CN107722057A - 基于花菁的有机化合物及其应用 - Google Patents
基于花菁的有机化合物及其应用 Download PDFInfo
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- CN107722057A CN107722057A CN201711089005.6A CN201711089005A CN107722057A CN 107722057 A CN107722057 A CN 107722057A CN 201711089005 A CN201711089005 A CN 201711089005A CN 107722057 A CN107722057 A CN 107722057A
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
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- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
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- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
Abstract
本发明涉及荧光探针,具体地说一种基于花菁的有机化合物及其应用。基于花菁的有机化合物,结构式如式Ⅰ所示,以所述化合物作为联动检测线粒体外膜上本发明化合物作为荧光探针可用于细胞内外MAO‑B水平的检测,这对深入研究MAO‑B在生物体内催化单胺类物质的方式以及催化产物的产生、聚积等过程的动力学机理,尤其是在研究MAO‑B在生物体中的生理作用以及催化产物对生物体的影响有重要的生物医学意义。
Description
技术领域
本发明涉及荧光探针,具体地说一种基于花菁的有机化合物及其应用。
背景技术
单胺氧化酶(monoamine oxidase,MAO,EC1.4.3.4)全名为单胺-氧氧化还原酶,是一种位于线粒体外膜上的黄素酶,在FAD辅酶的协同作用下催化氧化生物体内产生的胺,氧化脱氨产生活性氧物质,包括神经传递素多巴胺、去肾上腺素(NE)、血清素(5-HT)、酪胺、苯乙胺(PEA)以及神经毒素1-甲基-4-苯基-1,2,3,6-四氢嘧啶(MPTP)等。根据其对底物或抑制剂选择性、细胞分布、免疫特异性等不同,分为两种亚型:MAO-A和MAO-B。MAO广泛分布于体内的各个器官,尤以分泌腺、脑、肝、肾和小肠的含量最多。MAO-A和MAO-B维持生物胺的稳态,包括一级胺、二级胺三级胺以及一些长链的二胺类。这些酶的过度活化会导致一些活性氧副产物如(H2O2)的过度产生,从而促进引起神经性疾病和神经变性疾病的神经元功能障碍而MAO-B酶含量的失常跟与帕金森病、阿尔海默兹病、亨廷顿舞蹈症、衰老等多种疾病相关。因此,通过测定生物体内MAO-B的含量,可实现对某些疾病的早期诊断和治疗。实现实时地、灵敏地、特异性地检测不同亚型的单胺氧化酶以及其氧化分解副产物活性氧物质具有十分重要的意义。
目前,用于检测MAO-B的方法包括:分光光度法、放射性法、酶联免疫法、荧光分析法等。在上述方法中,荧光法相比较而言更加具有吸引力,不仅简单易行,便于操作,具有高灵敏度、高选择性的特点,而且可以实现活细胞内MAO-B以及其催化氧化副产物活性氧的联动“原位可视化”检测,从而对其在生命体内进行“实时在线”观测。Shao Q.Yao等公开了一类用于检测MAO-B的双光子荧光探针(Shao Q.Y.Nat.Commun.2014,5,3276),与MAO-B作用后荧光产生从而检测MAO-B的存在。但该探针只能在可见光区检测MAO-B,有一定的外部环境的干扰且不能同时检测MAO-B催化单胺类物质时的活性氧物质,因此,活性氧物质对细胞以及生物的损伤不能及时反馈。因此,开发具有良好选择性,可在近红外区进行联动检测生物体系中MAO-B以及该酶催化单胺类物质产生的活性氧物质的荧光探针具有重要意义。
