College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.
College of Pharmacy, Kyunghee University, Seoul 02447, Republic of Korea.
Bioorg Chem. 2020 Mar;96:103611. doi: 10.1016/j.bioorg.2020.103611. Epub 2020 Jan 22.
In our previous study, a PPAR-γ agonist (+)-(R,E)-6a1 was elaborated as an anti-inflammatory lead. However, in silico analysis showed that (+)-(R,E)-6a1 lacks key hydrogen bonding with Tyr of PPAR-γ LBD (ligand binding domain). To facilitate additional hydrogen bonding with Tyr, a more polar head group was introduced to the structure of (+)-(R,E)-6a1, and we also attempted to synthesize enzymatically stable derivatives. Of the synthetic derivatives, compound (+)-(R,E)-5f showed highest PPAR-γ transcriptional activity and reasonable metabolic stability. Compound (+)-(R,E)-5f suppressed the expression of pro-inflammatory mediators such as inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α). Reduction of nitric oxide (NO), and ROS was also observed. Compound (+)-(R,E)-5f was found to suppress the NF-κB pathway by inhibiting phosphorylation of IKK (IκB kinase), and this may lead to subsequent inhibition of IκBα (inhibitor of NF-κBα) phosphorylation and inhibition of NF-κB activation. These results indicate that (+)-(R,E)-5f exerts anti-inflammatory activity via NF-κB pathway inhibition, and may serve as a potential anti-inflammatory lead.
在我们之前的研究中，我们详细阐述了一种 PPAR-γ 激动剂 (+)-(R,E)-6a1，作为一种抗炎先导化合物。然而，计算机模拟分析表明，(+)-(R,E)-6a1 缺乏与 PPAR-γ LBD（配体结合域）中的 Tyr 形成关键氢键。为了促进与 Tyr 的额外氢键形成，我们在 (+)-(R,E)-6a1 的结构中引入了一个更极性的头基，并且还尝试合成酶稳定的衍生物。在所合成的衍生物中，化合物 (+)-(R,E)-5f 显示出最高的 PPAR-γ 转录活性和合理的代谢稳定性。化合物 (+)-(R,E)-5f 抑制了诱导型一氧化氮合酶（iNOS）、环氧化酶-2（COX-2）、白细胞介素 6（IL-6）和肿瘤坏死因子-α（TNF-α）等促炎介质的表达。还观察到一氧化氮（NO）和 ROS 的减少。化合物 (+)-(R,E)-5f 通过抑制 IKK（IκB 激酶）的磷酸化来抑制 NF-κB 途径，这可能导致随后抑制 IκBα（NF-κBα 抑制剂）的磷酸化和 NF-κB 激活的抑制。这些结果表明，(+)-(R,E)-5f 通过抑制 NF-κB 途径发挥抗炎活性，并且可能成为一种有潜力的抗炎先导化合物。
