University of Palermo, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Medicinal Chemistry and Pharmaceutical Technologies, Via Archirafi 32, 90123 Palermo, Italy.
University of Palermo, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Laboratory of Biochemistry, Via del Vespro 129, 90127 Palermo, Italy.
Bioorg Chem. 2019 Mar;83:367-379. doi: 10.1016/j.bioorg.2018.10.055. Epub 2018 Oct 29.
Based on some common structural features of known compounds interfering with p53 pathways and our previously synthesized benzamides, we synthesized new ethyl 5-(4-substituted benzamido)-1-phenyl-1H-pyrazole-4-carboxylates 26a-c, ethyl 5-(4-substituted benzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylates 27a-c and N-(1H-indazol-6-yl)-4-substituted benzamides 31a,b bearing in the 4 position of the benzamido moiety the 2-phenylpropanamido or 2-phenoxyacetamido or cinnamamido groups. A preliminary test to evaluate the antiproliferative activity against human lung carcinoma H292 cells highlighted how compound 26c showed the best activity. This last was therefore selected for further studies with the aim to find the mechanism of action. Compound 26c induces intrinsic apoptotic pathway by activating p53 and is also able to activate TRAIL-inducing death pathway by promoting increase of DR4 and DR5 death receptors, downregulation of c-FLIP and caspase-8 activation.
基于已知化合物干扰 p53 途径的一些常见结构特征和我们之前合成的苯甲酰胺，我们合成了新的乙基 5-(4-取代苯甲酰胺基)-1-苯基-1H-吡唑-4-羧酸酯 26a-c、乙基 5-(4-取代苯甲酰胺基)-1-(吡啶-2-基)-1H-吡唑-4-羧酸酯 27a-c 和 N-(1H-吲唑-6-基)-4-取代苯甲酰胺 31a,b，这些化合物在苯甲酰胺部分的 4 位带有 2-苯基丙酰胺基、2-苯氧基乙酰胺基或肉桂酰胺基。初步测试评估了对人肺癌 H292 细胞的抗增殖活性，结果表明化合物 26c 具有最佳活性。因此，选择该化合物进行进一步研究，旨在寻找其作用机制。化合物 26c 通过激活 p53 诱导内在凋亡途径，还能够通过促进 DR4 和 DR5 死亡受体的增加、c-FLIP 的下调和 caspase-8 的激活来激活 TRAIL 诱导的死亡途径。
