CN111175410A - N-甲基苯乙胺及其同位素试剂在羧基化合物检测中的应用 - Google Patents
N-甲基苯乙胺及其同位素试剂在羧基化合物检测中的应用 Download PDFInfo
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Abstract
本发明公开了N‑甲基苯乙胺(MPEA)及其同位素试剂(d3‑MPEA)在羧基化合物检测中的应用,以MPEA和d3‑MPEA为标记试剂,结合液相色谱‑质谱联用技术检测生物样本中的羧基化合物。该试剂普适性强,可同时标记短链脂肪酸,中、长链脂肪酸,多羧酸和氨基酸。羧酸经MPEA标记以后,灵敏度可以提高1‑2个数量级,标记效果明显优于已报导的标记试剂,分析通量大大提高。
Description
技术领域
本发明涉及N-甲基苯乙胺(MPEA)及其同位素在羧基化合物检测中的应用,具体涉及一对可以标记各种类型羧基化合物的同位素试剂的开发和使用,属于有机化学和分析化学领域。
背景技术
羧基类代谢物是生命体中一类重要的代谢物,种类较多,如短链脂肪酸,中、长链脂肪酸,多羧酸和氨基酸等。羧基代谢物不仅所含官能团的种类多,化学性质差异较大,而且生物活性也大大不同。同时,这些羧基类代谢物大多来自于不同的代谢路径,并且相互关联。越来越多的报道指出,羧基代谢物与二型糖尿病,肠道代谢疾病,癌症等疾病的发生发展息息相关。因此,建立能够同时分析各种结构的羧基代谢物的方法十分重要。由于多数羧基代谢物不具备易电离基团,在应用较多的质谱检测器如电喷雾电离源(ESI)的质谱上响应较低。
稳定同位素标记技术则可以在一定程度上解决以上问题。但目前报导的标记试剂应用范围较局限,仅仅适合标记一类羧基化合物,要想实现多种类型羧基代谢物的分析检测,需要几种标记试剂联合使用,导致操作复杂,检测通量较低。
发明内容
针对目前存在的问题,本发明选择商品化的MPEA作为唯一的标记试剂,可同时标记短链脂肪酸,中、长链羧酸,多羧酸和氨基酸等多种羧基化合物,并在此基础上,首次合成了相应的同位素试剂d3-N-甲基苯乙胺(d3-MPEA),来辅助生物样本中羧基类化合物的筛查和相对定量。结合LC-MS,建立了一种高灵敏度、高通量的内源性羧基代谢物的分析检测方法。
本发明的技术方案如下:
MPEA及其同位素试剂在羧基化合物检测中用于羧基化合物的标记试剂。
优选地,所述羧基化合物为内源性羧酸。
优选地,所述羧基化合物为短链脂肪酸或中、长链脂肪酸或多羧酸、氨基酸。
优选地,所述MPEA及其同位素试剂用于羧基化合物检测过程包括如下步骤:
(1)以MPEA及其同位素试剂为标记试剂,使之与样品中的羧基化合物反应,得到羧基化合物的标记产物;
(2)将所得标记产物混合后采用液相色谱-质谱联用方法对羧基化合物进行检测分析。
优选地,步骤(1)采用MPEA标记一份样品,在步骤(2)中与MPEA的同位素试剂标记的混合样品在进入质谱分析前混合。
优选地,以三苯基膦和二硫二吡啶为催化剂,使MPEA或者其同位素试剂与羧基化合物反应进行标记。
优选地,所述MPEA同位素包括d3-N-甲基苯乙胺(d3-MPEA)。
进一步地,本发明所提供的技术方案还包括d3-MPEA的制备过程:
(1)将N-(2-苯乙基)乙酰胺:氢化钠:d3-碘甲烷按照1:2:5混合,反应结束后,进行柱层析,洗脱液为石油醚:乙酸乙酯=10:1;
(2)向步骤(1)所得产物中加入10%的盐酸进行回流反应,洗脱液为二氯甲烷:甲醇:三乙胺=15:1:0.16,最终得到d3-MPEA。
反应式如下:
其中(A)d3-MPEA的合成步骤,(B)MPEA和d3-MPEA的标记条件。
本发明提供的一对标记羧基化合物的同位素试剂,可以标记短链脂肪酸,中、长链羧酸,多羧酸和氨基酸,可以提高分析物的灵敏度,实现了高通量分析,同时可以辅助生物样本中羧基代谢物的筛查。
