CN101054397A - 一种n-烟酰基壳寡糖及其制备 - Google Patents
一种n-烟酰基壳寡糖及其制备 Download PDFInfo
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Abstract
本发明公开了一种N-烟酰基壳寡糖,其特征在于:其为混合组份,均分子量为800-6000,混合组份的脱乙酰度为50%~100%;N-烟酰取代度为30%-100%,其组成成份的结构通式如上。其具有降血脂、降血糖,降胆固醇,增强免疫功能,抑制肿瘤和抗疲劳,延缓衰老,抑菌,抗病毒等作用。可作为某些医药、保健食品、化妆品和生物农药的重要原料。
Description
技术领域
本发明涉及壳寡糖,具体地说是一种N-烟酰基壳寡糖及其制备。
背景技术
壳寡糖,学名为β-(1,4)-2-脱氧-2-氨基葡萄寡糖。是一种难得又有着特殊理化性质和优良生物活性的动物性寡糖。他所具有的降血糖、降血酯,降胆固醇,增强免疫功能,抑制肿瘤和抗疲劳、延缓衰老,抑菌,抗病毒等作用,已应用于医药、保健食品、化妆品、农业等方面。烟酸及烟酸环己醇酯和烟酸生育酚酯是用于治疗高血压症和动脉硬化症的药物,但存在引起消化道障碍的副作用缺点,因而限制了其临床应用。有人将烟酰基接在氨基葡萄糖分子中的N原子上(见文献1 Chinese Journal ofChemistry,2005,23,190-193),以减少其毒性。与文献1不同的是:本发明将烟酰基接在壳寡糖分子链的N原子上,前者是单糖的衍生物,后者是壳寡糖的衍生物,属高分子范畴;前者是化合物,后者既可是混合物,也可是化合物;两者都有较好的水溶性,后者较前者具有更好的生物相溶性和更好的食疗、医疗作用(见文献2,中华医学研究杂志,2005.Vol.5.No.8.729-732;3食品科学,2003.Vol.24.No.8.250-248;)更能减少其毒副作用和清除体内有害物质。壳寡糖及其衍生物比氨基葡萄糖对受损心肌细胞和组织有显具的保护作用,前者还有抑制心肌细胞凋亡的现象(见文献3高技术通讯.2005.Vol.15.No.11.96-100),本发明的物质有望能发挥壳寡糖与烟酸的协同作用,使其生物活性及对人体的有益功能得到进一步改善和加强,从而筛选出具有高效、低毒的用于一类新药、新食品添加剂、保健食品和生物农药等的重要原料。
发明内容
本发明的目的在于提供一种N-烟酰基壳寡糖及其制备;其具有降血酯、降血糖,降胆固醇,增强免疫功能,抑制肿瘤和抗疲劳、延缓衰老,抑菌,抗病毒等作用;可作为某些医药、保健食品、化妆品和生物农药的重要原料。
为实现上述目的,本发明采用的技术方案为:
一种N-烟酰基壳寡糖,其为混合组份,均分子量为800-6000,N-烟酰取代度为30%-100%,混合组份的脱乙酰度为50%~100%;
其组成成份的结构通式如下,
其中,R为
或CH3,n=0-30。
所述N-烟酰基壳寡糖的的制备:
氨解法:
1)烟酸对硝基苯酯的制备
A.取烟酸溶于有机溶剂中,加对硝基苯酚,搅拌,滴加二环己基碳二亚胺(DCC)溶于有机溶剂的溶液,滴完后在60-70℃下加热条件下反应2~6h,过滤,滤液倾入冰水中,析出白色固体,过滤,重结晶,得到烟酸对硝基苯酯;其中有机溶剂为:N,N-二甲基甲酰胺(DMF)、吡啶、二甲亚砜或二氯甲烷,其中二环己基碳二亚胺、硝基苯酚和烟酸的摩尔比为1-1.5∶1-2∶1,重结晶过程可采用无水乙醇、甲醇、氯仿、二氯甲烷或丙酮;
