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 s...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-11, Vol.48 (23), p.7315-7321
Main Authors: Zhou, Jin-Lin, Lu, Yu-Jing, Ou, Tian-Miao, Zhou, Jun-Min, Huang, Zhi-Shu, Zhu, Xiao-Feng, Du, Cui-Juan, Bu, Xian-Zhang, Ma, Lin, Gu, Lian-Quan, Li, Yue-Ming, Chan, Albert Sun-Chi
Format: Article
Language:English
Subjects:
Alkaloids - chemical synthesis
Alkaloids - chemistry
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Biological and medical sciences
Circular Dichroism
Dialysis
DNA - chemistry
Electrophoretic Mobility Shift Assay
General aspects
Humans
Indoles - chemical synthesis
Indoles - chemistry
Ligands
Medical sciences
Pharmacology. Drug treatments
Quinolines - chemical synthesis
Quinolines - chemistry
Structure-Activity Relationship
Telomerase - antagonists & inhibitors
Telomerase - chemistry
Thermodynamics
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Summary: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 (TelIC50 > 138 μM for quindoline, 0.44−12.3 μM 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm050041b