CN116284056A - 一种青蒿烯生物素标记物及其制备方法 - Google Patents
一种青蒿烯生物素标记物及其制备方法 Download PDFInfo
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- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 title claims abstract description 46
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- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical group N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims abstract description 26
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Abstract
Description
技术领域
本发明涉及药物技术领域,尤其涉及一种青蒿烯生物素标记物及其制备方法。
背景技术
青蒿烯是与青蒿素密切相关的内过氧化物,结构与青蒿素非常相似,可从复合花序植物黄花蒿茎叶中提取和化学合成获得。青蒿烯具有良好的生物活性,可激活Nrf-2依赖的抗氧化反应,治疗化疗药物博来霉素诱导的肺损伤(Faseb Journal,2016,30(7):2500-2510;Biomed Res Int,2019,2019:5198138.),并对多种肿瘤细胞具有杀伤作用(Phytomedicine,2011,18(11):959-969;Phytomedicine,2015,22(11):1045-1054;实用医学杂志,2016,32(9):1384-387.)。Chen等也证实青蒿烯在细胞和动物水平均展现出广谱、高效的抗肿瘤作用,而且对正常组织无明显的毒性作用(Oncogene.2018,37(37):5079-5087),但是作用机制尚未阐明。此外,Chen等也证实青蒿烯在具有治疗类风湿关节炎的潜能(ClinTransl Med.2022,12(12):e1148.),但是作用靶点尚不明确。
靶点是药物化学成分和人体生物系统相互作用的衔接点和枢纽,靶点发现对药物化学结构优化和效应机制阐释具有重要意义。如今药物靶点的确认正逐渐成为阻碍药物化学发展的瓶颈问题,更有甚者,药物的作用机制是在其应用于临床后才逐渐被揭开。尽管青蒿烯具有良好的生物活性和广阔的临床应用前景,但是靶蛋白不明确是影响青蒿烯应用于临床的最关键瓶颈之一。明确青蒿烯的靶蛋白,将有助于青蒿烯的结构优化、构效关系及其分子作用机制等方面的研究,为其临床应用奠定基础,同时也可为相关靶点应用于临床转化医学提供科学依据。
生物素-亲和素系统(Biotin-Avidin System)是一种具有高亲和力、灵敏度高、特异性强和稳定性好等优点的信号放大标记技术。目前,寻找药物靶蛋白最常用和有效的手段是设计合成天然产物的分子探针,利用生物素与亲和素之间高度的亲和力及蛋白质谱技术获得候选靶蛋白。由于青蒿烯结构的不稳定性,其生物素标记物的合成至今没有文献报道。
发明内容
为了解决现有技术的问题,本发明实施例提供了一种青蒿烯生物素标记物及其制备方法。所述技术方案如下:
第一方面,提供一种青蒿烯生物素标记物,所述青蒿烯生物素标记物具有以下结构:
第二方面,提供一种青蒿烯生物素标记物的制备方法,包括:
(1)取化合物1和D-生物素辅酶R溶于乙腈,再加入4-二甲氨基吡啶和二环己基碳二亚胺,进行反应,反应完成后加水淬灭,用乙酸乙酯萃取反应液,收集合并有机相,将有机相干燥后过滤、浓缩,硅胶柱分离得到化合物2;
(2)取青蒿烯溶于甲醇,加入硼氢化钠,反应1小时后加入化合物2的四氢呋喃溶液,再加入氢氧化钾和18-冠醚-6,继续反应,反应完成后加水淬灭,用乙酸乙酯萃取反应液,收集合并有机相,将有机相干燥后过滤、浓缩,硅胶柱分离得到化合物ATT-P1;
进一步的,所述步骤(1)中以摩尔比计,化合物1:D-生物素辅酶R:入4-二甲氨基吡啶:二环己基碳二亚胺=1.5:1.5:0.15:2.2。
进一步的,所述步骤(2)中以摩尔比计,青蒿烯:硼氢化钠:化合物2:氢氧化钾:18-冠醚-6=1.2:1.2:2:1.2:1。
