一种新型含氮杂环甾体化合物的设计合成及其抗炎生物活性的研究

Synthesis and Evaluation of a New Kind of Nitrogen Heterocyclic Steroid Compounds with Anti-inflammatory Bioactivities

目的:设计合成一种具有抗炎活性的含氮杂环新型留体化合物。方法:以孕烯醇酮为基本母核的取代醛和酮通过ClasienSchmidt缩合反应合成查尔酮衍生物后和氨基硫脲反应环合成具有吡唑啉结构的甾体化合物;其结构通过核磁氢谱、质谱、红外图谱确证;以RAW264.7巨噬细胞为实验细胞株,通过用硝酸还原酶法检测NO的浓度来评估其抗炎活性。结果:共设计合成3个含氮杂环甾体化合物(b1~3),在3个新型含氮杂环甾体化合物中b1抗炎效果最佳(IC_(50)=3.17μmol/L),其抑制LPS(脂多糖)诱导RAW264.7巨噬细胞产生的NO的效果随浓度的增强而增强;b1在体外抑制LPS诱导RAW264.7巨噬细胞生成NO的效果与地塞米松相当。结论:新型含氮杂环留体化合物具有抑制炎症介质NO增长的作用;新型含氮杂环甾体化合物b1具有良好的抗炎效果。

Objective： To design and synthesis of a novel nitrogen heterocyclic steroidal compounds with anti-inflammatory bioactivities. Methods： First, chalcone derivatives were obtained via the base-catalyzed Claisen-Schmidt condensation with corresponding pregnenolone and aromatic aldehydes. Followed by nucleophilic addition of thiosemicarbazide across a,P-unsaturated carbonyl as a second step to obtain target compounds; After characterization by infrared（IR）, 1 H-NMR, and MS, the target compounds were tested for their inhibitory activities of NO production in activated RAW 264.7 Macrophages to evaluate their anti-inflammatory activities. Results： Three nitrogen heterocyclic steroidal derivatives were synthesized,compounds b1 shows the superior anti-inflammatory activities（IC_（50）=3.17μmol/L） compared with b2 and b3;b1 has a concentration dependency in inhibiting NO produced by LPS-activated RAW 264.7 Macrophages, and the effect of NO production decreases with increasing concentration;bl almost shows the same effects to dexamethasone on the inhibitory activities of NO production in LPS-activated macrophages. Conclusion： The new nitrogen-containing heterocyclic steroid compound b has the effect of inhibiting the growth of inflammatory mediators NO; Compound b 1 shows the best anti-infla mmatory effect in b1~3.