發(fā)布時(shí)間：2018-04-30 12:30

  本文選題：類風(fēng)濕性關(guān)節(jié)炎 + 脾酪氨酸激酶�。� 參考：《華東理工大學(xué)》2013年碩士論文

【摘要】：類風(fēng)濕性關(guān)節(jié)炎(RA)是一種高致殘、危害嚴(yán)重、難治療的全身性自身免疫疾病,目前尚無特效治療藥物。非受體型脾酪氨酸激酶(Syk)被證明與類風(fēng)濕性關(guān)節(jié)炎相關(guān)的關(guān)鍵介質(zhì)的釋放、信號通路的傳導(dǎo)以及相關(guān)細(xì)胞家族的激活有密切聯(lián)系。Syk被視為是最具有前景的治療RA的靶標(biāo)。我們課題組前期通過盲篩得到一個(gè)具有較好Syk抑制活性的化合物A01,基于A01的結(jié)構(gòu),我們設(shè)計(jì)合成了46個(gè)雜環(huán)取代苯乙烯類衍生物(A02-47),其中36個(gè)衍生物(A12-A47)為全新結(jié)構(gòu)。對這46個(gè)衍生物進(jìn)行了Syk抑制活性測試,結(jié)果顯示,有27個(gè)目標(biāo)化合物對Syk有較強(qiáng)的抑制活性,半數(shù)有效抑制濃度IC50≤2μM的活性化合物有11個(gè),半數(shù)有效抑制濃度2μMIC50≤10μM的活性化合物有16個(gè),抑制活性優(yōu)于先導(dǎo)化合物A01(IC50=3.2的衍生物有17個(gè),激酶抑制活性最強(qiáng)的衍生物All (IC50=0.39μM)相對于先導(dǎo)物A01活性提高了近10倍。佐劑性關(guān)節(jié)炎成纖維樣滑膜細(xì)胞(AA FLS)增殖抑制活性測試結(jié)果表明,有3個(gè)衍生物(A02、A06和A11)在高濃度(10μM)下,能明顯抑制TNF-α刺激的滑膜細(xì)胞的增生(抑制率30%),并且A06(抑制率=59.95%@10μM)和All(抑制率=61.71%@10μM)抑制AA FLS的異�；罨�增殖作用最為明顯,且表現(xiàn)出良好的濃度依賴性,明顯強(qiáng)于臨床Ⅲ期候選藥物R788(抑制率=36.13%@10μM),這兩個(gè)衍生物的半數(shù)有效抑制濃度估算在5-10μM之間。尤其是All,在分子和細(xì)胞水平這兩個(gè)測試實(shí)驗(yàn)中,均表現(xiàn)出最佳的活性結(jié)果。因此,綜合兩次活性測試結(jié)果,All具有良好的Syk抑制作用及治療RA的潛力,可作為本課題進(jìn)一步研究的對象�；�于生物測試結(jié)果,總結(jié)歸納了雜環(huán)取代苯乙烯類Syk抑制劑的構(gòu)效關(guān)系,為今后進(jìn)一步設(shè)計(jì)Syk抑制劑提供了結(jié)構(gòu)信息,也為開發(fā)具有自主知識產(chǎn)權(quán)的RA治療藥物提供了有益線索。
[Abstract]:Rheumatoid arthritis (RA) is a systemic autoimmune disease with high disability, serious harm and difficult treatment. Non-recipient spleen tyrosine kinase (Syk) has been shown to be the most promising target for the treatment of RA. The release of key mediators, signal transduction and activation of the associated cell family have been shown to be the most promising targets for RA. A compound A01 with good Syk inhibitory activity was obtained by blind screening. Based on the structure of A01, we designed and synthesized 46 heterocyclic substituted styrene derivatives (A02-47N), of which 36 derivatives (A12-A47) were novel. The Syk inhibitory activity of the 46 derivatives was tested. The results showed that 27 target compounds had strong inhibitory activity against Syk, and 11 of them had a half effective inhibitory concentration of IC50 鈮，

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