发明内容
本发明目的在于提供一种基于花菁的有机化合物及其应用。
为实现上述目的,本发明采用的技术方案为:
一种基于花菁的有机化合物,基于花菁的有机化合物,结构式如式Ⅰ所示,
一种基于花菁的有机化合物的应用,所述式Ⅰ所示的基于花菁的有机化合物在作为联动检测线粒体外膜上单胺氧化酶B(MAO-B)、及单胺氧化酶B催化反应单胺类物质产生的活性氧物质中的应用。
所述式Ⅰ所示的基于花菁的有机化合物在定性联动检测细胞或生物体内的MAO-B以及该酶催化反应单胺类物质时产生的活性氧物质中的应用。
一种荧光探针,探针为结构式如式Ⅰ所示基于花菁的有机化合物。
一种荧光探针的应用,所述探针在联动检测线粒体外膜上单胺氧化酶B(MAO-B)、及单胺氧化酶B催化反应单胺类物质产生的活性氧物质中的应用。
所述探针在定性联动检测细胞或生物体内的MAO-B以及该酶催化反应单胺类物质时产生的活性氧物质中的应用。
本发明的有益效果:
本发明化合物作为联动检测细胞或生物体内的MAO-B以及该酶催化单胺类物质时产生的活性氧物质的荧光探针化合物,其在MAO-B存在下发生氧化脱氨基作用,同时有活性氧物质的生成,使探针有明显的荧光产生,紫外吸收亦发生明显的变化,进而可以用于生物体内MAO-B及其催化底物产生活性氧的检测。本发明化合物用作荧光探针,可用于细胞内MAO-B及其催化产物进行检测,还可对细胞内的线粒体进行定位,这对深入研究MAO-B以及这类化合物作为荧光探针可用于细胞内外MAO-B水平的检测,这对深入研究MAO-B在生物体内催化单胺类物质的方式以及催化产物的产生、聚积等过程的动力学机理,尤其是在研究MAO-B在生物体中的生理作用以及催化产物对生物体的影响有重要的生物医学意义。
附图说明
图1为本发明实施例提供的采用的荧光探针对MAO-B及其催化产物检测前后紫外吸收变化图。
图2为本发明实施例提供的采用的荧光探针对MAO-B及其催化产物检测前后荧光变化图。
图3为本发明实施例提供的所采用的荧光探针对MAO-B的选择性示意图;其中,横坐标从左至右依次为:空白对照、氯化镁、氯化铁、硫酸锌、葡萄糖、精氨酸、丝氨酸、谷胱甘肽、尿素、基质金属蛋白酶-2、基质金属蛋白酶-9、基质金属蛋白酶-14、磷酸水解酶、单胺氧化酶A、MAO-B。
图4为本发明实施例提供的采用荧光探针用于检测细胞线粒体内MAO-B以及催化产物的共聚焦显微镜成像。
具体实施方式
下面实施例用于进一步说明本发明,但本发明不限于实施例。
本发明化合物如结构式Ⅰ所示,以所述化合物作为联动检测线粒体外膜上单胺氧化酶B(MAO-B)以及在该酶催化反应单胺类物质时产生的活性氧物质的荧光探针。本发明联动检测MAO-B以及该酶催化单胺类物质产生的活性氧的荧光探针的这类化合物,探针本身没有荧光,在MAO-B的存在下,响应基团氨基甲酸酯作为MAO-B的底物,通过MAO-B催化的氨基氧化成醛(通过亚胺中间体)同时在FAD辅酶的作用下,产生O2 ·-这类的活性氧物质,探针在活性氧的作用下,花菁母体会形成π-共轭体系,产生荧光,丙醛部分通过β消除和一个CO2的自发释放,荧光团被释放。本发明用于联动检测MAO-B以及该催化单胺类物质产生的活性氧这类化合物,在MAO-B存在下对应的荧光波长发生明显位移,可用于MAO-B及该酶催化反应单胺类物质时产生的活性氧物质的检测,并可大大降低外部检测条件的干扰,提高检测精度。本发明MAO-B及该酶催化反应单胺类物质时产生的活性氧物质荧光探针的化合物,在MAO-B存在时,紫外吸收亦发生明显变化,可同时用紫外分光光度计及肉眼进行检测。该化合物作为荧光探针可用于细胞内外MAO-B水平的检测,这对深入研究MAO-B在生物体内催化单胺类物质的方式以及催化产物的产生、聚积等过程的动力学机理,尤其是在研究MAO-B在生物体中的生理作用以及催化产物对生物体的影响有重要的生物学意义。
本发明式Ⅰ所示
基于花菁的有机化合物结构式为:
式Ⅰ化合物与待测定生物体内外中的MAO-B结合,氨基甲酸酯被催化氧化成醛(通过亚胺中间体),释放出O2 ·-这类的活性氧物质,从而使花菁母体形成π-共轭体系,产生荧光,丙醛部分通过β消除和一个CO2的自发释放,得到结构式II的化合物。从而导致式Ⅰ化合物的荧光产生,紫外吸收的改变,进而可以用来进行MAO-B及对其催化产物进行定性的检测。
