School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas (CSIC), PTS Granada, Avenida del Conocimiento 17, 18016, Armilla, Granada, Spain.
Chemistry. 2020 May 15;26(28):6224-6233. doi: 10.1002/chem.201905753. Epub 2020 Apr 28.
G-quadruplex nucleic acid structures have long been studied as anticancer targets whilst their potential in antiparasitic therapy has only recently been recognized and barely explored. Herein, we report the synthesis, biophysical characterization, and in vitro screening of a series of stiff-stilbene G4 binding ligands featuring different electronics, side-chain chemistries, and molecular geometries. The ligands display selectivity for G4 DNA over duplex DNA and exhibit nanomolar toxicity against Trypasanoma brucei and HeLa cancer cells whilst remaining up to two orders of magnitude less toxic to non-tumoral mammalian cell line MRC-5. Our study demonstrates that stiff-stilbenes show exciting potential as the basis of selective anticancer and antiparasitic therapies. To achieve the most efficient G4 recognition the scaffold must possess the optimal electronics, substitution pattern and correct molecular configuration.
G-四链体核酸结构一直以来被作为抗癌靶点进行研究，而其在寄生虫病治疗方面的潜力最近才被认识到，并刚刚开始探索。在此，我们报告了一系列刚性联苯 G4 结合配体的合成、物理化学特性表征和体外筛选，这些配体具有不同的电子、侧链化学和分子几何形状。这些配体对 G4 DNA 具有选择性，对 Trypasanoma brucei 和 HeLa 癌细胞具有纳摩尔毒性，而对非肿瘤哺乳动物细胞系 MRC-5 的毒性低两个数量级以上。我们的研究表明，刚性联苯具有作为选择性抗癌和抗寄生虫病治疗基础的巨大潜力。为了实现最有效的 G4 识别，支架必须具有最佳的电子、取代模式和正确的分子构型。