或B.于冰浴下,向盛烟酸的反应瓶中滴加过量的二氯亚砜制得烟酰氯,减压蒸馏去除多余的二氯亚砜,向反应瓶中滴入5-20滴的无水丙酮、二甲亚砜、二氯甲烷、DMF或氯仿,强烈搅拌,先后滴加无水三乙胺和对硝基苯酚的无水丙酮、二甲亚砜、二氯甲烷、DMF或氯仿溶液,反应2-8h,过滤,滤液倾入冰水中,析出晶体,过滤,用重量浓度1-60%Na2CO3、NaHCO3、K2CO3或KHCO3溶液洗涤,重结晶,得烟酸对硝基苯硝;烟酸、三乙胺和对硝基苯酚的摩尔比为1∶0.5-1.5∶0.5-1.5,重结晶过程可采用无水乙醇、甲醇、氯仿、二氯甲烷或丙酮;
2)酯的氨解
取烟酸对硝基苯酯溶于有机溶剂中,有机溶剂为:N,N-二甲基甲酰胺(DMF)、吡啶、二甲亚砜或二氯甲烷;加壳寡糖,按壳寡糖中氨基葡萄糖残基计算,烟酸对硝基苯酯与寡糖的摩尔比为1-2∶1,在60-70℃下反应2-10小时,向反应液加入其体积1-8倍的乙醚、丙酮、乙醇、甲醇、或0-1.5摩尔/升NaOH的乙醇或甲醇溶液,产生大量黄色沉淀,抽滤,滤饼用无水丙酮、乙醚、乙醇或甲醇洗1-5次,得黄色粉末,真空干燥,得到N-烟酰基壳寡糖粉末固体。
该法的优点:利用了氨基与羟基的活性差异,酯的氨解优先发生,而无须保护,对比文献1(Chinese Journal of Chemistry,2005,23,190-193),减少了合成步骤,提高了产量;相对酰氯法不产生氯化氢气体,因而保护环境,生产安全;反应条件温和,甚至常温下也可进行,不用强腐蚀性(如酰氯)为原料;副产物易于分离。
酰氯法:
1)烟酰氯的制备:于冰浴下,向盛烟酸的反应瓶中滴加过量的二氯亚砜制得烟酰氯,减压蒸馏去除多余的二氯亚砜;
2)在氢氧化钠、碳酸钾、氢氧化钾、碳酸钠或三乙胺存在下,在氮气保护下,将烟酰氯的有机溶液滴入重量浓度2-12%的壳寡糖水溶液中,,温度为-10℃~10℃,反应0.5-3h,向反应液加入其体积1-8倍的乙醚、丙酮、乙醇、甲醇、或0-1.5摩尔/升NaOH的乙醇或甲醇溶液,产生大量黄色沉淀,抽滤,滤饼用无水丙酮、乙醚、乙醇或甲醇洗1-5次,得黄色粉末,真空干燥,得到N-烟酰基壳寡糖粉末固体。
所述有机溶剂为:N,N-二甲基甲酰胺(DMF)、吡啶、二甲亚砜或二氯甲烷。
本发明具有如下优点:
本发明公开了一种N-烟酰基壳寡糖衍生物,可为单组分的壳寡糖衍生物,也可为混合组分的壳寡糖衍生物。既可由烟酸对硝基苯酯的氨解,也可由烟酰氯的氨解得到。无须保护,合成步骤少,不会破坏壳寡糖的主链,提高了产量;反应条件温和;生产安全;产物易于分离。产物为浅黄色或黄色粉末固体。用核磁共振光谱测定其取代度为70%(不包括原来的已酰基)以上。室温下水中溶解度为8-10g/100g。
本化合物结构上以壳寡糖为主体,在每个结构单元上接上烟酸分子。烟酰类化合物本身就有降血脂、降血糖和植物诱导抗病活性。本化合物既具有壳寡糖本身具有的一系列生物活性,如:降血酯、降血糖,降胆固醇,增强免疫功能,抑制肿瘤和抗疲劳、延缓衰老、抑菌、抗病毒等作用,引入烟酰基后,在降血脂、降血糖、降胆固醇和植物诱导抗病等功能得到大大增强。可作为某些医药、保健食品、化妆品和生物农药的重要原料。
附图说明
图1为N-烟酰壳寡糖诱导抗病毒病斑数示意图;
图2为N-酰化壳寡糖诱导烟草抗病毒效果图。
具体实施方式
下面结合实施实例对本发明做进一步说明:
实施例1:N-烟酰基壳寡糖的制备(氨解法):
取1.23g烟酸溶于N,N-二甲基甲酰胺(DMF)中(溶剂也可为吡啶,二甲亚砜,二氯甲烷等),加2.7g对硝基苯酚,搅拌,加入0.1g二甲胺基吡啶,滴加2.06g二环己基碳二亚胺溶于5mLDMF的溶液,滴完后在60-70℃下加热条件下反应2~6h,过滤,滤液倾入冰水中,析出白色晶体,过滤,用无水乙醇重结晶,得到烟酸对硝基苯酯1.0g,
