Bisoi Asim, Majumdar Trideep, Sarkar Sunipa, Singh Prashant Chandra
School of the Chemical Science, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India.
J Phys Chem B. 2025 Jan 23;129(3):835-843. doi: 10.1021/acs.jpcb.4c05133. Epub 2025 Jan 14.
The folding of the guanine repetitive region in the telomere unit into G-quadruplex (G4) by drugs has been suggested as an alternative approach for cancer therapy. Hydroxychloroquine (HCQ) and chloroquine (CQ) are two important drugs in the trial stage for cancer. Both drugs can induce the folding of telomere-guanine-rich sequences into G4 even in the absence of salt. However, the guanine repetitive telomeric sequences are always flanked by other nucleobases at both the terminal (5' or 3') that can affect the drug-induced folding pathways and stability of the G4 significantly. Hence, in this study, the HCQ and CQ drug-induced folding of the guanine repetitive telomeric sequences into G4 and its stability by varying the chemical nature, number, and positions of the flanking nucleobases has been explored using several biophysical techniques and docking studies. It has been found that the drug-induced folding of telomere with single flanking nucleobases is similar to that without flanking nucleobases irrespective of the chemical nature and position of the flanking nucleobase. However, the propensity of the folding and the stability of the telomeric G4 induced by drugs decrease significantly with the increase of the flanking nucleobases more than one of any chemical nature and position. The data suggest that the number of flanking nucleobases rather than their chemical nature and location is a critical factor in the folding of the telomere into G4 induced by both drugs. Further, it has been observed that both drugs mainly interact with the G-tract and thymine of the loop region rather than the flanking nucleobases of the telomeric sequences without or with one flanking nucleobase. In contrast, the flanking nucleobases also participate in the interaction with the HCQ and CQ along with the core guanine repeat telomeric unit in the case of the telomeric sequences with more than one flanking nucleobases. The participation of the flanking nucleobases in the interaction with the HCQ and CQ affects the hydrogen bonding of the positively charged side chain of drugs with G quartet and loop nucleobases of telomere along with the with π···π and C-H···π weak interactions between the quinoline part of the drugs with the core telomeric guanine repeat unit which affects the folding pattern of the telomere sequences with more than one flanking nucleobases into G4.
通过药物将端粒单元中的鸟嘌呤重复区域折叠成G-四链体（G4）已被认为是癌症治疗的一种替代方法。羟氯喹（HCQ）和氯喹（CQ）是处于癌症试验阶段的两种重要药物。即使在没有盐的情况下，这两种药物也能诱导富含端粒鸟嘌呤的序列折叠成G4。然而，鸟嘌呤重复端粒序列在末端（5'或3'）总是被其他核碱基侧翼包围，这会显著影响药物诱导的折叠途径和G4的稳定性。因此，在本研究中，使用多种生物物理技术和对接研究，探索了HCQ和CQ药物诱导鸟嘌呤重复端粒序列折叠成G4及其通过改变侧翼核碱基的化学性质、数量和位置的稳定性。研究发现，无论侧翼核碱基的化学性质和位置如何，单侧翼核碱基的端粒药物诱导折叠与无侧翼核碱基的情况相似。然而，随着侧翼核碱基数量超过一个，无论其化学性质和位置如何，药物诱导的端粒G4折叠倾向和稳定性会显著降低。数据表明，侧翼核碱基的数量而非其化学性质和位置是这两种药物诱导端粒折叠成G4的关键因素。此外，还观察到，这两种药物主要与环区域的G链和胸腺嘧啶相互作用，而不是与无端粒侧翼或单侧翼核碱基的端粒序列的侧翼核碱基相互作用。相比之下，在具有多个侧翼核碱基的端粒序列中，侧翼核碱基也会与HCQ和CQ以及核心鸟嘌呤重复端粒单元一起参与相互作用。侧翼核碱基参与与HCQ和CQ的相互作用会影响药物带正电侧链与端粒G四重体和环核碱基的氢键，以及药物喹啉部分与核心端粒鸟嘌呤重复单元之间的π···π和C-H···π弱相互作用，这会影响具有多个侧翼核碱基的端粒序列折叠成G4的模式。
