Benzofuroquinoline Derivatives Had Remarkable Improvement of their Selectivity for Telomeric G-Quadruplex DNA over Duplex DNA upon Introduction of Peptidyl Group

详细信息    查看全文

• 作者：Yi Long ; Zeng Li ; Jia-Heng Tan ; Tian-Miao Ou ; Ding Li ; Lian-Quan Gu ; Zhi-shu Huang
• 刊名：Bioconjugate Chemistry
• 出版年：2012
• 出版时间：September 19, 2012
• 年：2012
• 卷：23
• 期：9
• 页码：1821-1831
• 全文大小：405K
• 年卷期：v.23,no.9(September 19, 2012)
• ISSN：1520-4812

文摘

In order to improve the selectivity of 5-N-methyl quindoline (cryptolepine) derivatives as telomeric quadruplex binding ligands versus duplex DNA, a series of peptidyl-benzofuroquinoline (P-BFQ) conjugates (2a鈥?b>2n) were designed and synthesized. Their interactions with telomeric quadruplex and duplex DNA were examined by using the fluorescence resonance energy transfer (FRET) melting assay, surface plasmon resonance (SPR), circular dichroism spectroscopy (CD), and molecular modeling studies. Introduction of a peptidyl group at 11-position of the aromatic benzofuroquinoline scaffold not only effectively increased its binding affinity, but also significantly improved its selectivity toward telomeric quadruplex versus duplex DNA. Combined with the data for their inhibitory effects on telomerase activity, their structure鈥揳ctivity relationships (SARs) studies showed that the types of amino acid residues and the length of the peptidyl side chains were important for the improvement of their interactions with the telomeric G-quadruplex. Long-term exposure of human cancer cells to 2c showed a remarkable cessation in population growth and cellular senescence phenotype, and accompanied by a shortening of the telomere length.