附图说明
利用附图对本发明作进一步说明,但附图中的实施例不构成对本发明的任何限制。
图1为d3-MPEA的表征信息,其中(A)1H NMR图谱,(B)13C NMR图谱;
图2为d3-MPEA的高分辨信息;
图3为代表性的羧基分析物经MPEA和d3-MPEA标记后的二级质谱图,其中图(A)、(C)、(E)、(G)分别MPEA标记的乳酸、反式-11-二十碳烯酸、苹果酸和苯丙氨酸的二级质谱图;(B)、(D)、(F)、(H)分别d3-MPEA标记的乳酸、反式-11-二十碳烯酸、苹果酸和苯丙氨酸的二级质谱图;
图4为MPEA与另外两种标记试剂的比较结果热图;
图5为姜黄素或R-3-羟基丁酸孵育的肝癌细胞中的差异性代谢物的火山图。
具体实施方式
通过以下详细说明结合附图可以进一步理解本发明的特点和优点。所提供的实施例仅是对本发明方法的说明,而不以任何方式限制本发明揭示的其余内容。
实施例1:MPEA和d3-MPEA在短链羧酸的检测应用
d3-MPEA的合成:
第一步:无水无氧条件下,在装有1.84mmol的N-(2-苯乙基)乙酰胺的容器中加入10mL无水四氢呋喃,搅拌至溶解,然后加入氢化钠(3.68mmol)搅拌45min。滴加碘甲烷-d3(9.19mmol)后,反应过夜。将四氢呋喃真空旋干,然后用二氯甲烷和水进行液液萃取。连续萃取三次,无水硫酸钠干燥,合并有机相并浓缩,然后进行柱层析,洗脱液为石油醚:乙酸乙酯=10:1。最终得172.4mg油状液体。
第二步:将上述所得中间体用3mL乙二醇溶解,加0.2mL 10%稀盐酸,回流24h。反应结束后,将溶剂旋转蒸发,然后用饱和碳酸氢钠溶液调pH至强碱性,再用二氯甲烷进行液液萃取。连续萃取三次,无水硫酸钠干燥,合并有机相并浓缩,然后进行柱层析,洗脱液为二氯甲烷:甲醇:三乙胺=15:1:0.16。最终得63.1mg油状液体。1H谱和13C谱在SI中(如图1所示)。d3-MPEA的高分辨精确分子量为139.1305Da(如图2所示)。
实施例2:标记效果
样品分析所使用的仪器为UPLC-ESI-LTQ-Orbitrap MS质谱。质谱系统为ThermoFisher公司的LTQ/Orbitrap XL ETD质谱(Waltham,MA,USA)配有ESI离子源。数据采集和分析软件为Thermo Xcalibur 2.1Software version。液相系统为Dionex Ultimate3000RSLC色谱仪(Thermo Scientific,Sunnyvale,CA,USA),配有LPG-3400A四元梯度泵内置在线脱气机、WPS-3000SL自动进样器、TCC-3000柱温箱。色谱柱型号为Waters ACQUITYUPLC BEH C18(2.1×100mm,1.7μm),色谱柱温度为40℃。0.1%甲酸水溶液(A相)和ACN(B相)作为流动相进行色谱分析,色谱梯度为:0-5min 10%B,5-42min 10%-90%B,45-58min90%B,58-60min 10%B,流速为0.4mL/min。
我们挑选了几种居于代表性的羧基化合物来考察该衍生化反应。其中,羧酸标准品的浓度为100ng/mL,反应溶剂为200μL乙腈,在60℃下反应30分钟,然后接色谱柱进高分辨质谱分析,进样体积为5μL。实验结果表明,各种类型的羧基代谢物均可以较好地被MPEA标记(如图3所示),实现了高通量分析。
然后,在上述反应条件下,我们考察了MPEA标记反应的衍生化效率,发现各类羧基代谢物的标记效率均>95%(如表1所示),说明标记效率较高。
表1.羧基化合物经MPEA标记后的转化率
