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首页> 外文期刊>ChemMedChem >Aromatic Core Extension in the Series of N-Cyclic Bay-Substituted Perylene G-Quadruplex Ligands: Increased Telomere Damage, Antitumor Activity, and Strong Selectivity for Neoplastic over Healthy Cells
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Aromatic Core Extension in the Series of N-Cyclic Bay-Substituted Perylene G-Quadruplex Ligands: Increased Telomere Damage, Antitumor Activity, and Strong Selectivity for Neoplastic over Healthy Cells

机译：N-环湾取代的G G-四链体配体系列中的芳香核心扩展：端粒损伤增加，抗肿瘤活性和对健康细胞的肿瘤的强选择性。

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摘要

Based on previous work on both perylene and coronene derivatives as G-quadruplex binders, a novel chimeric compound was designed: N,N'-bis[2-(1-piperidino)-ethyl]-1-(1-piperidinyl)-6-[2-(1-piperidino)-ethyl]-benzo[ghi]perylene-3,4:9,10-tetracar-boxylic diimide (EMICORON), having one piperidinyl group bound to the perylene bay area (positions 1,12 and 6, 7 of the aromatic core), sufficient to guarantee good selectivity, and an extended aromatic core able to increase the stacking interactions with the terminal tetrad of the G-quadruplex. The obtained "chimera" molecule, EMICORON, rapidly triggers extensive DNA damage of telomeres, associated with the derealiza- tion of telomeric protein protection of telomeres 1 (POT1), and efficiently limits the growth of both telomerase-positive and-negative tumor cells. Notably, the biological effects of EMICORON are more potent than those of the previously described perylene derivative (PPL3C), and more interestingly, EMICORON appears to be detrimental to transformed and tumor cells, while normal fibroblasts expressing telomerase remain unaffected. These results identify a new promising G-quadruplex ligand, structurally and biologically similar on one side to coronene and on the other side to a bay-monosubsti-tuted perylene, that warrants further studies.
机译：基于先前关于per和co烯衍生物作为G-四链体粘合剂的研究，设计了一种新型的嵌合化合物：N，N'-双[2-（1-哌啶子基）-乙基] -1-（1-哌啶基）-6 -[2-（1-哌啶子基）-乙基]-苯并[-3,4：9,10-四羧酸二亚胺（EMICORON），其中一个哌啶基与per湾区域相连（位置1,12和芳族核的6、7），足以保证良好的选择性，以及延伸的芳族核能够增加与G-四链体的末端四联体的堆积相互作用。获得的“嵌合体”分子EMICORON迅速引发端粒的广泛DNA损伤，与端粒1（POT1）端粒蛋白保护的失活相关，并有效地限制了端粒酶阳性和阴性肿瘤细胞的生长。值得注意的是，EMICORON的生物学效应比先前描述的per衍生物（PPL3C）更为有效，而且更有趣的是，EMICORON似乎对转化细胞和肿瘤细胞有害，而表达端粒酶的正常成纤维细胞仍不受影响。这些结果确定了一种新的有前途的G-四链体配体，其结构和生物学方面与二甲苯均相似，而另一侧与海湾-单取代-形成的，相似，值得进一步研究。

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