Abdel-Halim Mohammad, Abadi Ashraf H, Engel Matthias
Department of Pharmaceutical Chemistry , Faculty of Pharmacy and Biotechnology , German University in Cairo , Cairo 11835 , Egypt.
Pharmaceutical and Medicinal Chemistry , Saarland University , Campus C2.3 , D-66123 Saarbrücken , Germany . Email:
Medchemcomm. 2018 May 7;9(6):1076-1082. doi: 10.1039/c8md00100f. eCollection 2018 Jun 1.
Much light has been shed on the vital role of protein kinase Czeta (PKCζ) in NF-κB activation and the potential use of PKCζ inhibitors as anti-inflammatory agents. We previously reported a series of 1,3,5-trisubstituted pyrazolines as potent and selective allosteric inhibitors of PKCζ; in that series of compounds, the phenolic OH at the 5-phenyl was essential for binding to the PKCζ PIF pocket. In the present study, we surprisingly found that replacing it by a halogen and at the same time moving the OH to the 3-phenyl still resulted in active compounds. An extension of this class of compounds with a new focused library is presented herein, where the phenolic OH at the 5-phenyl, which was reported to be an irreplaceable feature for activity, was moved to the 3-phenyl and replaced by halogen. The new set of compounds maintained the same level of potency against PKCζ and selectivity against PKC isoforms, and showed reduced potency against the PIF pocket mutant PKCζ[Val297Leu]. Of note, the repositioning of the key functional groups resulted in a marked enhancement of cellular potency. One of the most potent new PKCζ inhibitors, , was able to suppress NO production in RAW 264.7 macrophage cells with 8 times higher efficacy than the previous series, and inhibited the NF-κB transcriptional activity in U937 cells with a sub-micromolar IC.
蛋白激酶Cζ（PKCζ）在核因子κB（NF-κB）激活中的关键作用以及PKCζ抑制剂作为抗炎剂的潜在用途已得到了充分的研究。我们之前报道了一系列1,3,5-三取代吡唑啉作为PKCζ的强效和选择性变构抑制剂；在该系列化合物中，5-苯基上的酚羟基对于与PKCζ的脯氨酸富集区（PIF）口袋结合至关重要。在本研究中，我们意外地发现，用卤素取代它并同时将羟基移至3-苯基仍然能得到活性化合物。本文展示了用一个新的聚焦文库对这类化合物进行的扩展，其中据报道对活性而言不可替代的5-苯基上的酚羟基被移至3-苯基并被卤素取代。新的一组化合物对PKCζ保持了相同水平的效力以及对PKC同工型的选择性，并且对PIF口袋突变体PKCζ[Val297Leu]的效力降低。值得注意的是，关键官能团的重新定位导致细胞效力显著增强。其中一种最有效的新型PKCζ抑制剂能够抑制RAW 264.7巨噬细胞中一氧化氮（NO）的产生，其效力比前一系列高8倍，并能在U937细胞中以亚微摩尔级的半数抑制浓度（IC）抑制NF-κB的转录活性。
