CN112266410A - 一类腺苷二磷酸核糖多肽及其合成方法和应用 - Google Patents

一类腺苷二磷酸核糖多肽及其合成方法和应用 Download PDF

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CN112266410A
CN112266410A CN202011066434.3A CN202011066434A CN112266410A CN 112266410 A CN112266410 A CN 112266410A CN 202011066434 A CN202011066434 A CN 202011066434A CN 112266410 A CN112266410 A CN 112266410A
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adenosine diphosphate
ribose
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李凌君
朱安莲
尤延博
白莉莉
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Henan Normal University
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Abstract

本发明公开了一类腺苷二磷酸核糖多肽及其合成方法和应用，属于腺苷二磷酸核糖多肽的合成技术领域。本发明的技术方案要点为：一类腺苷二磷酸核糖多肽，其结构式为：

Description

一类腺苷二磷酸核糖多肽及其合成方法和应用
技术领域
本发明属于新型腺苷二磷酸核糖多肽的合成技术领域，具体涉及一类腺苷二磷酸核糖多肽及其合成方法和应用。
背景技术
腺苷二磷酸核糖多肽(ADP-核糖多肽)是研究蛋白质ADP-核糖化的重要工具，其参与一系列重要的生理和病理过程，例如DNA的修复和复制、染色体结构的调节和转录、细胞分化等过程。设计合成ADP-核糖多肽对于研究蛋白质ADP-核糖化的生理功能，发现新的药物作用靶点及药物先导化合物设计均具有重要意义。
ADP-核糖基化合物的传统合成路线通常以碱修饰核苷为起始原料，随后进行磷酸化反应，该合成路线需要各种核苷酸作为反应物在苛刻的反应条件下进行反应。此外，反应中得到多种核苷酸中间体具有高极性和高水溶性，这使的对这些化合物的纯化和后处理过程非常繁琐且效率较低。因此，开发新的简洁的合成路线，有效地合成结构多样的ADP-糖基化合物非常重要且具有挑战性。
发明内容
本发明解决的技术问题是提供了一类腺苷二磷酸核糖多肽及其合成方法，该方法合成的腺苷二磷酸核糖多肽能够用于作为蛋白质ADP-核糖化模拟物。
本发明为解决上述技术问题采用如下技术方案，一类腺苷二磷酸核糖多肽，其特征在于其结构式为：
Figure BDA0002713882170000011
其中R为多肽，X＝H或Br，Y＝磷酸或H，三氮唑与核糖间的糖苷键为α-构型。
本发明所述的包含腺苷二磷酸核糖多肽的合成方法，其特征在于具体过程为：以烟酰胺腺嘌呤二核苷酸(NAD)和叠氮化合物为原料制备α-型ADP-核糖叠氮(α-ADPr-N3)；以α-型ADP-核糖叠氮和包含末端炔基的多肽为原料制备腺苷二磷酸核糖多肽。
本发明所述的腺苷二磷酸核糖多肽的具体合成路线为：
Figure BDA0002713882170000021
本发明提供了一种以商品化NAD为原料，立体化学控制地两步合成腺苷二磷酸核糖多肽的新方法，该方法具有以下有益效果：(1)反应特异性好，选择性高；(2)反应步骤简单，无需繁琐的保护脱保护程序；(3)反应过程以水为溶剂，清洁高效，生物兼容性好；(4)可以方便地实现腺苷二磷酸核糖多肽的结构多样化修饰。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
Figure BDA0002713882170000022
首先将NAD(0.1mmol)溶于水，叠氮钠(2.0mmol)溶于水中，乳酸(2.0mmol),二乙醇胺(2.0mmol)等比例混合。取10mL干净的圆底烧瓶，依次加入NAD(0.1mmol)和叠氮钠(2.0mmol)水溶液和等比例混合的乳酸(2.0mmol)和二乙醇胺(2.0mmol)，将反应瓶放入90℃的水浴中快速搅拌反应，反应1h后取样进行HPLC检测。检测波长254nm，流动相为TEAB和乙腈，梯度洗脱，0-10min乙腈由体积分数0％-35％，10-20min乙腈由体积分数35％-60％，在12-20min检测到产物峰，用制备液相分离得到产物。
1H NMR(600MHz,D2O)δ8.64(s,1H),8.44(s,1H),6.18(d,J＝5.4Hz,1H),5.46(d,J＝4.8Hz,1H),4.76(d,J＝5.2Hz,1H),4.55-4.54(m,1H),4.41(s,1H),4.30-4.22(m,5H),4.09-4.05(m,2H).31P NMR(162MHz,D2O)δ-11.31(s)，-11.40(s).MALDI-TOF-MS:m/zC15H22N8O13P2[M+H]+585.34,found 585.35。
实施例2
Figure BDA0002713882170000031
首先将8-Br-NAD(0.1mmol)溶于水，叠氮钠(2.0mmol)溶于水中，乳酸(2.0mmol),二乙醇胺(2.0mmol)等比例混合。取10mL干净的圆底烧瓶，依次加入8-Br-NAD(0.1mmol)和叠氮钠(2.0mmol)水溶液和等比例混合的乳酸(2.0mmol)和二乙醇胺(2.0mmol)，将反应瓶放入90℃的水浴中快速搅拌反应，反应1h后取样进行HPLC检测。检测波长254nm，流动相为TEAB和乙腈，梯度洗脱，0-10min乙腈由体积分数0％-35％，10-20min乙腈由体积分数35％-60％，在12-20min检测到产物峰，用制备液相分离得到产物。
