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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
1,4,5,6-Tetrahydrobenzo[2,3]oxepino[4,5-d]pyrimidine derivatives as anti-neuroinflammatory agents: Design, synthesis,
De-Li Xia1, Yu Chen1, Guang-Sen Xu1
1School of Pharmacy, the Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Shandong Provincial Key Laboratory of Membrane Receptor Target Discovery and Lead Drug Screening, Shandong Medical and Pharmaceutical University, Yantai 264003, PR China.
Abstract:
Neuroinflammation has been identified as a causative factor of multiple neurological diseases. Microglia cells are the primary immune cells that regulate the neuroinflammation response. Hence, twenty-six 1,4,5,6-tetrahydrobenzo[2,3]oxepino[4,5-d]pyrimidine derivatives (BPMs) as anti-inflammatory molecules were designed and synthesized through two-step structural modification on the basis of the structure of the initial hit DL-1 from an in-house chemical library. The most potent compound 10a, modified with piperidine and benzamidine hydrochloride, was identified as the optimal candidate with strong anti-neuroinflammatory efficacies with no evident cellular cytotoxicity. Treatment with 10a efficiently attenuated LPS-induced neuroinflammation in microglia, as evidenced by reduced levels of inflammatory mediators, including ROS, NO, IL-1β, IL-6, TNF-α, and IL-18. Mechanistic studies demonstrated that 10a inhibits the NF-κB/NLRP3 pathway by suppressing phosphorylation of p65 and IκBα and decreasing NLRP3 protein expression. These results provide a promising strategy and good starting point for the development of a therapeutic candidate for neuroinflammation-related diseases.