烟酸对硝基苯酯还可按下面方法制备:
向盛有用0.8g烟酸制的烟酰氯的干燥反应瓶中于冰浴下加入适量无水丙酮,强烈搅拌,先后滴加无水三乙胺10mL和1.0g对硝基苯酚的20mL丙酮溶液,反应4h,过滤,滤液倾入冰水中,析出晶体,过滤,用5%Na2CO3溶液洗,在无水乙醇中重结晶,得烟酸对硝基苯硝0.5g。
酯的氨解:
取烟酸对硝基苯酯0.8g(3.2mmol)溶于30mL无水二甲亚砜中,加壳寡糖0.6g(3.1mmol)(酯与寡糖的摩尔比为1~2∶1(按壳寡糖中氨基葡萄糖残基计算),在60-70℃下反应4小时,向反应液加入乙醚/丙酮溶液50~100mL(1∶1,v/v),产生大量黄色沉淀,抽滤,滤饼用无水丙酮洗3次,得黄色粉末,真空干燥,得到N-烟酰基壳寡糖0.5g,粉末固体。
紫外(UVλmax nm):229.240.320;红外光谱(KBr)主要吸收峰(IRυ,cm-1)3580~3390(OH,NH);2939;2860(CH+CH2);1680(amide-I band);1651(amide-II band);1593(C-N in pyridinering)1116,1054,1033(C-O),891(β,C-H)。1H-NMR(CD3SOCD3)δ:2.90-3.01(m,1H,H-2),3.37-3.42(m,1H,H-5),3.54-3.59(m,2H,H-6,H-6′),3.65-3.71(m,1H,H-3),3.78-3.83(m,1H,H-4),4.40-4.49(m,2H,2OH),6.40-6.48(1H,NH),7.40-7.48(m,J1,2=7.8Hz,1H,β-H-1),8.18-8.25(m,J=7.8Hz,1H,H-9),8.29-8..37(d,J10,9=7.5Hz,1H,H-10),8.58-8.67(d,J8,9=3.6Hz,1H,H-8),8.90-8.95(S,1H,H-7)证实该目标物的存在。用核磁共振法测定取代度为71%。
实施例2:N-烟酰基壳寡糖的制备(酰氯法)
烟酰氯的制备:将10mLSOCl2加入装有HCl气体吸收装置的反应瓶中,在-10~5℃与氮气保护下向其中加入1.67g烟酸,搅拌,滴入数滴无水DMF,在油浴中缓慢升温到90℃,回流3h后,减压蒸去过量的SOCl2,得黄色固体物质烟酰氯,产率80%,可不经分离往下反应。
取3.0g烟酸制备的烟酰氯溶解在50mL DMF中;另取K2CO3 2g溶解在20mL水中,加入壳寡糖(COS)1.6g搅拌使其充分溶解,在氮气保护和低温(-10℃~5℃)下将其酰氯溶液缓慢滴加在壳寡糖(COS)溶液中,滴完后再反应1.5h。往反应液里加入适量无水丙酮(或异丙醇),产生大量黄色沉淀,抽滤,滤饼用丙酮洗涤两次,得到黄色粉末,真空干燥。得烟酰基壳寡糖产品1.8g。粉末固体。用紫外,红外和核磁光谱测定,其数据与实例1完全相同或基本相同。用核磁共振法测定取代度为71%,室温下水中溶解度8.2g/100g。
应用例:
1.N-烟酰基壳寡糖对烟草诱导抗性实验:N-烟酰基壳寡糖对TMV诱导抗性的浓度(ppm)分别为:1、25、50和100。
TMV接种实验采用各个浓度的N-酰化壳寡糖水溶液对整株烟草叶面喷雾,清水为对照,处理1天后接种病毒。接种后每天观察,记录第一批病斑出现得时间和数目,计算病斑抑制率。结果为病斑全部产生后的统计数。采用t检验法进行数据显著分析;