实施例1
基于花青的式Ⅰ有机化合物的制备:
(1)化合物一的制备
在氩气保护下,(4-溴丁基)三苯基溴化磷(14.35g,30mmol)和叠氮钠(3.9g,60mmol)溶于50mL DMF中。90℃条件下,搅拌,过夜。溶液的颜色由无色到浅黄色到红色。将反应瓶冷却到室温,加入50mL二氯甲烷,直到产生大量的沉淀。过滤,收集滤液。收集滤液经乙酸乙酯与水1:1(v/v)萃取,收集有机相,旋蒸。旋蒸后的产物置入圆底烧瓶中,安装回流装置,搅拌,加入约7.5毫升的二氯甲烷使其完全溶解,加热至溶液温度约为40℃,回流。溶液微沸时,加入乙酸乙酯,使溶液有白色晶体析出又消失,直至浑浊出现时,再加入二氯甲烷,如此重复3次,冷却,析出晶体,得到化合物一。
1H NMR(400MHz,CDCl3)δ(ppm):7.89-7.85(q,6H),7.82-7.79(t,3H),7.73-7.71(m,6H),3.98-3.92(m,2H),3.46-3.44(t,2H),2.06-2.01(m,2H),1.76-1.74(m,2H).13C NMR(100MHz,CDCl3,ppm)δ134.98,133.72,133.64,130.52,130.42,118.54,117.86,50.59,29.19,29.06,22.34,21.93,19.84,19.80.GC-MS(API-ES):m/z C22H23N3P+[M]+Calcd:360.1624,found:360.4022.
(2)化合物二的制备
在氩气保护下,将抗坏血酸钠(0.01M,1mL)和CuSO4·5H2O(0.01M,1mL)的水溶液混合,得到含有铜(I)催化物质溶液。将商业花菁染料(63.6mg,0.1mmol),化合物一(39.6mg,0.11mmol)和DIPEA(1.5mg,0.01mmol)加入到6.0mL四氢呋喃中,通过恒压滴液漏斗滴加到上述溶液。将混合物在氮气保护下,在25℃下进一步搅拌24小时。真空除去溶剂,所得蓝色固体残余物用梯度洗脱剂CH2Cl2和CH3OH(100:0-85:15,v/v)的硅胶色谱纯化(200-300目),收集洗脱组分即为化合物二。
1H NMR(400MHz,CD3OD)δ(ppm):8.07(s,2H),7.90-7.88(m,6H),7.38-7.37(d,3H),7.32-7.29(m,6H),7.10-7.08(t,3H),7.04-7.00(t,5H),5.75-5.72(d,2H),5.25(s,5H),5.12(s,3H),4.55-4.52(t,3H),4.14-4.08(m,1H),3.43-3.37(m,1H),3.10-3.08(m,2H),2.97-2.93(m,3H),2.69-2.64(m,3H).2.20-2.18(m,3H),2.03(s,1H),1.85-1.81(m,1H),1.76-1.75(d,2H),1.50-1.46(m,1H),1.29-1.21(m,12H),1.05-1.00(m,2H),0.94-0.92(m,2H).13C NMR(100MHz,CD3OD)δ(ppm):169.97,166.81,159.96,157.15,143.82,140.03,137.84,134.94,133.49,133.41,130.26,130.16,128.00,127.91,124.09,122.39,121.69,118.63,117.94,114.55,108.27,93.21,93.08,62.27,61.06,52.30,49.95,38.33,36.31,33.07,30.30,30.17,29.24,29.11,27.70,27.56,21.08,20.93,20.66,20.52,19.49,19.46,19.09,10.27,7.87,6.34.GC-MS(API-ES):m/z C66H73N6OP+[M]+Calcd:996.557,found:498.6522.
