Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, 80131 Naples, Italy.
Institute of Biostructures and Bioimaging, CNR, Via Mezzocannone 16, 80134 Naples, Italy.
J Med Chem. 2020 Mar 12;63(5):2035-2050. doi: 10.1021/acs.jmedchem.9b00262. Epub 2019 Jul 10.
In the search for new drug-like selective G-quadruplex binders, a bioinspired design focused on the use of nucleobases as synthons in a multicomponent reaction was herein proved to be viable and successful. Hence, a new class of multifunctionalized imidazo[2,1-]purine derivatives, easily synthesized with a convergent approach, allowed for the identification of the first dual / gene promoter G-quadruplex ligand. Biophysical studies involving circular dichroism melting experiments, microscale thermophoresis measurements, NMR titrations, and computational docking calculations, as well as biological investigations including cytotoxicity and apoptotic assays, and quantitative polymerase chain reaction and Western blot analyses, were performed to assess the potency and to characterize the binding mode of the newly identified lead compound. The absence of toxicity toward normal cells, together with the small molecular weight (≅500 Da), the water solubility, the ease of functionalization, and the selectivity profile, are promising and desirable features to develop G-quadruplex binders as safe and effective anticancer agents.
在寻找新的类药物选择性 G-四链体结合物的过程中，本文证明了一种基于生物灵感的设计，该设计侧重于将核碱基用作多组分反应中的合成子是可行且成功的。因此，一类新的多功能咪唑并[2,1-]嘌呤衍生物，可通过收敛方法轻松合成，从而鉴定出首个双重/基因启动子 G-四链体配体。进行了涉及圆二色性熔融实验、微量热泳动测量、NMR 滴定、计算对接计算以及包括细胞毒性和凋亡测定以及定量聚合酶链反应和 Western blot 分析在内的生物学研究，以评估新鉴定的先导化合物的效力和表征其结合模式。新型化合物没有对正常细胞产生毒性，并且分子量小（≅500 Da）、水溶性好、易于功能化，以及具有选择性，这些都是开发 G-四链体结合物作为安全有效的抗癌药物的有希望和理想的特征。
