期刊
BIOORGANIC CHEMISTRY
卷 125, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105851
关键词
Carbohydrate conjugates; 2-aryl-imidazo[4,5-f][1,10]phenanthroline derivatives; G-quadruplex DNA ligands; DNA interactions; Antitumor agents
资金
- Spanish MICINN [PID2019-108251RB-I00/AEI/10.13039/50110001 1033, CTQ2015-72625-EXP/AEI]
- Spanish MICINN and MINECO [PID2019-108251RB-I00/AEI/10.13039/50110001 1033, CTQ2015-72625-EXP/AEI]
- Consejeria de Educacion, Juventud y Deporte de la Comunidad de Madrid and Fondo Social Europeo (YEI) [PID2019-108251RB-I00/AEI/10.13039/50110001 1033]
- Universidad de Alcala [CTQ2015-72625-EXP/AEI, PEJ-2017-AI/SAL-6160, CCG2016/EXP-044, CCG2018/EXP-024]
- [CCG2020/CC-024]
- [UAH-AE-2017-2]
In this study, a novel family of carbohydrate conjugates based on the 2-aryl-imidazo[4,5-f][1,10]phenanthroline core modified with carbohydrates (carb-APIPs) were presented. The carb-APIPs exhibited high affinity and selectivity towards telomeric G-quadruplex DNA structure, and showed significant cytotoxic properties in cancer cells.
Here we present a novel family of carbohydrate conjugates based on the 2-aryl-imidazo[4,5-f][1,10]phenanthroline core modified with carbohydrates (carb-APIPs). The hybrid compounds were prepared by direct treatment of the unprotected carbohydrate with 2-(4-aminophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (APIP). The N- glycosylation reactions with the monosaccharides tested afforded stereoselectively the more stable N-beta-glyco-pyranosylamines that, in solution, underwent a dynamic equilibrium leading to anomeric mixtures with a small participation of the alpha isomer. DNA interaction experiments with telomeric G-quadruplex DNA included DNA FRET melting assays, circular dichroism, and equilibrium dialysis and revealed that the novel carb-APIPs bind the G-quadruplex structure with high affinity. Interestingly, the presence of the carbohydrate confers good selectivity towards the telomeric quadruplex structure, as suggested by competition DNA FRET melting assays. Besides the extended aromatic surface that allows it-stacking interactions, the carbohydrate part of the conjugate may contribute to groove binding recognition, as indicated by viscosity experiments. In addition, the novel carbAPIPs showed significant cytotoxic properties in PC3 and HeLa cells and, to a lesser extent, in MCF7 cells and normal human fibroblasts (HFF1).
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