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New insights into the mechanism of action of pyrazolo[1,2‐a]benzo[1,2,3,4]tetrazin‐3‐one derivatives endowed with anticancer potential
Chemical Biology & Drug Design ( IF 3 ) Pub Date : 2017-10-11 , DOI: 10.1111/cbdd.13108
Antonino Lauria 1 , Francesco Mingoia 2 , Aída Nelly García-Argáez 3, 4 , Riccardo Delisi 1 , Annamaria Martorana 1 , Lisa Dalla Via 3
Affiliation  

Due to the scarce biological profile, the pyrazolo[1,2‐a]benzo[1,2,3,4]tetrazine‐3‐one scaffold (PBT) has been recently explored as promising core for potential anticancer candidates. Several suitably decorated derivatives (PBTs) exhibited antiproliferative activity in the low‐micromolar range associated with apoptosis induction and cell cycle arrest on S phase. Herein, we selected the most active derivatives and submitted them to further biological explorations to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism experiments so as to evaluate how small planar molecules might interact with DNA, including the interference with the catalytic cycle of topoisomerase II and the influence on the cleavable complex stabilization (poisoning effect). In support of the experimental data, in silico studies have been achieved to better understand the chemical space of the interactions. Interestingly some meaningful structural features, useful for further developments, were found. The 8,9‐di‐Cl substituted derivative revealed as the most effective in the intercalative process, as well as on the inhibition of catalytic activity of topoisomerase II. Predicted ADME studies confirm that PBTs are promising as potential drug candidates.

中文翻译:

吡唑并[1,2-a]苯并[1,2,3,4]四嗪-3-酮衍生物具有抗癌潜力的作用机理的新见解

由于生物学特性的稀缺,吡唑并[1,2-a]苯并[1,2,3,4]四嗪-3-酮支架(PBT)最近被探索为潜在抗癌候选药物的有希望的核心。几种适当修饰的衍生物(PBT)在低微摩尔范围内表现出抗增殖活性,与S期细胞凋亡诱导和细胞周期停滞有关。在此,我们选择了活性最高的衍生物并将其提交进一步的生物学探索以加深作用机理。首先,通过流动线性二色性实验接近DNA靶点,以评估平面分子可能与DNA相互作用的程度,包括对拓扑异构酶II催化循环的干扰以及对可裂解复合物稳定化的影响(中毒作用)。 。为了支持实验数据,为了更好地了解相互作用的化学空间,已经进行了计算机分析研究。有趣的是,发现了一些有意义的结构特征,这些特征对于进一步的发展很有用。这8,9-di-Cl取代的衍生物在插入过程中以及对拓扑异构酶II的催化活性的抑制方面显示出最有效的作用。预测的ADME研究证实PBT有望成为潜在的候选药物。
更新日期:2017-10-11
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