysis; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D007536:Isomerism; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000470:Alkaloids; D000970:Antineoplastic Agents; D007211:Indoles; D016271:Proto-Oncogene Proteins c-myc; D011804:Quinolines; C016712:quindoline; D006147:Guanine; D004247:DNA