进一步的,所述步骤(1)在室温下反应3小时;所述步骤(2)反应12小时后加水淬灭。
第三方面,提供一种青蒿烯生物素标记物的制备方法,包括:
取青蒿烯溶于甲醇,加入硼氢化钠,反应1小时后加入化合物4的乙腈溶液,再加入碳酸钾,继续反应,反应完成后加水淬灭,用乙酸乙酯萃取反应液,收集合并有机相,将有机相干燥后过滤、浓缩,硅胶柱分离得到化合物ATT-P2;
进一步的,以摩尔比计,青蒿烯:硼氢化钠:化合物4:碳酸钾=1.2:1.2:2:1.2。
进一步的,反应15小时后加水淬灭。
本发明实施例提供的技术方案带来的有益效果是:本发明首先将青蒿烯的酯羰基还原,不分离产物,“一锅”加入生物素片段,与半缩醛羟基反应得到目标分子。本发明通过化学方法首次实现了一类青蒿烯生物素标记物(ATT-P1和ATT-P2)的合成。此类分子的设计思路为青蒿烯生物素标记物的合成以及青蒿烯靶点的研究提供了新的思路和途径。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将对本发明实施方式作进一步地详细描述。
(一)青蒿烯生物素标记物的合成
(1)ATT-P1的合成
①取化合物11.5mmol和D-生物素辅酶R(D-biotin)1.5mmol溶于15ml乙腈中,再加入4-二甲氨基吡啶(DMAP)0.15mmol和二环己基碳二亚胺(DCC)2.2mmol;于室温下反应3小时,然后加水淬灭,再用乙酸乙酯(EA)萃取反应液,收集合并有机相,将有机相用无水硫酸钠干燥后过滤、浓缩,硅胶柱分离得到化合物2(产品70%)。
化合物21H NMR(500MHz,Chloroform-d)δ5.59(d,J=7.8Hz,1H),5.19(d,J=7.5Hz,1H),4.46–4.35(m,2H),4.26(dt,J=7.7,3.1Hz,1H),4.05(dt,J=12.4,6.2Hz,1H),3.94–3.81(m,2H),3.72–3.58(m,7H),3.58–3.49(m,1H),3.09(td,J=4.6,2.8Hz,1H),2.99(dd,J=14.3,3.1Hz,1H),2.81(dd,J=14.3,2.2Hz,1H),2.41–2.24(m,2H),1.81(dtd,J=13.2,6.5,4.6Hz,1H),1.69–1.49(m,4H),1.47–1.35(m,1H).
②取青蒿烯(ATT)1.2mmol溶于10ml甲醇,分批加入硼氢化钠1.2mmol,反应1小时后加入化合物2的四氢呋喃溶液3ml(化合物2含量2mmol),再加入氢氧化钾1.2mmol和18-冠醚-6(18-crowen-6)1mmol,反应12小时,然后加水淬灭,用乙酸乙酯(EA)萃取反应液,收集合并有机相,将有机相用无水硫酸钠干燥后过滤、浓缩,硅胶柱分离得到化合物ATT-P1(产品61%)。
化合物ATT-P11H NMR(500MHz,Chloroform-d)δ5.66(d,J=7.8Hz,1H),5.42(d,J=7.5Hz,1H),5.16(t,J=1.0Hz,1H),4.98(dt,J=2.0,0.9Hz,1H),4.94–4.89(m,2H),4.43(dtd,J=7.9,3.2,2.3Hz,1H),4.29–4.21(m,3H),3.79–3.73(m,2H),3.73–3.63(m,8H),3.12(td,J=4.6,2.8Hz,1H),2.98(dd,J=14.3,3.1Hz,1H),2.80(dd,J=14.4,2.3Hz,1H),2.73(ddt,J=6.6,4.4,1.0Hz,1H),2.32(d,J=6.9Hz,1H),2.31–2.22(m,2H),2.08–1.96(m,2H),1.92(dddd,J=12.6,8.1,5.9,4.4Hz,1H),1.83–1.64(m,5H),1.64–1.40(m,9H),1.22(dddd,J=12.8,8.2,5.9,4.2Hz,1H),0.97(d,J=7.5Hz,3H).
13C NMR(125MHz,Chloroform-d)δ173.34,163.71,144.42,112.82,104.58,98.80,91.12,80.67,70.69,70.68,69.29,68.32,67.79,64.30,63.56,60.06,55.77,49.84,42.73,39.01,36.51,35.75,34.43,31.98,30.04,26.06,25.52,24.88,24.03,22.89,20.26.
