Chłoń-Rzepa Grażyna, Jankowska Agnieszka, Ślusarczyk Marietta, Świerczek Artur, Pociecha Krzysztof, Wyska Elżbieta, Bucki Adam, Gawalska Alicja, Kołaczkowski Marcin, Pawłowski Maciej
Department of Medicinal Chemistry, Jagiellonian University, Medical College, Medyczna 9, 30-688, Kraków, Poland.
Department of Medicinal Chemistry, Jagiellonian University, Medical College, Medyczna 9, 30-688, Kraków, Poland.
Eur J Med Chem. 2018 Feb 25;146:381-394. doi: 10.1016/j.ejmech.2018.01.068. Epub 2018 Feb 4.
A novel butanehydrazide derivatives of purine-2,6-dione designed using a ligand-based approach were synthesized and their in vitro activity against both PDE4B and PDE7A isoenzymes was assessed. The 7,8-disubstituted purine-2,6-dione derivatives 31, 34, 37, and 40 appeared to be the most potent PDE4/7 inhibitors with IC values in the range of that of the reference rolipram and BRL-50481, respectively. Moreover, docking studies explained the importance of N-(2,3,4-trihydroxybenzylidene)butanehydrazide substituent in position 7 of purine-2,6-dione core for dual PDE4/7 inhibitory properties. The inhibition of both the cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect. Compounds 31, 34, and 37 in the in vivo study in rats with LPS-induced endotoxemia decreased the maximum concentration of this proinflammatory cytokine by 53, 84 and 88%, respectively.
采用基于配体的方法设计合成了新型嘌呤 - 2,6 - 二酮丁酰肼衍生物，并评估了它们对磷酸二酯酶4B（PDE4B）和磷酸二酯酶7A（PDE7A）同工酶的体外活性。7,8 - 二取代嘌呤 - 2,6 - 二酮衍生物31、34、37和40似乎是最有效的PDE4/7抑制剂，其半数抑制浓度（IC）值分别在参考药物咯利普兰和BRL - 50481的范围内。此外，对接研究解释了嘌呤 - 2,6 - 二酮核心7位的N - （2,3,4 - 三羟基亚苄基）丁酰肼取代基对双重PDE4/7抑制特性的重要性。对两种环磷酸腺苷（cAMP）特异性磷酸二酯酶同工酶的抑制导致了强烈的抗肿瘤坏死因子 - α（TNF - α）效应。在脂多糖（LPS）诱导的内毒素血症大鼠体内研究中，化合物31、34和37分别使这种促炎细胞因子的最大浓度降低了53%、84%和88%。
