Novel modified leucine and phenylalanine dipeptides modulate viability and attachment of cancer cells.,European Journal of Medicinal Chemistry

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Novel modified leucine and phenylalanine dipeptides modulate viability and attachment of cancer cells.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.ejmech.2020.112036
Radek Jorda ₁ , Pratibha Magar ₂ , Denisa Hendrychová ₃ , Karel Pauk ₂ , Michal Dibus ₄ , Eliška Pilařová ₂ , Aleš Imramovský ₂ , Vladimír Kryštof ₁

Affiliation

Here, we describe the synthesis and biological characterization of 32 novel phenylalanine and leucine dipeptides modified on both the N and C termini by salicylic acid and aromatic or alicyclic amines, respectively. All compounds displayed antiproliferative activity in the tested cancer cell lines and eight of the compounds exhibited single digit micromolar GI50 values. Treated cells rapidly detached from surface of tissue culture dishes and we found that focal adhesion kinase (FAK), p130CAS and paxillin, which are important regulators of cell adhesion, were dephosphorylated at Y397, Y410 and Y118, respectively. The most potent compound reduced proliferation in the HCT-116 cell line in a dose-dependent manner, as shown by a decrease in 5-bromo-2'-deoxyuridine incorporation into DNA. Furthermore, this compound increased the levels of several apoptotic markers, including activated caspases, and increased site-specific poly-(ADP-ribose)polymerase (PARP) cleavage.

中文翻译：

新型修饰的亮氨酸和苯丙氨酸二肽可调节癌细胞的活力和附着力。

在这里，我们描述了分别由水杨酸和芳香族或脂环族胺在N和C末端修饰的32种新的苯丙氨酸和亮氨酸二肽的合成和生物学特性。所有化合物在测试的癌细胞系中均显示出抗增殖活性，其中八种化合物均显示出一位数的微摩尔GI50值。处理过的细胞迅速从组织培养皿表面脱落，我们发现粘着斑激酶（FAK），p130CAS和paxillin（它们是细胞粘附的重要调节剂）分别在Y397，Y410和Y118处被去磷酸化。最有效的化合物以剂量依赖的方式减少了HCT-116细胞系的增殖，这表现为5-溴-2'-脱氧尿苷掺入DNA的减少。此外，

更新日期：2020-01-07

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