Department of Pharmacy, University of Naples Federico II, I-80131 Napoli, Italy.
Int J Mol Sci. 2022 Nov 29;23(23):14921. doi: 10.3390/ijms232314921.
In this paper, we study the biological properties of two TBA analogs containing one and two extra G-tetrads, namely TBAG3 and TBAG4, respectively, and two further derivatives in which one of the small loops at the bottom (TBAG41S) or the large loop at the top (TBAG4GS) of the TBAG4 structure has been completely modified by replacing all loop residues with abasic site mimics. The therapeutical development of the TBA was hindered by its low thermodynamic and nuclease stability, while its potential as an anticancer/antiproliferative molecule is also affected by the anticoagulant activity, being a side effect in this case. In order to obtain suitable TBA analogs and to explore the involvement of specific aptamer regions in biological activity, the antiproliferative capability against DU 145 and MDAMB 231 cancer cell lines (MTT), the anticoagulant properties (PT), the biological degradability (nuclease stability assay) and nucleolin (NCL) binding ability (SPR) of the above described TBA derivatives have been tested. Interestingly, none of the TBA analogs exhibits an anticoagulant activity, while all of them show antiproliferative properties to the same extent. Furthermore, TBAG4 displays extraordinary nuclease stability and promising antiproliferative properties against breast cancer cells binding NCL efficiently. These results expand the range of G4-structures targeting NCL and the possibility of developing novel anticancer and antiviral drugs.
在本文中，我们研究了两种含有一个和两个额外 G-四联体的 TBA 类似物的生物学特性，分别为 TBAG3 和 TBAG4，以及另外两种进一步的衍生物，其中一种位于 TBAG4 结构底部的小环（TBAG41S）或顶部的大环（TBAG4GS）已通过用无碱基类似物替换所有环残基而被完全修饰。TBA 的治疗开发受到其热力学和核酸酶稳定性低的阻碍，而其作为抗癌/抗增殖分子的潜力也受到抗凝活性的影响，在这种情况下，这是一种副作用。为了获得合适的 TBA 类似物并探索特定适体区域在生物学活性中的参与，对上述 TBA 衍生物针对 DU 145 和 MDAMB 231 癌细胞系（MTT）的增殖能力、抗凝特性（PT）、生物可降解性（核酸酶稳定性测定）和核仁素（NCL）结合能力（SPR）进行了测试。有趣的是，没有一种 TBA 类似物具有抗凝活性，而所有类似物都具有相同程度的抗增殖特性。此外，TBAG4 表现出非凡的核酸酶稳定性和对乳腺癌细胞的有希望的增殖抑制特性，能够有效地结合 NCL。这些结果扩展了靶向 NCL 的 G4 结构的范围，并为开发新型抗癌和抗病毒药物提供了可能性。
