Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
Department of Sciences, University of Basilicata, Viale dell'Ateneo Lucano 10, I-85100 Potenza, Italy.
Nucleic Acids Res. 2020 Dec 16;48(22):12556-12565. doi: 10.1093/nar/gkaa1109.
The thrombin binding aptamer (TBA) possesses promising antiproliferative properties. However, its development as an anticancer agent is drastically impaired by its concomitant anticoagulant activity. Therefore, suitable chemical modifications in the TBA sequence would be required in order to preserve its antiproliferative over anticoagulant activity. In this paper, we report structural investigations, based on circular dichroism (CD) and nuclear magnetic resonance spectroscopy (NMR), and biological evaluation of four pairs of enantiomeric heterochiral TBA analogues. The four TBA derivatives of the d-series are composed by d-residues except for one l-thymidine in the small TT loops, while their four enantiomers are composed by l-residues except for one d-thymidine in the same TT loop region. Apart from the left-handedness for the l-series TBA derivatives, CD and NMR measurements have shown that all TBA analogues are able to adopt the antiparallel, monomolecular, 'chair-like' G-quadruplex structure characteristic of the natural D-TBA. However, although all eight TBA derivatives are endowed with remarkable cytotoxic activities against colon and lung cancer cell lines, only TBA derivatives of the l-series show no anticoagulant activity and are considerably resistant in biological environments.
凝血酶结合适体（TBA）具有有前景的抗增殖特性。然而，其伴随的抗凝活性极大地阻碍了其作为抗癌剂的发展。因此，需要对 TBA 序列进行适当的化学修饰，以保持其抗增殖活性超过抗凝活性。在本文中，我们报告了基于圆二色性（CD）和核磁共振波谱（NMR）的结构研究以及四对对映异构杂手性 TBA 类似物的生物学评价。四个 d-系列的 TBA 衍生物由 d-残基组成，除了在小 TT 环中的一个 l-胸腺嘧啶外，而它们的四个对映异构体由 l-残基组成，除了在同一 TT 环区域中的一个 d-胸腺嘧啶外。除了 l-系列 TBA 衍生物的左手性外，CD 和 NMR 测量表明，所有 TBA 类似物都能够采用天然 D-TBA 的反平行、单分子、“椅式”G-四链体结构。然而，尽管所有八个 TBA 衍生物都对结肠和肺癌细胞系具有显著的细胞毒性活性，但只有 l-系列的 TBA 衍生物没有抗凝活性，并且在生物环境中具有相当的抗性。
