Toward the Development of Specific G‑Quadruplex Binders: Synthesis, Biophysical, and Biological Studies of New Hydrazone Derivatives

G-Quadruplex-binding
compounds are currently perceived as possible
anticancer therapeutics. Here, starting from a promising lead, a small
series of novel hydrazone-based compounds were synthesized and evaluated
as G-quadruplex binders. The in vitro G-quadruplex-binding properties
of the synthesized compounds were investigated employing both human
telomeric and oncogene promoter G-quadruplexes with different folding
topologies as targets. The present investigation led to the identification
of potent G-quadruplex stabilizers with high selectivity over duplex
DNA and preference for one G-quadruplex topology over others. Among
them, selected derivatives have been shown to trap G-quadruplex structures
in the nucleus of cancer cells. Interestingly, this behavior correlates
with efficient cytotoxic activity in human osteosarcoma and colon
carcinoma cells.

G-四链体（G-Quadruplex）结合化合物目前被视作潜在的抗癌治疗药物。本研究以一款极具潜力的先导化合物为起点，合成了一系列新型腙类化合物，并对其作为G-四链体结合剂的活性进行了评价。本研究以具有不同折叠拓扑结构的人类端粒及癌基因启动子区G-四链体为靶点，考察了所合成化合物的体外G-四链体结合特性。本次研究成功筛选得到强效G-四链体稳定剂，这类化合物不仅对双链DNA（duplex DNA）展现出极高的选择性，同时对特定G-四链体折叠拓扑结构具有显著偏好性。其中部分优选衍生物被证实可在癌细胞细胞核内捕获G-四链体结构。值得注意的是，该活性与人类骨肉瘤及结肠癌细胞中展现出的高效细胞毒活性密切相关。