CN106085415B - 一种小檗碱亲和标记探针及其制备方法 - Google Patents

一种小檗碱亲和标记探针及其制备方法 Download PDF

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CN106085415B
CN106085415B CN201610562804.XA CN201610562804A CN106085415B CN 106085415 B CN106085415 B CN 106085415B CN 201610562804 A CN201610562804 A CN 201610562804A CN 106085415 B CN106085415 B CN 106085415B
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田平芳
尹鸣
尹一鸣
李映
曹哲统
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Abstract

一种小檗碱亲和标记探针及其制备方法属于生物检测领域。探针包括:活性基团小檗碱、亲和标记基团、连接部位和报告基团四个功能部位。此小檗碱标记探针与靶蛋白作用后,通过光照使亲和标记基团分解,得到活泼的中间体,从而使探针分子与靶点蛋白共价结合,将靶标蛋白调出,确定靶标蛋白。本探针可用于小檗碱与机体、组织、细胞、菌体作用后靶标的探究。此小檗碱亲和标记探针基于活性小分子与靶标蛋白之间的作用,具有方便、准确、灵敏高、适用于非模式生物的特点,其灵敏度明显高于蛋白质光谱探针、RNA干扰。小檗碱亲和标记探针可用于钓取人体、实验动物和微生物中的靶标蛋白,具有重要生物和医学应用价值。