1H NMR(400MHz,D2O)δ8.03(s,1H),6.04(d,J＝7.7Hz,1H),5.43(d,J＝4.7Hz,1H),4.74-4.72(m,1H),4.48-4.46(m,1H),4.34-4.33(m,1H),4.28-4.24(m,3H),4.23-4.19(m,2H),4.04(dd,J1＝9.2Hz,J2＝4.9Hz,2H).31P NMR(162MHz,D2O)δ-11.31(s),-11.81(s).MALDI-TOF-MS:m/z C15H21N8O13P2Br[M+2Na-H]+706.96,Found 706.87.IR:-N3:2110.22cm-1。
实施例3
Figure BDA0002713882170000032
首先将烟酰胺腺嘌呤二核苷酸磷酸NADP(0.1mmol)溶于水，叠氮钠(2.0mmol)溶于水中，乳酸(2.0mmol),二乙醇胺(2.0mmol)等比例混合。取10mL干净的圆底烧瓶，依次加入NADP(0.1mmol)和叠氮钠(2.0mmol)水溶液和等比例混合的乳酸(2.0mmol)和二乙醇胺(2.0mmol)，将反应瓶放入90℃的水浴中快速搅拌反应，反应1h后取样进行HPLC检测。检测波长254nm，流动相为TEAB和乙腈，梯度洗脱，0-10min乙腈由体积分数0％-35％，10-20min乙腈由体积分数35％-60％，在12-20min检测到产物峰，用制备液相分离得到产物。
1H NMR(400MHz,D2O)δ8.51(s,1H),8.27(s,1H),6.22(d,J＝4.8Hz,1H),5.39(d,J＝4.8Hz,1H),5.00-4.96(m,1H),4.61(t,J＝5.0Hz,1H),4.38(s,1H),4.26-4.23(m,1H),4.19(d,J＝5.6Hz,2H),3.98-3.96(m,2H).31P NMR(162MHz,D2O)δ3.53(d,J＝6.0Hz),-11.41(d,J＝19.6Hz).MALDI-TOF-MS:m/z C15H23N8O16P3[M-H]-663.04,Found 663.04.IR:-N3:2110.56cm-1。
实施例4
Figure BDA0002713882170000041
首先将环腺苷二磷酸核糖(cADPR)溶于水，叠氮钠(2.0mmol)溶于水中，乳酸(2.0mmol),二乙醇胺(2.0mmol)等比例混合。取10mL干净的圆底烧瓶，依次加入cADPR(0.1mmol)和叠氮钠(2.0mmol)水溶液和等比例混合的乳酸(2.0mmol)和二乙醇胺(2.0mmol)，将反应瓶放入90℃的水浴中快速搅拌反应，反应1h后取样进行HPLC检测。检测波长254nm，流动相为TEAB和乙腈，梯度洗脱，0-10min乙腈由体积分数0％-35％，10-20min乙腈由体积分数35％-60％，在12-20min检测到产物峰，用制备液相分离得到产物。
1H NMR(400MHz,D2O)δ8.03(s,1H),6.04(d,J＝7.7Hz,1H),5.43(d,J＝4.7Hz,1H),4.74-4.72(m,1H),4.48-4.46(m,1H),4.34-4.33(m,1H),4.28-4.24(m,3H),4.23-4.19(m,2H),4.04(dd,J1＝9.2Hz,J2＝4.9Hz,2H).31P NMR(162MHz,D2O)δ-11.31(s),-11.81(s).MALDI-TOF-MS:m/z C15H21N8O13P2Br[M+2Na-H]+706.96,Found 706.87.IR:-N3:2110.22cm-1。
实施例5
Figure BDA0002713882170000051
将包含炔基的多肽(P-1)(0.012mmol)溶于水，α-ADPr-N3(0.012mmol)溶于水。取5mL的EP管，加入多肽(P-1)(0.012mmol)水溶液，α-ADPr-N3(0.012mmol)水溶液，加入五水硫酸铜和抗坏血酸钠，并补充水保持五水硫酸铜的浓度为0.09mM,抗坏血酸钠的浓度为0.25mM。将反应瓶放入37℃的水浴中快速搅拌反应，反应12小时后取样进行HPLC检测。检测波长254nm，流动相为TEAB和乙腈，梯度洗脱，0-10min乙腈由体积分数0％-35％，10-20min乙腈由体积分数35％-60％，在15-35min检测到产物峰，用制备液相分离得到产物。LC-MS:m/z C131H206N38O40S1P2[M+2H]2+1523.73,found 1523.96。
实施例6
Figure BDA0002713882170000061
将包含炔基的多肽(P-2)(0.012mmol)溶于水，α-ADPr-N3(0.012mmol)溶于水。取5mL的EP管，加入多肽(P-2)(0.012mmol)水溶液，α-ADPr-N3(0.012mmol)水溶液，加入五水硫酸铜和抗坏血酸钠，并补充水保持五水硫酸铜的浓度为0.09mM,抗坏血酸钠的浓度为0.25mM。将反应瓶放入37℃的水浴中快速搅拌反应，反应12小时后取样进行HPLC检测。检测波长254nm，流动相为TEAB和乙腈，梯度洗脱，0-10min乙腈由体积分数0％-35％，10-20min乙腈由体积分数35％-60％，在15-35min检测到产物峰，用制备液相分离得到产物。MALDI-TOF-MS:m/z C105H179N35O36P2[M-H]-2568.27,found2568.51。
以上实施例描述了本发明的基本原理、主要特征及优点，本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (5)

