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Synthesis and Evaluation of Quindoline Derivatives as G-Quadruplex Inducing and Stabilizing Ligands and Potential Inhibitors of Telomerase

2005; American Chemical Society; Volume: 48; Issue: 23 Linguagem: Inglês

10.1021/jm050041b

1520-4804

Jin-Lin Zhou, Yu‐Jing Lu, Tian-Miao Ou, Jun-Min Zhou, Zhi-Shu Huang, Xiao‐Feng Zhu, Cui-Juan Du, Xian-Zhang Bu, Lin Ma, Lian-Quan Gu, Yue-Ming Li, Albert Sun-Chi Chan,

bioluminescence and chemiluminescence research

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.