Description

一种小檗碱亲和标记探针及其制备方法
技术领域
本发明涉及一种高灵敏小檗碱亲和标记探针及其制备方法,属于生物技术、生物检测领域。
背景技术
小檗碱为异喹啉类生物碱,是中药黄连、黄柏等的主要成分。文献表明,小檗碱对痢疾杆菌、大肠杆菌、肺炎双球菌、金黄葡菌球菌等有抑制作用,传统主要用于治疗肠道感染及菌痢等。现代药理学证明小檗碱具有显著的抗心力衰竭、抗心律失常、降低胆固醇、抗制血管平滑肌增殖、改善胰岛素抵抗、抗血小板、抗炎、抗癌等作用,且具有显著的耐药性消除作用,因而在心血管系统、抗炎、神经系统疾病方面具有广阔的应用前景,堪称老药新用的典范。小檗碱对部分真菌病害有抑制作用,2013-2014年期间先后有十四家农药企业申请以小檗碱为主要成分防治植物病原真菌的田间试验,主要用于褐腐病、白粉病、灰霉病、晚疫病等病虫害的防治,说明小檗碱作为农药杀菌剂已被越来越多的科技工作者所关注。
作为传统抗细菌药物,小檗碱的抗细菌机制研究较多。有报道认为小檗碱与蛋白或膜蛋白的非特异性结合是其抗菌的主因,研究发现小檗碱对G+菌的stortase酶、转肽酶的活性有很强抑制作用,推断抑制上述酶的活性是小檗碱的抗菌机制之一。90%的药物靶标为蛋白质,小分子药物靶标绝大多数是蛋白质,如酶、受体、离子通道等。确定靶蛋白的方法有很多,包括基因芯片技术、生物信息学、化学基因组学、亲和色谱技术等,但这些技术大都适用于模式生物细胞中靶标的发现。对于非模式生物,小檗碱亲和标记探针是发现未知靶蛋白的有效手段,本发明一种高灵敏小檗碱亲和标记探针是活性小分子探针,它基于活性小分子与靶标蛋白之间的作用,具有方便、准确的特点。经大量查询,未发现以亲和标记探针研究小檗碱作用靶点的文献。
发明内容
小檗碱是一种异喹啉类生物碱,其分子结构如下:
一种小檗碱亲和标记探针,其特征在于:探针包括活性基团、亲和标记基团、连接部位、报告基团四部分;是活性基团为小檗碱;亲和标记基团是氮苯、氮杂苯、苯基叠氮、苯甲基三氟双吖丙啶、二苯甲酮、苯并三哇类、邻羟基二苯甲酮类、Tinuvin 400,Cya-sorb UV1164,Tinuvin 1577中的一种或几种。
报告基团与亲和基团连接基团为R1,R1为三乙二醇、聚乙二醇、C原子数n=5-7的长链烷烃;亲和基团与小檗碱活性基团连接基团为R2,R2为乙二胺,乙酰胺,乙胺,C原子数n=2-4的长链烷烃等中的一种或几种。
报告基团为:多肽标签、荧光素如FITC、Rhodamine、FAM、BODIPY、Cy3、Cy5以及生物素等。
探针与靶点蛋白接触后,在紫外光照射下,(照射距离3-5cm,震荡下光照15-30min,光照波长300-375nm。)亲和标记基团分解,得到活泼的中间体,中间体可与靶点蛋白共价结合,将靶标调出。其基本结构如下(其中报告基团以生物素为例,亲和基团以苯甲基三氟双吖丙啶为例,连接基团为R1,R2):
部分化合物结构如下:
其中Y1制备反应路线如下:
以小檗碱(berberine,BBR)A1为起始原料,经真空裂解得到小檗红碱A2,A2与卤代物R2X反应,进行连接臂的延长得到A3,然后将A3与经过以B2为起点制得的B1反应,得到小檗碱亲和标记探针BBR-BP。
其中B1为报告基团与亲和基团连接物。
通常,小檗碱A1经高温反应制得A2在真空下进行,用乙醇或者水进行重结晶,得到A2,A2酚羟基成醚一般在N-N二甲基甲酰胺(DMF)、丙酮、乙腈中,以碳酸钾、碳酸铯、氢氧化钠作为缚酸剂,反应温度为20-90℃,反应时间为2-22h,反应结束后,一般用乙酸乙酯,二氯甲烷,氯仿等溶剂萃取,经饱和食盐水洗,真空除溶剂,硅胶柱层析得到A3,产物用NMR等方法证明。
A3与B1的连接,一般在二氯甲烷,DMF或混合溶剂,加入催化剂二环己基碳二亚胺(DCC),4-二甲氨基吡啶(DMAP),1-羟基苯并三唑(HoBt)等进行缩合,反应温度0-80℃,反应时间为1-28h,反应完成后一般真空除溶剂,用乙酸乙酯、乙醚、二氯甲烷等溶剂萃取,洗涤,除溶剂,硅胶柱层析得到目标探针BBR-BP。产物通过NMR,MS等方法证明。
这种高灵敏小檗碱亲和标记探针及其制备方法,其特征是小檗碱亲和标记探针用于研究或探讨小檗碱作用于人体、动物和微生物的靶标蛋白。
具体实施方式
现结合实例详细说明本发明的技术方案。所有的实例都严格按照上述的制备方法的操作步骤进行操作
实施例1:
小檗红碱A2的制备
9.0g(25mmol)小檗碱于250ml三口烧瓶内,将烧瓶抽真空,于195℃,机械搅拌2h。反应完毕后,将粗产物溶于250ml无水乙醇,过滤出去不溶物。蒸干溶剂,硅胶柱层析,体积比(甲醇:二氯甲烷=1:15),得红色固体(6.35g,19.7mmol),产率78.8%。1HNMR(400MHz,DMSO)δ11.23(s,1H),9.89(s,1H),8.82(s,1H),8.09(d,J=9.0Hz,1H),7.79(d,J=5.3Hz,1H),7.69(d,J=8.9Hz,1H),7.07(s,1H),6.17(d,J=4.3Hz,2H),4.89(t,J=6.1Hz,2H),4.03(s,3H),3.22–3.14(m,2H).HRMS(ESI):计算值C19H16NO4 +322.1079,实测值322.1079.
实施例2:
小檗红碱连接臂A3的制备:
100ml单口烧瓶中,化合物A2(0.5g,1.55mmol)溶于35ml乙腈中,加入带保护的溴乙胺(R2X)(433.05mg,1.93mmol,1.3equiv),碳酸铯(970.943mg),氢氧化钠(60mg),60℃磁力搅拌16h,反应结束后,过滤,滤液蒸干溶剂,硅胶柱层析,体积比(甲醇:二氯甲烷=1:10),得黄色固体(340mg,0.73mmol),产率49.13%。1H NMR(400MHz,DMSO)δ9.88(s,1H),8.95(d,J=6.9Hz,1H),8.19(d,J=8.9Hz,1H),8.00(dd,J=17.0,9.1Hz,1H),7.80(s,1H),7.11(d,J=14.8Hz,2H),6.18(s,2H),4.95(d,J=17.9Hz,2H),4.34(t,J=5.1Hz,2H),4.03(d,J=14.0Hz,3H),3.41(t,J=11.5Hz,2H),3.22(d,J=5.5Hz,2H),1.40–1.25(m,9H).HRMS(ESI):计算值C26H29N2O6 +465.2026,实测值465.2023.