1.一类腺苷二磷酸核糖多肽，其特征在于其结构式为：
Figure FDA0002713882160000011
其中R为多肽，X＝H或Br，Y＝磷酸或H，三氮唑与核糖间的糖苷键为α-构型。
2.一种权利要求1所述的腺苷二磷酸核糖多肽的合成方法，其特征在于具体步骤为：以烟酰胺腺嘌呤二核苷酸(NAD)和叠氮化合物为原料制备α-型ADP-核糖叠氮(a-ADPr-N3)；以α-型ADP-核糖叠氮和包含末端炔基的多肽为原料制备腺苷二磷酸核糖多肽。
3.根据权利要求2所述的腺苷二磷酸核糖多肽的合成方法，其特征在于：所述烟酰胺腺嘌呤二核苷酸(NAD)和叠氮化合物为原料制备α-型ADP-核糖叠氮(α-ADPr-N3)的反应条件条件为以水为溶液，乳酸和二乙醇胺为添加剂。
4.根据权利要求2所述的腺苷二磷酸核糖多肽的合成方法，其特征在于：所述以α-型ADP-核糖叠氮和包含末端炔基的多肽为原料制备腺苷二磷酸核糖多肽的反应条件为以水为溶液，水合硫酸铜为催化剂，抗坏血酸钠为还原剂。
5.权利要求1所述的腺苷二磷酸核糖多肽作为蛋白质ADP-核糖化模拟物的应用。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2782459A1 (en) * 2009-12-04 2011-06-09 Katholieke Universiteit Leuven, K.U.Leuven R&D Arf6 as a new target for treating alzheimer's disease
US20140170643A1 (en) * 2012-04-30 2014-06-19 Board Of Regents, The University Of Texas System PARP Substrates and Biomarkers
CN104725484A (zh) * 2013-12-19 2015-06-24 中国科学院微生物研究所 一种糖基化多肽及其制备方法和其应用
US20160299141A1 (en) * 2015-04-08 2016-10-13 The Board Of Regents Of The University Of Texas System Nad analogs and methods of using said nad analogs in determining ribosylation of proteins with parp mutants
CN107629100A (zh) * 2017-08-10 2018-01-26 河南师范大学 一类包含三氮唑衍生物二核苷酸和肽缀合物及其合成方法
WO2019195240A1 (en) * 2018-04-02 2019-10-10 The Johns Hopkins University Methods and uses of enzymatic labeling of adp-ribose containing molecules