病斑抑制率=(对照叶斑平均数—处理叶斑平均数)/对照叶斑平均数×100%。
结果如图1和2所示,从图可以看出,N-烟酰壳寡糖对烟草具有较好的诱导抗病性。最好的诱抗效果浓度为25ppm,抑制率为53.23%。可作为新的诱抗类生物农药应用。
Claims (4)
2.一种权利要求1所述N-烟酰基壳寡糖的制备方法,其特征在于:
氨解法:
1)烟酸对硝基苯酯的制备
A.取烟酸溶于有机溶剂中,加对硝基苯酚,搅拌,加如一定量二甲胺基吡啶,滴加二环己基碳二亚胺和和溶于有机溶剂的溶液,滴完后在60-70℃下加热条件下反应2~6h,过滤,滤液倾入冰水中,析出白色固体,过滤,重结晶,得到烟酸对硝基苯酯;其中有机溶剂为:N,N-二甲基甲酰胺、吡啶、二甲亚砜或二氯甲烷,其中二环己基碳二亚胺、硝基苯酚和烟酸的摩尔比为1-1.5∶1-2∶1,重结晶过程可采用无水乙醇、甲醇、氯仿、二氯甲烷或丙酮;
或B.于冰浴下,向盛烟酸的反应瓶中滴加过量的二氯亚砜制得烟酰氯,减压蒸馏去除多余的二氯亚砜,向反应瓶中滴入5-20滴的无水丙酮、二甲亚砜、二氯甲烷、DMF或氯仿,强烈搅拌,先后滴加无水三乙胺和对硝基苯酚的无水丙酮、二甲亚砜、二氯甲烷、DMF或氯仿溶液,反应2-8h,过滤,滤液倾入冰水中,析出晶体,过滤,用重量浓度1-60%Na2CO3、NaHCO3、K2CO3或KHCO3溶液洗涤,重结晶,得烟酸对硝基苯酯;烟酸、三乙胺和对硝基苯酚的摩尔比为1∶0.5-1.5∶0.5-1.5,重结晶过程可采用无水乙醇、甲醇、氯仿、二氯甲烷或丙酮;
2)酯的氨解
取烟酸对硝基苯酯溶于有机溶剂中,有机溶剂为:N,N-二甲基甲酰胺(DMF)、吡啶、二甲亚砜或二氯甲烷;加壳寡糖,按壳寡糖中氨基葡萄糖残基计算,烟酸对硝基苯酯与寡糖的摩尔比为1-2∶1,在60-70℃下反应2-10小时,向反应液加入其体积1-8倍的乙醚、丙酮、乙醇、甲醇、或0-1.5摩尔/升NaOH的乙醇或甲醇溶液,产生大量黄色沉淀,抽滤,滤饼用无水丙酮、乙醚、乙醇或甲醇洗1-5次,得黄色粉末,真空干燥,得到N-烟酰基壳寡糖粉末固体。
3.一种权利要求1所述N-烟酰基壳寡糖的制备方法,其特征在于:
酰氯法:
1)烟酰氯的制备:于冰浴下,向盛烟酸的反应瓶中滴加过量的二氯亚砜制得烟酰氯,减压蒸馏去除多余的二氯亚砜;
2)在氢氧化钠、碳酸钾、氢氧化钾、碳酸钠或三乙胺存在下,在氮气保护下,将烟酰氯的有机溶液滴入重量浓度2-12%的壳寡糖水溶液中,温度为-10℃~10℃,反应0.5-3h,向反应液加入其体积1-8倍的乙醚、丙酮、乙醇、甲醇、或0-1.5摩尔/升NaOH的乙醇或甲醇溶液,产生大量黄色沉淀,抽滤,滤饼用无水丙酮、乙醚、乙醇或甲醇洗1-5次,得黄色粉末,真空干燥,得到N-烟酰基壳寡糖粉末固体。
4.按照权利要求3所述N-烟酰基壳寡糖的的制备方法,其特征在于:所述有机溶剂为:N,N-二甲基甲酰胺(DMF)、吡啶、二甲亚砜或二氯甲烷。
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CN102532207A (zh) * | 2010-12-24 | 2012-07-04 | 大连中科格莱克生物科技有限公司 | 一类n-不饱和脂肪酸酰化壳寡糖及其制备和应用 |
CN106046197A (zh) * | 2016-05-31 | 2016-10-26 | 中国科学院海洋研究所 | 一种具有抑菌活性的化合物及其制备和应用 |
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