(3)化合物三的制备
在氩气保护下,将3-氨基-1丙醇(0.13g,1.7mmol)溶于二氯甲烷(1.6mL)中,逐滴加入三乙胺,直至检测所得溶液为碱性,所得溶液搅拌15min,待用;
二碳酸二叔丁酯(0.34g,1.6mmol)溶于二氯甲烷(5.0mL)通过恒压滴液漏斗逐滴加入上述混合物中,滴加的时间为1h,室温反应,过夜。用饱和NaHCO3水溶液洗涤3次,有机相用无水NaSO4干燥过夜。目标化合物三为无色粘稠液体,浓缩后直接进行下一步合成。
1H NMR(400MHz,CD3Cl3)δ(ppm):1.46(s,9H),1.58(q,2H),2.95(s,1H),3.21(t,2H),3.58(t,2H),4.39(s,1H).13C NMR(100MHz,CD3OD,ppm)δ28.1,32.6,38.7,59.4,80.1,156.8.
(4)化合物四的制备
在氩气保护下,冷阱控制反应温度在0℃以下,将化合物二(0.10g,0.1mmol)和三光气(12.0mg,0.04mmol)溶于干燥的二氯甲烷(5.0mL)所得溶液搅拌3min,待用;
三乙胺(12.1mg,0.12mmol)溶于二氯甲烷(2.0mL)通过恒压滴液漏斗逐滴滴入上述混合溶液中,溶液全部由蓝色变为绿色,用饱和NaHCO3水溶液淬灭反应,减压浓缩,所得产物和化合物三(52.5mg,0.3mmol)溶于干燥的二氯甲烷(5.0mL)所得溶液搅拌3min,三乙胺(30.3mg,0.3mmol)溶于二氯甲烷(2.0mL)通过恒压滴液漏斗逐滴滴入混合溶液中,开始反应温度为0℃以下,滴加完毕,升至室温,反应过夜。真空除去溶剂,所得绿色固体残余物用梯度洗脱剂CH2Cl2和CH3OH(100:0-85:15,v/v)的硅胶色谱纯化(200-300目),收集洗脱组分即为化合物四。
1H NMR(400MHz,CD3OD)δ(ppm):8.07(d,2H),7.38-7.35(m,24H),7.06-7.04(d,1H),6.95-6.89(d,1H),6.72(m,4H),6.35(s,1H),5.79(s,1H),5.33(d,2H),4.46(t,2H),4.13-4.07(m,6H),3.67(s,3H),3.18(t,2H),2.83(m,1H),2.36(m,4H),1.84-1.79(m,8H),1.41-1.37(m,24H).13C NMR(100MHz,CD3OD)δ(ppm):173.1,172.8,156.3,152,149.1,146.6,144.6,142.3,141.2,140.9,135.4,129.1,128.4,120,118,114,111,79.5,72.3,60.1,55.0,51.1,42,38,36.8,35.1,34,31.5,24.7,16.4,13.8,7.84,6.35.GC-MS(API-ES):m/z C74H86N7O5P2+[M]+Calcd:1183.66,found:592.34.
