School of Pharmacy, the Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai 264003, PR China; School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China.
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China.
Bioorg Chem. 2023 Mar;132:106360. doi: 10.1016/j.bioorg.2023.106360. Epub 2023 Jan 12.
Excessive inflammation can cause loss of tissue or organ function, leading to a number of chronic diseases and sometimes even death. Traditional treatment strategies for inflammation have mainly involved steroidal and non-steroidal anti-inflammatory drugs, but both have increasingly prominent side effects. Nuclear factor kappa B (NF-κB) inhibitors with anti-inflammatory properties and low toxicity are a new therapeutic strategy for the treatment of inflammatory diseases. To obtain novel NF-κB inhibitors, a series of 3,4-dihydronaphthalen-1(2H)-one derivatives (DHNs 6a-s), 1,4,5,6-tetrahydrobenzo[h]quinazolin-2-amine derivatives (BQAs 7a-c) and 5,6-dihydrobenzo[h]quinazolin-2-amine derivatives (BQAs 8a-p) were designed and synthesized, and characterized by NMR and HRMS. By evaluating toxicity and anti-inflammatory properties, fluorine-substituted 8c showed more potential anti-inflammatory activity and lower toxicity. 8c significantly reduced the phosphorylation of IκBα and p65, thereby inhibiting the NF-κB signaling pathway. In addition, 8c markedly decreased reactive oxygen species (ROS) production and downregulated the expression of NOD-like receptor pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC) and cysteine aspartate protein hydrolase-1 (caspase-1). Therefore, compound 8c is expected to be a candidate compound for NF-κB inhibition and deserves further research and development.
过度的炎症会导致组织或器官功能丧失，从而引发许多慢性疾病，有时甚至导致死亡。传统的炎症治疗策略主要涉及甾体和非甾体抗炎药，但两者的副作用越来越明显。具有抗炎作用和低毒性的核因子 kappa B（NF-κB）抑制剂是治疗炎症性疾病的一种新的治疗策略。为了获得新型 NF-κB 抑制剂，设计并合成了一系列 3,4-二氢萘-1(2H)-酮衍生物（DHNs 6a-s）、1,4,5,6-四氢苯并[h]喹唑啉-2-胺衍生物（BQAs 7a-c）和 5,6-二氢苯并[h]喹唑啉-2-胺衍生物（BQAs 8a-p），并通过 NMR 和 HRMS 进行了表征。通过评估毒性和抗炎特性，氟取代的 8c 表现出更有潜力的抗炎活性和更低的毒性。8c 显著降低了 IκBα 和 p65 的磷酸化，从而抑制了 NF-κB 信号通路。此外，8c 显著减少了活性氧（ROS）的产生，并下调了 NOD 样受体含吡喃结构域蛋白 3（NLRP3）、凋亡相关斑点样蛋白含有 CARD（ASC）和半胱天冬氨酸蛋白酶-1（caspase-1）的表达。因此，化合物 8c 有望成为 NF-κB 抑制的候选化合物，值得进一步的研究和开发。