接着,对羧酸标记前后的灵敏度进行了考察,然后考察了羧基代谢物标记前后的检测限(LODs),发现各类羧基代谢物经MPEA标记以后,灵敏度都有所提高。其中,短链脂肪酸和多羧酸响应较差,经MPEA标记以后,检测灵敏度可以提高两个数量级。中、长链羧酸和氨基酸本身质谱响应较好,但检测灵敏度仍可提高一个数量级(如表2所示)。
表2.羧基化合物经MPEA标记前后的灵敏度
实施例3:与已报导的试剂标记效果的比较
为了进一步评估MPEA的标记效果,我们选择了另外两种文献报导的灵敏度较高的衍生化试剂来加入比较,分别为:N,N-二甲基乙二胺(DMED)和N-4-甲氨基苄基苯胺(4-AMBA)。实验结果以热图的形式如图4展示,颜色越深,说明质谱信号越强,标记试剂的效果越优越。结果表明,MPEA对各类羧基化合物的标记效果明显优于DMED和4-AMBA。
实施例4:MPEA和d3-MPEA在生物样品中的应用
我们结合稳定同位素标记策略和液相色谱质谱联用技术,将该衍生化反应应用于肝癌细胞中羧基代谢物的筛查和相对定量分析中。姜黄素和R-3-羟基丁酸作为细胞信号调节分子,对癌症具有缓解作用。为此我们培养了分别用姜黄素和R-3-羟基丁酸孵育过的肝癌细胞和正常对照组,来筛查潜在的生物标志物。用MPEA标记一份肝癌细胞(3.0×106个),取正常对照组、姜黄素组和R-3-羟基丁酸组中的各一部分细胞进行混合,然后用d3-MPEA进行标记,作为内标在进入质谱分析前加入来进行相对定量。借助相关软件进行数据的抽提和匹配,按照分子量相差3d(三个氘原子)来确定检测到的代谢物,然后根据所得代谢物的轻重标强度,计算轻重标的比值,得到相对含量。实现结果显示,在肝癌细胞中共检测到418种羧基代谢物(包括短链脂肪酸,中、长链脂肪酸,多羧酸和氨基酸),其中,姜黄素组有137种p<0.05,含量变化2倍以上的羧基代谢物;R-3-羟基丁酸组有114种p<0.05,含量变化2倍以上的羧基代谢物。通过比较两组数据,我们发现相似度较高,说明这些差异性代谢物不是由姜黄素或R-3-羟基丁酸自身在肝癌细胞中发生代谢产生的,姜黄素和R-3-羟基丁酸对肝癌细胞具有相似的抑制作用。我们以火山图的形式呈现出来(如图5所示),浅棕色原形表示含量没有发生明显变化的代谢物,深棕色正方形表示含量降低的代谢物,黑色三角形表示含量升高的代谢物)。以上结果表明MPEA/d3-MPEA说的标记反应稳定可靠,可以用于生物样品中羧基化合物的检测。
以上结合附图揭示了本发明优选的具体实施方式和实施例,但是本发明并不局限于上述实施方式和实施例,在不脱离本发明的精神和范围内,当可以作些修改和完善,因此本发明的保护范围当以权利要求书所界定的为准。
Claims (7)
1.N-甲基苯乙胺(MPEA)及其同位素试剂在羧基化合物检测中的应用,其特征在于,是用于羧基化合物的标记试剂。
2.根据权利要求1所述的应用,其特征在于,所述羧基化合物为内源性羧酸。
3.根据权利要求1所述的应用,其特征在于,所述羧基化合物为短链脂肪酸或中、长链脂肪酸或多羧酸、氨基酸。
4.根据权利要求1所述的应用,其特征在于,包括如下步骤:
(1)以MPEA或者对应的同位素试剂为标记试剂,使之与样品中的羧基化合物反应,得到相应的羧基化合物的标记产物;
(2)将所得标记产物混合后,采用液相色谱-质谱联用方法对生物样本中的羧基化合物进行筛查。
5.根据权利要求4所述的应用,其特征在于,步骤(1)采用MPEA标记一份样品,在步骤(2)中与对应的同位素试剂标记的混合样品在进入质谱分析前混合。
6.根据权利要求1所述的应用,其特征在于,以三苯基膦和二硫二吡啶为催化剂,使MPEA或者对应的同位素试剂与羧基化合物反应进行标记。
7.根据权利要求1所述的应用,其特征在于,所述MPEA同位素包括d3-N-甲基苯乙胺(d3-MPEA)。
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