Université de Bordeaux, ARNA laboratory, INSERM U1212, UMR CNRS 5320, UFR des Sciences Pharmaceutiques, 33076 Bordeaux CEDEX, France.
Université de Bordeaux, INSERM U1053, Cutaneous Lymphoma Oncogenesis Team, 33076 Bordeaux CEDEX, France.
Molecules. 2017 Dec 30;23(1):81. doi: 10.3390/molecules23010081.
G-quadruplexes (G4) are stacked non-canonical nucleic acid structures found in specific G-rich DNA or RNA sequences in the human genome. G4 structures are liable for various biological functions; transcription, translation, cell aging as well as diseases such as cancer. These structures are therefore considered as important targets for the development of anticancer agents. Small organic heterocyclic molecules are well known to target and stabilize G4 structures. In this article, we have designed and synthesized 2,6-di-(4-carbamoyl-2-quinolyl)pyridine derivatives and their ability to stabilize G4-structures have been determined through the FRET melting assay. It has been established that these ligands are selective for G4 over duplexes and show a preference for the parallel conformation. Next, telomerase inhibition ability has been assessed using three cell lines (K562, MyLa and MV-4-11) and telomerase activity is no longer detected at 0.1 μM concentration for the most potent ligand . The most promising G4 ligands were also tested for antiproliferative activity against the two human myeloid leukaemia cell lines, HL60 and K562.
G-四链体（G4）是在人类基因组中特定的富含 G 的 DNA 或 RNA 序列中发现的堆叠的非经典核酸结构。G4 结构易于各种生物功能；转录、翻译、细胞衰老以及癌症等疾病。因此，这些结构被认为是开发抗癌药物的重要靶标。小有机杂环分子是众所周知的靶向和稳定 G4 结构的物质。在本文中，我们设计并合成了 2,6-二-(4-氨甲酰基-2-喹啉基)吡啶衍生物，并通过 FRET 融解测定法确定了它们稳定 G4 结构的能力。已经确定，这些配体对 G4 具有选择性，而对双链体则没有选择性，并且对平行构象具有偏好性。接下来，使用三种细胞系（K562、MyLa 和 MV-4-11）评估了端粒酶抑制能力，对于最有效的配体，在 0.1 μM 浓度下不再检测到端粒酶活性。最有前途的 G4 配体还针对两种人髓性白血病细胞系 HL60 和 K562 进行了抗增殖活性测试。
