Disubstituted 2-phenyl-benzopyranopyrimidine derivatives as a new type of highly selective ligands for telomeric G-quadruplex DNA.

Abstract

A series of 2-phenyl-benzopyranopyrimidine (PBPP) derivatives with alkylamino side chains were synthesized and found to be a new type of highly selective ligand to bind with telomeric G-quadruplex DNA, and their biological properties were reported for the first time. Their interactions with telomeric G-quadruplex DNA were studied with FRET melting, surface plasmon resonance, CD spectroscopy, and molecular modeling. Our results showed that the disubstituted PBPP derivatives could strongly bind to and effectively stabilize the telomeric G-quadruplex structure, and had significant selectivity for G-quadruplex over duplex DNA. In comparison, the mono substituted derivatives had much less effect on the G-quadruplex, suggesting that the disubstitution of PBPP is essential for its interaction with the G-quadruplex. Furthermore, telomerase inhibition of the PBPP derivatives and their cellular effects were studied, and compound 11b was found to be the most promising compound as a telomerase inhibitor and telomeric G-quadruplex binding ligand for further development for cancer treatment.

• Authors: Wei-Bin Wu, Shu-Han Chen, Jin-Qiang Hou, Jia-Heng Tan, Tian-Miao Ou, Shi-Liang Huang, Ding Li, Lian-Quan Gu, Zhi-Shu Huang
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 9 Issue 8 Pg. 2975-86 (Apr 21 2011) ISSN: 1477-0539 [Electronic] England
• PMID: 21373680 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-phenyl-benzopyranopyrimidine
• Benzopyrans
• Ligands
• Pyrimidines
• Telomerase

Topics

• Benzopyrans (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• G-Quadruplexes
• Humans
• Ligands
• Models, Molecular
• Pyrimidines (chemistry, pharmacology)
• Telomerase (antagonists & inhibitors)
• Telomere (chemistry)