(5)化合物五的制备
在氩气条件下,保持反应体系温度为0℃,将化合物四(0.3g,0.25mmol)溶解在10mL乙醇中,然后将1.5当量的NaBH4水溶液(1mL)滴加到反应体系中。10分钟后,混合物的颜色从绿色变为黄色,用饱和KI溶液洗涤混合物,通过旋转蒸发器蒸发有机相,将所得产物溶于二氯甲烷(1.5mL),TFA(100uL)溶于二氯甲烷(0.5mL)通过恒压滴液漏斗逐滴加入,室温下搅拌30min。所得的棕黄色溶液洗涤,真空除去溶剂,所得固体残余物用梯度洗脱剂EA和CH3OH(100:0-85:15,v/v)的硅胶色谱纯化(200-300目),收集洗脱组分即为式Ⅰ所示有机化合物五。
1H NMR(400MHz,CD3OD)δ(ppm):7.61(s,1H),7.38-7.35(m,20H),7.16-7.01(m,3H),6.80-6.72(m,9H),6.41(s,3H),6.36-6.31(m,3H),5.78(s,1H),5.64(s,1H),5.24(s,1H),4.56(t,2H),4.23(q,2H),3.78(s,3H),3.51(t,2H),2.94(m,4H),2.33(m,4H),1.95(m,2H),1.81(m,6H),1.45(m,6H),1.35(m,6H).13C NMR(100MHz,CD3OD)δ(ppm):172.3,158.4,150.1,149.5,148.1,147.5,145.3,140.2,135.6,134.6,132.5,130.1,129.8,128.5,127.6,123.2,121.6,110.6,106.5,98.5,78.6,60.1,55.6,53.2,40.5,35.4,19.8,13.2.GC-MS(API-ES):m/z C69H79N7O3P+[M]+Calcd:1084.61,found:1085.78.
实施例2
将制备所得式Ⅰ化合物作为探针应用于细胞、组织和器官进行对MAO-B及其催化产生的活性氧物质的检测,模拟生理条件,以下各项实验均在pH=7.4条件下进行(HEPES缓冲溶液,浓度为40mM),探针的浓度采用10μM。
上述制备所得式Ⅰ化合物对MAO-B及其催化产生的活性氧物质的紫外响应:
pH采用HEPES缓冲溶液控制。于10mL比色管中加入式Ⅰ化合物,保证其最终的浓度为10μM,再加入40mM HEPES,然后加入MAO-B,加入超纯水10mL定容后,使MAO-B的浓度分别为0μg mL-1,1μg mL-1,2μg mL-1,3μg mL-1,4μg mL-1,5μg mL-1,6μg mL-1,7μg mL-1,8μg mL-1,9μg mL-1,10μg mL-1。摇匀溶液,平衡60min后,将上述工作液加入比色皿中测定紫外吸收光谱。紫外吸收光谱在检测MAO-B前后的变化如图1所示。式Ⅰ化合物可用于实现生物体内的MAO-B及其催化产生的活性氧物质的检测。同时,本发明实施例所提供的探针与MAO-B及其催化产生的活性氧物质反应后的产物结构如下:
实施例3
式Ⅰ化合物对MAO-B及其催化产生的活性氧物质的荧光响应:
pH采用HEPES缓冲溶液控制。于10mL比色管中加入式Ⅰ化合物,保证其最终的浓度为10μM,再加入40mM HEPES,然后加入MAO-B,加入超纯水10mL定容后,使MAO-B的浓度分别为0μg mL-1,1μg mL-1,2μg mL-1,3μg mL-1,4μg mL-1,5μg mL-1,6μg mL-1,7μg mL-1,8μg mL-1,9μg mL-1,10μg mL-1。摇匀溶液,平衡60min后,将上述工作液加入荧光皿中测定荧光光谱光谱。荧光光谱在检测MAO-B前后的变化如图2所示。式Ⅰ化合物可用于实现生物体内的MAO-B及其催化产生的活性氧物质的检测。
