一种新型酯类甾体化合物的设计合成及其抗炎生物活性的研究
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摘要
目的:设计合成一种具有抗炎活性的新型酯类甾体化合物。方法:以孕烯醇酮为基本母核的取代醛和酮通过Clasien-Schmidt缩合反应合成查尔酮衍生物后和反式肉桂酸反应合成具有酯类结构的甾体化合物;其结构通过核磁氢谱、质谱、红外图谱确证;以RAW 264.7巨噬细胞为实验细胞株,通过硝酸还原酶法检测NO的浓度来评估其抗炎活性。结果:共设计合成3个新型酯类甾体化合物(b1~3),其中b2的抗炎效果最佳(IC_(50)=3.40μmol/L),其抑制脂多糖(LPS)诱导RAW 264.7巨噬细胞产生NO的效果随浓度的增大而增强;b2在体外抑制LPS诱导RAW 264.7巨噬细胞生成NO的效果与地塞米松相当。结论:新型酯类甾体化合物具有抑制炎症介质NO增长的作用,新型酯类甾体化合物b2具有良好的抗炎效果。
Objective: To design and synthesis of a novel ester steroidal derivatives with anti-inflammatory bioactivities. Methods: First, chalcone derivatives were obtained via the base-catalyzed Claisen-Schmidt condensation with corresponding pregnenolone and aromatic aldehydes. Chalcone derivatives with steroids and cinnamic acid reacted in methylene chloride to get ester steroid derivatives containing different substituents at the 17-position. After characterization by infrared(IR), ~1H-NMR, and MS, the target compounds were tested for their inhibitory activities of NO production in activated RAW 264.7 Macrophages to evaluate their antiinflammatory activities. Results: Three ester steroidal derivatives were synthesized, compounds b2 shows the superior anti-inflammatory activities(IC_(50)=3.40 μmol/L). b2 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; b2 almost shows the same effects to dexamethasone on the inhibitory activities of NO production in LPS-activated macrophages. Conclusion: The new ester steroid derivatives b1~3 has the effect of inhibiting the growth of inflammatory mediators NO; Compound b2 shows the best anti-inflammatory effect.
Objective: To design and synthesis of a novel ester steroidal derivatives with anti-inflammatory bioactivities. Methods: First, chalcone derivatives were obtained via the base-catalyzed Claisen-Schmidt condensation with corresponding pregnenolone and aromatic aldehydes. Chalcone derivatives with steroids and cinnamic acid reacted in methylene chloride to get ester steroid derivatives containing different substituents at the 17-position. After characterization by infrared(IR), ~1H-NMR, and MS, the target compounds were tested for their inhibitory activities of NO production in activated RAW 264.7 Macrophages to evaluate their antiinflammatory activities. Results: Three ester steroidal derivatives were synthesized, compounds b2 shows the superior anti-inflammatory activities(IC_(50)=3.40 μmol/L). b2 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; b2 almost shows the same effects to dexamethasone on the inhibitory activities of NO production in LPS-activated macrophages. Conclusion: The new ester steroid derivatives b1~3 has the effect of inhibiting the growth of inflammatory mediators NO; Compound b2 shows the best anti-inflammatory effect.
引文
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[21]LU X,MIN L,WEI J,et al.Heliangin inhibited lipopolysaccharide-induced inflammation through signaling NF-κB pathway on LPS-induced RAW264.7 cells[J].Biomedicine&Pharmacotherapy,2017,88:102-108.
[2]ZHANG Y Y,LIU C,DONG B,et al.Anti-inflamm atory activity and mechanism of surfactin in lipopo lysaccharide-activated macrophages[J].Inflammation,2015,38(2):756-764.
[3]RUIZ-Nú?EZ B,DIJCK-BROUWER D A,MUSKI ET F A.The relation of saturated acids with lowgrade inflammation and cardiovascular disease[J].J Nutr Biochem,2016,36:1-20.
[4]PESIC M,GRETEN F R.Inflammation and cancer:tissue regeneration gone awry[J].Curr Opin Cell Biol,2016,43:55-61.
[5]SUN H J,CAI W W,WANG X,et al.Vaccaria hypap horine alleviates lipopolysaccharide induced inflam mation via inactivation of NFκB and ERK pathways in Raw 264.7 cells[J].BMC Complement Altern Med,2017,17(1):120.
