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The cytotoxic potential of cationic triangulenes against tumour cells.
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2019-08-21 , DOI: 10.1039/c9md00305c
Euphemia Leung 1 , Lisa I Pilkington 2 , Mohinder M Naiya 2 , David Barker 2 , Ayesha Zafar 2 , Chatchakorn Eurtivong 3 , Jóhannes Reynisson 2, 4
Affiliation  

TOTA (trioxatriangulenium ion) is a close-shelled carbocation known to intercalate strongly with the DNA double helix (J. Reynisson, G. B. Schuster, S. B. Howerton, L. D. Williams, R. N. Barnett, C. L. Cleveland, U. Landman, N. Harrit, J. B. Chaires, J. Am. Chem. Soc. 2003, 125, 2072). The cytotoxicity of TOTA and its four close structural analogues, ADOTA, Pr-ADOTA, Pr-DAOTA and n-Butyl-TATA were tested against the breast cancer cell line MDA-MB-231 and colon cancer cell line HCT116. The most potent derivatives Pr-ADOTA and Pr-DAOTA had IC50 values of ∼80 nM for MDA-MB-231 but slightly higher for HCT116 in the low hundreds nM range. A 3D model assay of HCT116 spheroids was also used, mimicking a tumour environment, again both Pr-ADOTA and Pr-DAOTA were very active with IC50 values of 38 nM and 21 nM, respectively. Molecular modelling suggest that the planar derivatives intercalate between the base pairs of the DNA double helix. However, only modest DNA double stranded DNA cleavage was observed using the γH2AX assay as compared to camptothecin, a topoisomerase I poison suggesting a different mechanism. Finally, a robust density functional theory (DFT) model was built to predict the pKR+ stability values, i.e., to design derivatives, which predominantly have a non-intercalating buckled form in healthy tissues followed by a nucleophilic attach of water on the central carbon, but a planar form at relatively low pH values rendering them only cytotoxic in the interior of tumours.

中文翻译:


阳离子三角烯对肿瘤细胞的细胞毒性潜力。



TOTA (三氧三角鎓离子)是一种密壳碳正离子,已知可与 DNA 双螺旋强力嵌入(J. Reynisson、GB Schuster、SB Howerton、LD Williams、RN Barnett、CL Cleveland、U. Landman、N. Harrit、JB Chaires ,化学杂志2003,125,2072 )。 TOTA及其四种紧密结构类似物ADOTAPr-ADOTAPr-DAOTAn -Butyl-TATA对乳腺癌细胞系 MDA-MB-231 和结肠癌细胞系 HCT116 进行了细胞毒性测试。最有效的衍生物Pr-ADOTAPr-DAOTA对于 MDA-MB-231 的 IC 50值约为 80 nM,但对于 HCT116 略高,在数百 nM 范围内。还使用了 HCT116 球体的 3D 模型测定,模拟肿瘤环境, Pr-ADOTAPr-DAOTA都非常活跃,IC 50值分别为 38 nM 和 21 nM。分子模型表明平面衍生物插入 DNA 双螺旋的碱基对之间。然而,与喜树碱(一种拓扑异构酶 I 毒物)相比,使用 γH2AX 测定仅观察到适度的 DNA 双链 DNA 裂解,表明不同的机制。最后,建立了鲁棒的密度泛函理论(DFT)模型来预测p K R +稳定性值,设计衍生物,其在健康组织中主要具有非嵌入的弯曲形式,随后在中心碳上亲核水附着,但在相对较低的pH值下呈平面形式,使得它们仅在肿瘤内部具有细胞毒性。
更新日期:2019-08-21
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