Stabilization and Structural Alteration of the G-Quadruplex DNA Made from the Human Telomeric Repeat Mediated by Tr枚ger鈥檚 Base Based Novel Benzimidazole Derivatives

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• 作者：Ananya Paul ; Basudeb Maji ; Santosh K. Misra ; Akash K. Jain ; K. Muniyappa ; Santanu Bhattacharya
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7460-7471
• 全文大小：569K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

Ligand-induced stabilization of the G-quadruplex DNA structure derived from the single-stranded 3鈥?overhang of the telomeric DNA is an attractive strategy for the inhibition of the telomerase activity. The agents that can induce/stabilize a DNA sequence into a G-quadruplex structure are therefore potential anticancer drugs. Herein we present the first report of the interactions of two novel bisbenzimidazoles (TBBz1 and TBBz2) based on Tr枚ger鈥檚 base skeleton with the G-quadruplex DNA (G4DNA). These Tr枚ger鈥檚 base molecules stabilize the G4DNA derived from a human telomeric sequence. Evidence of their strong interaction with the G4DNA has been obtained from CD spectroscopy, thermal denaturation, and UV鈥搗is titration studies. These ligands also possess significantly higher affinity toward the G4DNA over the duplex DNA. The above results obtained are in excellent agreement with the biological activity, measured in vitro using a modified TRAP assay. Furthermore, the ligands are selectively more cytotoxic toward the cancerous cells than the corresponding noncancerous cells. Computational studies suggested that the adaptive scaffold might allow these ligands to occupy not only the G-quartet planes but also the grooves of the G4DNA.