[6]JASTRZEBSKA I,NIEMIROWICZ K,BRZOZO WSKA W I,et al.The synthesis and antifu ngal activ ity of(20S)-3b-acetoxy-5α-pregnane-20,16β-carb olactone against fluconazole-Resistant Candida cells[J].Steroids,2017,118:55-60.
[7]HAMID A A,KAUSHAL T,ASHRAF R,et al.(22β,25R)-3β-Hydroxy-spirost-5-en-7iminoxy-heptanoic acid exhibits anti-prostate cancer activity through caspase pathway[J].Steroids,2017,119:43-52.
[8]JIANG C S,GUO X J,GONG J X,et al.Synthesis and biological evaluation of 21-arylidenepregnenolone derivatives as neuroprotective agents[J].Bioorg Med Chem Lett,2012,22(6):2226-2229.
[9]蔡晓锐,蔡德,朱志伟,等.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[J].汕头大学医学院学报,2017,30(4):193-196.
[10]LIU X K,YE B J,WU Y,et al.Synthesis and Antitu mor Activity of Dehydroepiandrosterone Derivati ves on Es-2,A549,and Hep G2 Cells in vitro[J].Chem Biol Drug Des,2012,79(4):523-529.
[11]BYEON S E,CHUNG J Y,LEE Y G,et al.In vitro and in vivo anti-inflammatory effects of taheebo,a water extract from the inner bark of Tabebuia avellanedae[J].Journal of Ethnopharmacology,2008,119(1):145–152.
[12]CASTARDO J C,PRUDENTE A S,FRREIRA J,et al.Anti-inflammatory effects of hydroalcoholic extract and two biflavonoids from Garcinia gardneriana leaves in mouse paw oedema[J].Journal of Ethnopharmacology,2008,118(3):405–411.
[13]LI W,HUANG H,ZHANG Y,et al.Anti-inflammatory effect of tetrahydrocoptisine from Corydalis impatiens is a function of possible inhibition of TNF-α,IL-6 and NO production in lipopolysaccharide-stimulated peritoneal macrophages through inhibiting NF-κB activation and MAPK pathway[J].European Journal of Pharmacology,2013,715(1-3):62-71.
[14]NIU X F,ZHANG H L,LI W F,et al.Anti-inflammatory Effects of Cavidine In Vitro and In Vivo,a Selective COX-2 Inhibitor in LPS-Induced Peritoneal Macrophages of Mouse[J].Inflammation,2015,38(2):923-933.
[15]BASKARAN A,CHUA K H,SABARATNAM V,et al.Pleurotus giganteus(Berk.Karun&Hyde),the giant oyster mushroom inhibits NO production in LPS/H2O2 stimulated RAW 264.7 cells via STAT 3and COX-2 pathways[J].BMC Complementary and Alternative Medicine,2017,17:40.
[16]H?M?L?INEN M,LILJA R,KANKAANRANTAH,et al.Inhibition of i NOS expression and NO production by anti-inflammatory steroids Reversal by histone deacetylase inhibitors[J].Pulmonary Pharmacology&Therapeutic,2008,21(2):331-339.
[17]ALDERTON W K,COOPER C E,KNOWLES R G.Nitric oxide synthases:structure,function and inhibition[J].Biochem J,2001,357(Pt 3):593-615.
[18]BOGDAN C.Nitric oxide and the immune response[J].Nat Immunol,2001,2:907-916.
[19]KORHONEN R,LAHTI A,KANKAANRANTA H,et al.Nitric oxide production and signaling in inflammation[J].Curr Drug Targets,2005,4(4):471-479.
[20]RADOMSKI M W,PALMER R M,MONCADA S.Glucocorticoids inhibit the expression of an inducible,but not the constitutive,nitric oxide synthase in vascular endothelial cells[J].Proc Natl Acad Sci USA,1990,87(24):10043-10047.
[21]LU X,MIN L,WEI J,et al.Heliangin inhibited lipopolysaccharide-induced inflammation through signaling NF-κB pathway on LPS-induced RAW264.7 cells[J].Biomedicine&Pharmacotherapy,2017,88:102-108.