Dipartimento di Scienze della Salute, Università "Magna Græcia", Campus Salvatore Venuta, Viale Europa, 88100, Catanzaro, Italy; Net4Science srl, Università "Magna Græcia", Campus Salvatore Venuta, Viale Europa, 88100, Catanzaro, Italy.
Dipartimento di Scienze della Salute, Università "Magna Græcia", Campus Salvatore Venuta, Viale Europa, 88100, Catanzaro, Italy; Net4Science srl, Università "Magna Græcia", Campus Salvatore Venuta, Viale Europa, 88100, Catanzaro, Italy; Department of Pharmacy, University "Federico II" of Naples, Via D. Montesano 49, 80131, Naples, Italy.
Eur J Med Chem. 2019 Nov 15;182:111627. doi: 10.1016/j.ejmech.2019.111627. Epub 2019 Aug 16.
It is well recognized that the non-canonical DNA structures known as G-quadruplexes (G4s) have a potential anticancer significance and several compounds have been discovered and evaluated as promising G4 binders with anticancer activity. Here, starting from a promising hit with an indolo-naphthyridine scaffold, a small series of five indolo-naphthyridine based derivatives have been designed and evaluated as G4-targeting compounds. FRET biophysical studies were performed on multiple DNA G4 structures, leading to the identification of a multi-target G4 stabilizer with a slight preference for the c-KIT1 and a good G4 over duplex selectivity. The good affinity of this compound against c-KIT1 G4 was also confirmed by SPR and MST experiments, while biological assays revealed its cytotoxic activity on tumour cells. Finally, Molecular Dynamics simulations helped to elucidate the stabilization effect of the selected compound against the c-KIT1 G4.
众所周知，非经典 DNA 结构，即 G-四链体（G4s），具有潜在的抗癌意义，已有多种化合物被发现并被评估为具有抗癌活性的有前途的 G4 结合物。在这里，我们从具有吲哚并萘啶骨架的有前景的命中化合物开始，设计并评估了一系列五种基于吲哚并萘啶的衍生物作为 G4 靶向化合物。在多种 DNA G4 结构上进行了 FRET 生物物理研究，确定了一种多靶 G4 稳定剂，对 c-KIT1 略有偏好，并且对 G4 具有良好的双链体选择性。SPR 和 MST 实验也证实了该化合物对 c-KIT1 G4 的良好亲和力，而生物学测定显示其对肿瘤细胞的细胞毒性活性。最后，分子动力学模拟有助于阐明所选化合物对 c-KIT1 G4 的稳定作用。
