Mohamed Hany I, Song Zibing, He Yi, Gao Chao
National R&D Center for Se-rich Agricultural Products Processing, Hubei Engineering Research Center for Deep Processing of Green Se-rich Agricultural Products, School of Modern Industry for Selenium Science and Engineering, Wuhan Polytechnic University, Wuhan, Hubei 430023, China.
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine; Hubei Hongshan Laboratory; Interdisciplinary Sciences Institute; National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
J Med Chem. 2025 Jul 24;68(14):14223-14238. doi: 10.1021/acs.jmedchem.3c00955. Epub 2025 Jul 12.
Traditional chemotherapy remains the main treatment option for cancer. However, drugs discovered through conventional targets are often accompanied by side effects and drug resistance, so more effective treatment options are urgently needed. Discovery of antitumor drugs targeting G-quadruplexes is an effective pathway. Here, a novel series of pyrazolo[4,3-]quinolines as potential stabilizing ligands for Pu27 and G-quadruplexes was synthesized. Compound PQ32 was observed to stabilize these G-quadruplexes with high Δ values. Biological investigations indicated that PQ32 inhibited tumor cell proliferation with an IC of ∼ 1.00 μM, arrested the cell cycle in the G2 phase, and caused cell apoptosis. Further studies revealed that PQ32 could inhibit the expression of and genes. Xenograft animal model assay suggested that PQ32 effectively inhibited the tumor growth in mice with comparable activity to cisplatin. Thus, the interaction of quinoline-based ligands with multiple G-quadruplex DNA provides a promising target for anticancer therapeutic strategy.
传统化疗仍然是癌症的主要治疗选择。然而，通过传统靶点发现的药物往往伴随着副作用和耐药性，因此迫切需要更有效的治疗选择。发现靶向G-四链体的抗肿瘤药物是一条有效的途径。在此，合成了一系列新型的吡唑并[4,3-]喹啉作为Pu27和G-四链体的潜在稳定配体。观察到化合物PQ32以高Δ值稳定这些G-四链体。生物学研究表明，PQ32以约1.00 μM的IC抑制肿瘤细胞增殖，使细胞周期停滞在G2期，并导致细胞凋亡。进一步研究表明，PQ32可抑制 和 基因的表达。异种移植动物模型试验表明，PQ32能有效抑制小鼠肿瘤生长，其活性与顺铂相当。因此，喹啉基配体与多种G-四链体DNA的相互作用为抗癌治疗策略提供了一个有前景的靶点。
