Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece.
Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece.
Eur J Med Chem. 2021 Jun 5;218:113387. doi: 10.1016/j.ejmech.2021.113387. Epub 2021 Mar 19.
In this study, a series of novel substituted pyrazolo[3,4-c]pyridin-5-ylamidines was synthesized and their cytotoxicity against three cancer cell lines (MDA-MB-231, HT-1080, PC-3), as well as a human normal cell line (AG01523) was evaluated. A number of derivatives could strongly reduce cancer cells proliferation and exhibit apoptotic induction capability, while reasonable structure-activity relationships could be extracted. Certain analogues were endowed with low toxicity against normal cells. Cell cycle analysis revealed that most of the active compounds induced a G/G arrest of HT-1080 cells. Moreover, the potential mechanisms of the cytotoxic activity of the promising compounds were investigated in HT-1080 cells, upon study of their effects on the phosphorylation of Akt, ERK and p38 MAPK. Most of the active derivatives inhibit phosphorylation of Akt and ERK and/or induce p38 MAPK phosphorylation, providing a potential indication on the mode of action of this class.
在这项研究中，合成了一系列新型取代的吡唑并[3,4-c]吡啶-5-甲脒，并评估了它们对三种癌细胞系（MDA-MB-231、HT-1080、PC-3）和一种人正常细胞系（AG01523）的细胞毒性。许多衍生物能够强烈抑制癌细胞增殖并表现出诱导凋亡的能力，同时可以提取出合理的构效关系。某些类似物对正常细胞的毒性较低。细胞周期分析显示，大多数活性化合物诱导 HT-1080 细胞的 G/G 期阻滞。此外，通过研究对 Akt、ERK 和 p38 MAPK 磷酸化的影响，研究了有前途的化合物在 HT-1080 细胞中的细胞毒性活性的潜在机制。大多数活性衍生物抑制 Akt 和 ERK 的磷酸化，和/或诱导 p38 MAPK 磷酸化，为该类化合物的作用模式提供了潜在的依据。
