CN107056855A - 一种16,17开环孕甾烷糖苷化合物及其应用 - Google Patents
一种16,17开环孕甾烷糖苷化合物及其应用 Download PDFInfo
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Abstract
本发明公开了一种结构式如下式所示的16,17开环孕甾烷糖苷化合物,实验证明该16,17开环孕甾烷糖苷化合物对ConA(伴刀豆蛋白)刺激的Balb/c小鼠脾淋巴细胞增殖有明显的抑制作用,与不加该化合物的对照组相比有显著性差异,这一特性表明该化合物具有作为免疫抑制剂的应用潜力。
Description
技术领域
本发明涉及一个新的16,17开环孕甾烷糖苷化合物及其在制备免疫抑制药物中的应用,特别是在制备治疗器官移植抗排斥反应和自身免疫性疾病的免疫药物中的应用。
背景技术
免疫应答反应本是机体自我保护、自身稳定的一种防御反应,长期抑制这种反应会带来感染和诱发肿瘤等一些严重的后果,这也是目前免疫抑制剂所遇到的一些问题。免疫抑制剂在临床为自身免疫病和器官移植后的排斥反应提供了有效的治疗药物,通常用来抑制器官移植后出现的排异反应,治疗骨髓移植后出现的移植物抗宿主病,或治疗类风湿性关节炎、克隆氏症等自身免疫性疾病,一般会通过药物进行免疫抑制。自身免疫性疾病大多为慢性或进行性疾病需要长期用药,而现有的糖皮质激素(如地塞米松)和免疫抑制剂长期用药普遍存在毒副作用大、使用不方便等缺点,如地塞米松等糖皮质激素类药物、氯霉素类药物、四环素类药物和磺胺类药物等常可导致机体免疫抑制。因此,迫切需要研制一类高效低毒的新型免疫抑制剂,相比于化学治疗,中药作为一种天然产物,具有与人组织相容性质好、副作用小等优点,在免疫抑制剂的研究中越来越受到人们的重视。
思茅藤(Epigynum auritum)是夹竹桃科思茅藤族思茅藤属的一个种,产于云南南部,根据我们前期的研究结果,思茅藤中含有较多结构新颖雄甾烷、C21甾体及其糖苷类化合物。在发现新药先导化合物的兴趣驱动下,我们对这些新化合物进行了大量的生物活性筛选实验,本发明提供的16,17开环孕甾烷糖苷化合物及其作为免疫抑制药物目前尚未见报道。
发明内容
本发明的目的在于提供式Ⅰ所示的孕甾烷糖苷化合物,其为具有药用价值的16,17开环孕甾烷糖苷化合物:
式Ⅰ:16-acetyl pregn-5-ene-20-one-17-ol-3-O-2′-methoxy-6-deoxy-β-D-idopyranose;
Epigynoside D,中文名为16-乙酰基-17-羟基-孕甾烷-5(6)-烯-20-酮3-O-2′-甲氧基-6′-去氧-β-D-艾杜糖苷,俗名为思茅藤苷丁。
本发明的另一目的是将上述思茅藤孕甾烷糖苷类化合物应用在制备免疫抑制药物中。
具体是免疫抑制药物应用在制备自身免疫性疾病的治疗药物中,或应用在制备器官移植抗排斥反应的治疗药物中。
本发明所述应用中还可以加入一种或多种药物上可接受的辅料,所述辅料包括药学领域常规的填充剂、稀释剂、粘合剂、赋形剂、吸收促进剂、填充剂、表面活性剂和稳定剂等,必要时还可加入香味剂、色素和甜味剂等。
本发明所述应用除制成胶囊外,还可以制成丸剂、粉剂、片剂、粒剂、口服液和注射液等多种形式。
本发明中用健康的Balb/c小鼠来制备脾细胞用于试验。脾细胞制备完成后,通过ConA或者LPS进行诱导,同时在试验组加入不同浓度供试化合物,培养72h后,通过CCK-8试剂法分别测定试验组、诱导对照组和未诱导对照组的吸光值,从而评价化合物刺激T细胞或者B细胞增殖的能力;实验结果表明本发明中涉及的孕甾烷糖苷化合物,思茅藤苷丁(epigynoside D)对ConA(伴刀豆蛋白)刺激的Balb/c小鼠脾淋巴细胞增殖有明显的抑制作用,与不加该化合物的对照组相比有显著性差异(p<0.05)。
具体实施方式
下面通过实施例对本发明作进一步详细说明,但本发明的内容并不局限于此,本实施例中方法如无特殊说明的均按常规方法操作,所用试剂如无特殊说明的采用常规市售试剂或按常规方法配置的试剂。
实施例1:思茅藤苷丁的制备
取风干后的11kg思茅藤茎样品,粉碎后用甲醇回流提取3次,回收溶剂,浓缩至小体积,再用乙酸乙酯萃取3次,浓缩乙酸乙酯层,称重得110g;将乙酸乙酯层部分用大孔吸附树脂D101进行粗分,分别用体积百分比40%、60%、80%、100%的甲醇水溶液进行洗脱总共得到4个部分(Fr.A、Fr.B、Fr.C、Fr.D)。Fr.C(25.7g)通过C18中压柱以体积百分比20%-70%甲醇水溶液进行梯度洗脱得到四个部分Fr.C1-C4。Fr.C2(1.2g)通过Sephadex LH-20(流动相为氯仿:甲醇=1:1)洗脱,紧接着再通过C18中压柱和半制备液相制备得到式Ⅰ的思茅藤苷丁(9.6mg)。经鉴定,式Ⅰ中的化合物为新化合物。
鉴定结果如下:
思茅藤苷丁(epigynoside D)为白色粉末,溶于氯仿甲醇混合液(氯仿:甲醇=1:1)、吡啶等。(c 0.04,MeOH);UV(MeOH)λmax(logε):279.8(2.32),202.4(3.13)nm;IR(KBr)νmax 3425 2934,1735,1709,1374,1251,1068cm–1;HRESIMS m/z 575.3190[M+Na]+(calcd.for C30H48O9Na+,575.3196).1H NMR(MeOD,500Mz)和13C NMR(MeOD,125Mz)见表1;以上数据结合2D NMR分析证实了思茅藤苷丁(epigynoside D)的化学结构式为式Ⅰ所示。
以上所述1个16,17开环孕甾烷糖苷化合物为新的天然有机化合物。
表1:思茅藤苷丁(epigynoside D)的1H NMR和13C NMR数据
实施例2:免疫抑制检测试验
(1)脾细胞悬液的制备
取18~22g的健康BABL/c小鼠放血处死,置于75%酒精中浸泡消毒5分钟,取出,置于无菌托盘中,左侧朝上,在超净台中,用消毒过的镊子夹起腹中部皮毛,作一切口,用另外一套器械剪开腹壁各层,用第三套器械将脾取出,去除脂肪和结缔组织,放入PBS(磷酸盐缓冲液)中,洗去浮血。然后将脾组织移至盛有RPMI 1640不完全培养液的平皿中,用剪刀剪成小块,用无菌注射器芯在200目不锈钢筛网中将脾研碎,用PBS少量多次冲洗,将悬液用移液器转移至15mL离心管中。1000r/min转速离心5min。吸弃上清液,加入3mL红细胞裂解液(Tris-NH4Cl)混匀,静置2min后加入10mL PBS终止反应,离心(1200rpm,5min),去上清,沉淀用5mL PBS洗涤两次,同样条件下离心。沉淀用5mL含10%胎牛血清的RPMI 1640完全培养液悬浮;以0.8%台盼兰活细胞拒染法计数,活细胞数不少于95%,加RPMI 1640完全培养液稀释,调整细胞浓度至1×106个/mL左右。
(2)供试液的制备
精密称取单体化合物2mg,加入适量的DMSO溶解,上样前用PBS稀释至所需浓度,并使得上样后的DMSO终浓度不超过0.1%。
(3)实验分组
正常对照组:100μL脾细胞悬液+10μL RPMI 1640完全培养基+10μLPBS
模型组:100μL脾细胞悬液+10μLConA(终浓度为10μg/mL)+10μLPBS
样品组:100μL脾细胞悬液+10μLConA(终浓度为10μg/mL)+10μL样品
96孔板中,每孔加入淋巴细胞悬液(1×106个/mL)100μL,ConA 10μL(终浓度为10μg/mL),不同浓度试药化合物稀释液10μL(终浓度分别为12.5、25、50μg/mL),地塞米松也做三个对应的浓度组,正常对照组孔分别用10μL的1640完全培养液(含10%胎牛血清)和10μL的PBS补齐,每个浓度组设4个平行。
(4)培养:置于37℃,5%CO2培养箱内培养72小时。
(5)CCK-8法测定细胞OD值
培养72小时后,每孔中加入10μL的CCK-8试剂(碧云天),置于37℃,5%CO2培养箱内继续培养4小时后,在450nm处测定每孔的吸光值以计算细胞增殖情况,并按下式计算刺激指数(SI):
SI(刺激指数)=加有丝分裂原培养物的OD值/不加有丝分裂原培养物的OD值
(6)数据处理
实验数据OD值采用“平均数±标准差”来表示,数理统计及方差分析工作采用Origin软件完成。
(7)实验结果
表2:思茅藤苷丁对ConA刺激的Balb/c小鼠脾淋巴细胞增殖的刺激指数
本发明式Ⅰ中思茅藤苷丁(epigynoside D)在浓度为12.5、25、50μM时的刺激指数分别为2.93,2.34,2.02;显著性分析表明,中浓度和高浓度组与模型组相比有显著性差异(P<0.05)
阳性对照结果为:
表3:地塞米松对ConA刺激的Balb/c小鼠脾淋巴细胞增殖的刺激指数
地塞米松在浓度为12.5、25、50μM时的刺激指数分别为1.62,1.41,1.21;
显著性分析表明,各浓度组与模型组相比有显著性差异(P<0.05)。
实验结果表明,思茅藤苷丁(epigynoside D)在浓度为25μM时具有免疫抑制活性。
Claims (4)
1.结构式如式Ⅰ所示的16,17开环孕甾烷糖苷化合物:
式Ⅰ:16-乙酰基-17-羟基-孕甾烷-5(6)-烯-20-酮3-O-2′-甲氧基-6′-去氧-β-D-艾杜糖苷。
2.权利要求1中所述的16,17开环孕甾烷糖苷化合物在制备免疫抑制药物中的应用。
3.根据权利要求2所述的应用,其特征在于:免疫抑制药物为自身免疫性疾病的治疗药物。
4.根据权利要求2所述的应用,其特征在于:免疫抑制药物为器官移植抗排斥反应的治疗药物。
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