二硫戊环衍生物和类似物的合成及其iNOS/PAF双重抑制剂活性(英文)

Synthesis of Dithiolane Derivatives and Analogues with Dual iNOS and PAF Inhibitory Activities

目的 :研究双重作用的新型抗炎药物。方法 :合成二硫戊环衍生物和类似物 ,研究这些化合物及选择性的PAF受体拮抗剂L6 5 9,989对PAF受体的结合 ,和对IFN γ或LPS诱导的NO生成 ,以及对iNOSmRNA表达的影响。结果 :合成了 4 0个新化合物 ,其中 19个在不同程度上抑制NO生成。选择 3个活性最高的化合物 (2 ,19,2 0 )进行深入研究 ,发现它们能抑制iNOSmRNA的表达 ,其抑制NO生成的效力从高到低依次为 :19,2 0 ,2 ,L6 5 9,989,其拮抗PAF受体的活性从高到低依次为 :L6 5 9,989,2 0 ,2 ,19。L6 5 9,989对NO生成和iNOSmRNA表达无影响。受试物的PAF受体拮抗活性与iNOS抑制活性之间无简单关联。结论 :二硫戊环类化合物是iNOS表达的新型调控剂 ,其中一些具有抑制iNOS的诱导和拮抗PAF受体的双重活性。

AIM:To investigate a new type of dual acting anti-inflammatory agents. METHOD:A group of novel dithiolane derivatives and their analogs were synthesized. The effects of several dithiolane compounds and a highly potent and selective PAF-receptor antagonist, L659,989 on PAF-receptor binding,IFN-γ and LPS-induced NO production and steady state iNOS mRNA expression were determined. RESULT:Among forty new compounds(1～40) synthesized,nineteen compounds were found to inhibit the production of NO at different levels. The three most active compounds(2,19,20) appeared to decrease iNOS mRNA expression. The order of relative potency of the inhibition of NO production from high to low is 19,20,2 , L659,989, while the potency for blocking PAF-receptor from high to low is L659,989,20,2,19 . The PAF antagonist, L659,989 showed no effect on NO production and iNOS mRNA expression. Among the dithiolane derivatives tested,there is also no simple correlation between their PAF-receptor antagonism and iNOS inhibitory activities. CONCLUSION:Dithiolane derivatives and their analogs are a new synthetic chemical class of iNOS expression regulators,some of which have dual biological functions:inhibiting iNOS induction and blocking PAF-receptor. More potent compounds with such dual actions may be useful synthetic therapeutic agents under various conditions such as septic shock and inflammatory disorders where the reduction of both NO production and PAF activity would be desirable.