由图2表示随MAO-B浓度的变化体系荧光强度的变化,表明随MAO-B浓度的增加,体系680-820nm波段的荧光强度明显增强。
实施例4
式Ⅰ化合物对MAO-B的选择性
pH采用HEPES缓冲溶液控制。取多个10ml比色管,并在每个10ml比色管中加入10μM式Ⅰ化合物,再加入40mM pH为7.4的HEPES缓冲液,然后分别加入如图3所示,待测物依次为:空白对照、氯化钾、氯化镁、氯化铁、硫酸锌、葡萄糖、VC、精氨酸、丝氨酸、谷胱甘肽、尿素、MMP-2、MMP-9、MMP-12、磷酸水解酶、MAO-A、MAO-B。最后用超纯水定容到10ml。摇匀溶液,25℃下平衡60min后,将各个比色管中工作液分别倒入到荧光皿中测定荧光光谱。式Ⅰ化合物对MAO-B及其催化产生的活性氧物种的选择性如图3所示。并由图3可知式Ⅰ化合物对MAO-B及其催化产生的活性氧物种具有很好的选择性。
实施例5
式Ⅰ化合物用于细胞线粒体内MAO-B及其催化产生的活性氧物种的检测
小鼠肝癌细胞HepG2细胞按照American type Tissue Culture Collection规定进行培养。10.0uM化合物式一孵育HepG2细胞10分钟,用培养基洗涤3次,置于共聚焦荧光显微镜下拍照,结果如图4a所示;然后将其再孵育50分钟后,置于共聚焦荧光显微镜下拍照,结果如图4b所示;然后加入1uM rhodamine 123(商品化线粒体染色染料)孵育HepG2细胞10分钟,用培养基洗涤3次,置于共聚焦荧光显微镜下拍照,结果如图4c所示;然后加入1uMHoechest(商品化细胞核染色染料)孵育HepG2细胞10分钟,用培养基洗涤3次,置于共聚焦荧光显微镜下拍照,结果如图4d所示;图4e是叠加图,表明探针主要对线粒体染色。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明,不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干简单推演或替换,都应当视为属于本发明的保护范围。作为荧光染料是本发明新化合物的一种用途,不能认定本发明的化合物仅用于荧光染料,对于本发明所属技术领域的普通技术人员来说,在基于本发明化合物用作荧光染料的相同作用机理的考虑下,还可以做出若干简单推理,得出本发明的化合物的其他应用用途,都应当视为属于本发明的保护范围。
Claims (6)
1.一种基于花菁的有机化合物,其特征在于:基于花菁的有机化合物,结构式如式Ⅰ所示,
2.一种权利要求1所述的基于花菁的有机化合物的应用,其特征在于:所述式Ⅰ所示的基于花菁的有机化合物在联动检测线粒体外膜上单胺氧化酶B(MAO-B)、及单胺氧化酶B催化反应单胺类物质产生的活性氧物质中的应用。
3.按权利要求1所述的基于花菁的有机化合物的应用,其特征在于:所述式Ⅰ所示的基于花菁的有机化合物在定性联动检测细胞或生物体内的MAO-B以及该酶催化反应单胺类物质时产生的活性氧物质中的应用。
4.一种荧光探针,其特征在于:探针为结构式如式Ⅰ所示基于花菁的有机化合物。
5.一种权利要求4所述的荧光探针的应用,其特征在于:所述探针在联动检测线粒体外膜上单胺氧化酶B(MAO-B)、及单胺氧化酶B催化反应单胺类物质产生的活性氧物质中的应用。
6.按权利要求5所述的荧光探针的应用,其特征在于:所述探针在定性联动检测细胞或生物体内的MAO-B以及该酶催化反应单胺类物质时产生的活性氧物质中的应用。
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