New quinazoline derivatives for telomeric G-quadruplex DNA: Effects of an added phenyl group on quadruplex binding ability

• Published in: European journal of medicinal chemistry 2013-05, Vol.63, p.1-13
• Main Authors: He, Jin-Hui, Liu, Hui-Yun, Li, Zeng, Tan, Jia-Heng, Ou, Tian-Miao, Huang, Shi-Liang, An, Lin-Kun, Li, Ding, Gu, Lian-Quan, Huang, Zhi-Shu
• Format: Article
• Language: English
• Subjects: Binding, Competitive; Cell Survival - drug effects; Cellular Senescence - drug effects; Circular Dichroism; DNA - chemistry; DNA - metabolism; G-Quadruplexes; HL-60 Cells; Humans; Inducing ability; Kinetics; Ligands; Molecular Structure; Phenol - chemistry; Phenol - metabolism; Quinazoline derivatives; Quinazolines - chemistry; Quinazolines - metabolism; Quinazolines - pharmacology; Surface Plasmon Resonance; Telomerase - antagonists & inhibitors; Telomerase - metabolism; Telomerase inhibitor; Telomere - chemistry; Telomere - genetics; Telomere - metabolism; Telomere shortening; Telomere Shortening - drug effects; Telomeric G-quadruplex DNA
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.01.051

To improve the selectivity of indoloquinoline or benzofuroquinoline derivatives, we previously reported several quinazoline derivatives [17]. These compounds could mimic a tetracyclic aromatic system through intramolecular hydrogen bond. Studies showed that these quinazoline derivatives were effective and selective telomeric G-quadruplex ligands. With this encouragement, here we synthesized a series of N-(2-(quinazolin-2-yl)phenyl)benzamide (QPB) compounds as modified quinazoline derivatives. In this modification, a phenyl group was introduced to the aromatic core. The evaluation results showed that part of QPB derivatives had stronger binding ability and better selectivity for telomeric G-quadruplex DNA than LZ-11, the most potential compound of reported quinazoline derivatives. Furthermore, telomerase inhibition of QPB derivatives and their cellular effects were studied. A series of compounds with an introduction of phenyl group to previous reported quinazoline derivatives were synthesized and evaluated. These compounds showed enhanced telomeric G-quadruplex DNA binding activity and selectivity [Display omitted] . ► Compounds with an introduction of phenyl group to quinazoline derivatives were synthesized. ► Compounds showed enhanced binding affinity and selectivity for telomeric G-quadruplex DNA. ► 15e could significantly inhibit cellular biological activity.