Design and Synthesis of Novel Purine Analogues as Potential IL-1β Inhibitors Targeting Vascular Inflammation

Proinflammatory cytokine interleukin (IL)-1β is a key mediator of the inflammatory response in atherosclerosis. Targeting IL-1β represents a new approach for the anti-inflammatory therapy of cardiovascular diseases. Based on our previous data demonstrating that cardioprotective 6-piperazinyl purines can effectively inhibit IL-1β release in vascular cells, in this study, we present the synthesis of a next generation of purine analogues bearing either a furoxan moiety as a nitric oxide (NO) donor, or a (methylsulfonyl)thio group, a benzothioamide, or a 5-phenyl-3H-1,2-dithiole-3-thione as putative hydrogen sulfide (H₂S) donor moieties. NO and H₂S are gaseous signaling molecules that can reduce vascular inflammation. The new purine analogues were evaluated for their anti-inflammatory activity by assessing their inhibitory effect on the secretion of lipopolysaccharide (LPS)-induced IL-1β in human aortic smooth muscle cells (HAoSMCs). Our initial findings revealed that compounds bearing a [methylsulfonyl)thio]propanoyl or [methylsulfonyl)thio]hexanoyl group (compounds MK175 and MK169, respectively) could effectively inhibit LPS-induced IL-1β release in HAoSMCs.