实施例3:
化合物B3的制备:
于25ml单口烧瓶中,化合物B2(80mg,0.347mmol)溶于10ml无水DMF,加入R1X(132.4mg,0.424mmol),四丁基碘化铵33mg,K2CO364mg,70℃磁力搅拌12h。反应完毕后,向反应液加入15ml水,用乙酸乙酯萃取3次,饱和氯化钠洗。有机相无 水Na2SO4干燥。硅胶柱层析,体积比(乙酸乙酯:石油醚=1:5),得黄色油状物B3(0.112g,0.243mmol),产率69.83%。1H NMR(400MHz,CDCl3)δ10.47(s,1H),7.84(d,J=8.1Hz,1H),6.86(d,J=8.2Hz,1H),6.75(s,1H),4.98(s,1H),4.28–4.22(m,2H),3.74–3.67(m,2H),3.66–3.60(m,2H),3.57–3.49(m,2H),3.31(d,J=5.0Hz,2H),1.43(s,9H).
实施例4:
化合物B4的制备:
于5ml单口烧瓶中,加入化合物B3(0.1g,0.217mmol),溶于1ml二氯甲烷中,在冰水浴下滴加三氟乙酸-二氯甲烷1ml(体积比TFA:CH2Cl2=1:1),磁力避光搅拌1h。反应完毕后,蒸干溶剂,将残余物溶于1mlDMF中,后向反应液中加入三乙胺98μl,加入溶于1mlDMF中的报告基团生物素(81.38mg,238.39μmol,1.1equiv),磁力搅拌过夜。反应完毕后,蒸干溶剂,将残渣溶于甲醇与二氯甲烷中,分别用1N氢氧化钠洗,饱和氯化钠溶液洗,1N盐酸洗,饱和氯化钠溶液洗,无水硫酸钠干燥。硅胶柱层析,体积比(甲醇:二氯甲烷=1:10)。得无色固体B4(68mg,115.72μmol),产率53.4%。1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.09(d,J=20.0Hz,2H),5.64(s,1H),5.54(s,1H),5.37(s,1H),4.59(m,1H),4.30(m,2H),4.07(m,1H),3.71(d,J=39.9Hz,4H),3.49(m,J=17.4Hz,5H),3.32–3.07(m,4H),2.13(m,2H),1.94(m,1H),1.70(m,J=8.1Hz,3H),1.25(m,2H).HRMS(ESI):计算值C25H32F3N5O6S[M+H]+587.2025,实测值[M+H]+588.2082.
实施例5:
Y1,BBR-BP的制备:
取10ml单口烧瓶,将化合物B1(42.86mg,71.01μmol)溶于3ml DMF中,加入B1摩尔数的百分之一量的DCC,搅拌0.5h,后将化合物A3(50mg)溶于3ml DMF中,加入到反应液中,并加入适量(B1摩尔数的百分之一量的DCC,)DMAP,磁力搅拌室温搅拌10h至反应完全。蒸干溶剂。硅胶柱层析,体积比(甲醇:二氯甲烷=1:10),得产物BBR-BP(34.6mg,34.32μmol).产率48.33%。HRMS(ESI):计算值C48H54F3N8O11S+1007.3585,实测值1007.3569。
实施例6:
小檗碱亲和标记探针活性测定:制备含有小檗碱亲和标记探针的PDA培养基,该探针终浓度分别为1.7、3.3、6.7、13.3、26.7μg/mL,并有一组PDA培养基加入等量的无菌水作为空白对照组,每组浓度设置三个重复。另外设置同浓度小檗碱作对照。取出培养好的桃褐腐菌(Monilinia fructicola)平板,无菌操作条件下,用打孔器打取菌块,每次打取菌块直径约为8mm,接种菌块贴到各个培养基平板的中心处(菌丝朝下),待菌饼贴好后(培养约24h)倒置平板,27℃恒温培养箱培养。用十字交叉法测定菌径大小,每隔24h记录一次生长情况,据此通过公式计算抑制率。
菌落直径(mm)=测量菌落直径平均值(mm)-8
杀菌剂对桃褐腐菌抑制率(%)=(空白对照组菌落直径-带探针组菌落)/空白对照组菌落直径×100%
选取84h的生长情况进行分析,小檗碱亲和探针对桃褐腐菌有明显的抑菌作用,随着小檗碱探针浓度的增大,对桃褐腐菌的抑制作用越明显,在小檗碱探针浓度达26.7μg/mL时,抑菌率89.6%,小檗碱探针EC50=6.64μg/mL,见表1。
表1小檗碱亲和探针对桃褐腐菌菌丝生长的抑制(84h)
选取84h的生长情况进行分析,小檗碱对桃褐腐菌有明显的抑制作用,随着小檗碱浓度的增大,对桃褐腐菌的抑制作用越明显,在小檗碱浓度达26.7μg/mL时,抑菌率达87.6%,小檗碱EC50=8.32μg/mL,见表2。
表2小檗碱对桃褐腐菌菌丝生长的抑制(84h)
由表1、2可知,小檗碱亲和探针对桃褐腐菌抑制作用与小檗碱没有明显区别,说明此小檗碱亲和探针与小檗碱具有生物活性,可用于用于钓取人体、实验动物和微生物中的靶标蛋白。

Claims (2)

1.一种小檗碱亲和标记探针,其特征在于:结构是下列任一化合物:
2.制备如权利要求1所述的探针方法,当以生物素为报告基团,苯甲基三氟双吖丙啶为亲和标记基团,包括如下步骤:以小檗碱A1为起始原料,经真空裂解得到小檗红碱A2,A2与溴乙胺反应,其中一端氨基被保护R2X进行连接臂的延长得到A3,然后将A3与经过B2与R1X反应的产物为起点制得的B1反应,得到小檗碱亲和标记探针BBR-BP;
R1X结构为
R2X结构为
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