Synthesis and evaluation of quindoline derivatives as G-quadruplex inducing and stabilizing ligands and potential inhibitors of telomerase.
A new series of quindoline derivatives (4a-j) were designed and synthesized to develop novel and potent telomerase inhibitors. The interaction of the G-quadruplex of human telomere DNA with these newly designed molecules was examined via circular dichroism spectroscopy and electrophoretic mobility shift assay (EMSA). The selectivity between the quindoline derivative (4a) and G-quadruplex or duplex DNA was investigated by competition dialysis. These new compounds as inhibitors of telomerase were also investigated through the utilization of modified telomerase repeat amplification protocol (TRAP) assay. The results revealed that the introduction of electron-donating groups such as substituted amino groups at the C-11 position of quindoline significantly improved the inhibitory effect on telomerase activity ((Tel)IC50 > 138 microM for quindoline, 0.44-12.3 microM for quindoline derivatives 4a-j). The quindoline derivatives not only stabilized the G-quadruplex structure but also induced the G-rich telomeric repeated DNA sequence to fold into quadruplex.
Zhou
Jin-Lin
JL
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.
Lu
Yu-Jing
YJ
Ou
Tian-Miao
TM
Zhou
Jun-Min
JM
Huang
Zhi-Shu
ZS
Zhu
Xiao-Feng
XF
Du
Cui-Juan
CJ
Bu
Xian-Zhang
XZ
Ma
Lin
L
Gu
Lian-Quan
LQ
Li
Yue-Ming
YM
Chan
Albert Sun-Chi
AS
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D003956:Dialysis; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013816:Thermodynamics
D000470:Alkaloids; D000970:Antineoplastic Agents; D007211:Indoles; D008024:Ligands; D011804:Quinolines; C016712:quindoline; D004247:DNA; D019098:Telomerase