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2782459A1 (en) * 2009-12-04 2011-06-09 Katholieke Universiteit Leuven, K.U.Leuven R&D Arf6 as a new target for treating alzheimer's disease
US20140170643A1 (en) * 2012-04-30 2014-06-19 Board Of Regents, The University Of Texas System PARP Substrates and Biomarkers
CN104725484A (zh) * 2013-12-19 2015-06-24 中国科学院微生物研究所 一种糖基化多肽及其制备方法和其应用
US20160299141A1 (en) * 2015-04-08 2016-10-13 The Board Of Regents Of The University Of Texas System Nad analogs and methods of using said nad analogs in determining ribosylation of proteins with parp mutants
CN107629100A (zh) * 2017-08-10 2018-01-26 河南师范大学 一类包含三氮唑衍生物二核苷酸和肽缀合物及其合成方法
WO2019195240A1 (en) * 2018-04-02 2019-10-10 The Johns Hopkins University Methods and uses of enzymatic labeling of adp-ribose containing molecules

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ANLIAN ZHU等: "An integrated high-throughput strategy enables the discovery of multifunctional ionic liquids for sustainable chemical processes", 《GREEN CHEM.》 *
ANLIAN ZHU等: "Biomimetic α-selective ribosylation enables two-step modular synthesis of biologically important ADP-ribosylated peptides", 《NATURE COMMUNICATIONS》 *
LINGJUN LI等: "ADP-ribosyl-N3: A Versatile Precursor for Divergent Syntheses of ADP-ribosylated Compounds", 《MOLECULES》 *
QIANG LIU等: "A General Approach Towards Triazole-Linked Adenosine Diphosphate Ribosylated Peptides and Proteins", 《ANGEWANDTE CHEMIE》 *
白莉莉 等: "利用结构改造模拟物研究蛋白质ADP-核糖化翻译后修饰过程", 《第十届全国化学生物学学术会议报告摘要集》 *
白莉莉等: "Studies on Physiological Functions of Some Nucleotides via Syntheses of Their Structural Mimics", 《河南省化学会2018年学术年会摘要集》 *

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