Abstract：
The progress of organicsyntheticmethod can promote late-stage lead compound modification and novel active compound discovery. Molecular editing technology in the field of organic synthesis, including peripheral and skeletal editing, facilitates rapid access to molecular diversity of a lead compound. Peripheral editing of CH bond activation is gradually used in lead optimization to afford novel active scaffolds and chemical space exploitation. To develop oridonin derivatives with high anti-inflammatory potency, novel oridonin sulfamides had been designed and synthesized by a scaffoldhopping strategy based on a visible-light photocatalysis peripheral editing. All novel compounds revealed measurable inhibition of IL-1β and low cytotoxicity in THP-1 cells. The docking study indicated that the best active compound ZM640 was accommodated in thebinding site of NLRP3 with two hydrogen bond interaction. These preliminary results confirm that α, β-unsaturated carbonyl of oridonin is not essential for NLRP3 inhibitory effect. This new oridonin scaffold has its potential to be further developed as a promising class of NLRP3 inhibitors.
摘要：
有机合成方法的进展可以促进后期铅化合物的改性和新型活性化合物的发现。有机合成领域的分子编辑技术，包括外围和骨骼编辑，促进快速获得先导化合物的分子多样性。CH键活化的外围编辑逐渐用于铅优化，以提供新型活性支架和化学空间开发。开发具有高抗炎效力的冬凌草甲素衍生物，新型冬凌草甲素磺酰胺是通过基于可见光光催化外周编辑的支架跳跃策略设计和合成的。所有新化合物都显示出可测量的IL-1β抑制和THP-1细胞中的低细胞毒性。对接研究表明，最佳活性化合物ZM640通过两个氢键相互作用被容纳在NLRP3的结合位点。这些初步结果证实了α，冬凌草甲素的β-不饱和羰基对于NLRP3抑制作用不是必需的。这种新的冬凌草甲素支架具有作为一类有前途的NLRP3抑制剂进一步开发的潜力。