高分辨质谱(ESI):M+H:641.3111。
③取青蒿烯(ATT)1.2mmol溶于10ml甲醇,分批加入硼氢化钠1.2mmol,反应1小时后加入化合物2的四氢呋喃溶液3ml(化合物2含量2mmol),再加入碳酸钾1.2mmol和18-冠醚-6(18-crowen-6)1mmol,反应12小时,然后加水淬灭,用乙酸乙酯(EA)萃取反应液,收集合并有机相,将有机相用无水硫酸钠干燥后过滤、浓缩,硅胶柱分离得到化合物ATT-P1(产品5%)。
④取青蒿烯(ATT)1.2mmol溶于10ml甲醇,分批加入硼氢化钠1.2mmol,反应1小时后加入化合物2的四氢呋喃溶液3ml(化合物2含量2mmol),再加入碳酸铯1.2mmol和18-冠醚-6(18-crowen-6)1mmol,反应12小时,然后加水淬灭,用乙酸乙酯(EA)萃取反应液,收集合并有机相,将有机相用无水硫酸钠干燥后过滤、浓缩,硅胶柱分离得到化合物ATT-P1(产品6%)。
(2)ATT-P2的合成
①取青蒿烯(ATT)1.2mmol溶于10ml甲醇,分批加入硼氢化钠1.2mmol,反应1小时后加入化合物4的乙腈溶液2ml(1mmol/ml),再加入碳酸钾1.2mmol,反应15小时,然后加水淬灭,用乙酸乙酯(EA)萃取反应液,收集合并有机相,将有机相用无水硫酸钠干燥后过滤、浓缩,硅胶柱分离得到化合物ATT-P2(产率56%)。
化合物ATT-P21H NMR(500MHz,Chloroform-d)δ5.76(d,J=7.9Hz,1H),5.41(d,J=7.5Hz,1H),5.13–5.04(m,2H),4.99(dt,J=2.0,0.9Hz,1H),4.91(s,1H),4.43(dtd,J=7.9,3.2,2.3Hz,1H),4.29–4.21(m,3H),4.15(dt,J=7.9,3.8Hz,1H),3.73–3.67(m,3H),3.67–3.59(m,3H),3.54(td,J=5.3,0.8Hz,2H),3.09(td,J=4.6,2.7Hz,1H),2.98(dd,J=14.3,3.1Hz,1H),2.91(td,J=5.3,3.8Hz,2H),2.80(dd,J=14.4,2.3Hz,1H),2.64(ddt,J=6.6,4.4,1.1Hz,1H),2.35–2.22(m,3H),2.09–1.96(m,2H),1.92–1.63(m,6H),1.63–1.54(m,2H),1.55–1.51(m,1H),1.51–1.38(m,6H),1.27–1.17(m,1H),0.97(d,J=7.5Hz,3H).
13C NMR(125MHz,Chloroform-d)δ173.34,163.71,143.67,113.84,104.70,90.92,83.67,81.01,70.50,69.72,69.37,68.32,64.30,63.56,60.06,55.77,49.85,45.12,41.57,39.01,36.51,35.75,34.43,31.90,30.04,26.06,25.52,24.88,24.54,24.03,20.26.
高分辨质谱(ESI):M+H:640.3261。
②取青蒿烯(ATT)1.2mmol溶于10ml甲醇,分批加入硼氢化钠1.2mmol,反应1小时后加入化合物4的乙腈2ml溶液(1mmol/ml),再加入碳酸铯1.2mmol,反应15小时,然后加水淬灭,用乙酸乙酯(EA)萃取反应液,收集合并有机相,将有机相用无水硫酸钠干燥后过滤、浓缩,硅胶柱分离得到化合物ATT-P2(产率8%)。
以上仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
3.根据权利要求2所述的制备方法,其特征在于,所述步骤(1)中以摩尔比计,化合物1:D-生物素辅酶R:入4-二甲氨基吡啶:二环己基碳二亚胺=1.5:1.5:0.15:2.2。
4.根据权利要求2所述的制备方法,其特征在于,所述步骤(2)中以摩尔比计,青蒿烯:硼氢化钠:化合物2:氢氧化钾:18-冠醚-6=1.2:1.2:2:1.2:1。
5.根据权利要求2所述的制备方法,其特征在于,所述步骤(1)在室温下反应3小时;所述步骤(2)反应12小时后加水淬灭。
7.根据权利要求6所述的制备方法,其特征在于,以摩尔比计,青蒿烯:硼氢化钠:化合物4:碳酸钾=1.2:1.2:2:1.2。
8.根据权利要求6所述的制备方法,其特征在于,反应15小时后加水淬灭。
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Non-Patent Citations (3)
Title |
---|
ISMAIL, HANAFY M.等: "Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 113, no. 8, 23 February 2016 (2016-02-23), pages 2080 - 2085 * |
仲春龙等: "青蒿素的生物素标记衍生物的合成", 化学学报, vol. 66, no. 9, 31 December 2008 (2008-12-31), pages 1074 - 1078 * |
张煚等: "小分子探针在确定活性化合物的生物靶点中的应用", 药学学报, vol. 47, no. 3, 31 December 2012 (2012-12-31), pages 299 - 306 * |
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