CN108640935A - 一种稀土绿原酸咪唑三元抑菌剂及制备方法 - Google Patents
一种稀土绿原酸咪唑三元抑菌剂及制备方法 Download PDFInfo
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Abstract
本发明的目的在于提供一种稀土绿原酸咪唑三元抑菌剂及制备方法,通式为REX‑(CA)Y‑(IM)Z;其中,X=1~2;Y=0~2;Z=0~5;Y、Z不同时等于0;稀土RE选取La、Ce、Pr、Nd、Sm、Eu、Gd、Tb、Dy、Ho、Er、Yb、Y中的任意一种三价离子的盐酸盐或硝酸盐;第一配体CA为绿原酸,第二配体IM为咪唑;绿原酸:咪唑:酸性溶剂的摩尔比为1~2:0~2:0~5:5~20。本发明的有益效果是该三元配合物表现出优良的抗炎、抗菌、抗癌、抗氧化等生物活性。
Description
技术领域
本发明属于生物技术领域,涉及一种稀土绿原酸咪唑三元配合物及其制备方法。
背景技术
稀土是有效的杀菌剂,经常用于生物活性剂改善药物的性能,但是直接利用稀土氧化物或稀土离子对生物体或细胞有氧化损害作用。绿原酸具有广泛的生物活性,现代科学对绿原酸生物活性的研究已深入到食品、保健、医药和日用化工等多个领域。绿原酸是一种重要的生物活性物质,具有抗菌、抗病毒、增高白血球、保肝利胆、抗肿瘤、降血压、降血脂、清除自由基和兴奋中枢神经系统等作用。金银花叶作为金银花的一种副产物,产量较大,而且常常被浪费掉,研究表明,金银花叶、紫锥菊、蒲公英等中草药中都含有丰富的绿原酸,对于绿原酸产品的分离、纯化并用于与稀土及咪唑合成具有生物活性的三元配合物还未见报道。本发明采用回流、萃取及沉淀分离相结合的方法从含有绿原酸的中草药中分离出绿原酸,并与稀土和咪唑在特定溶液中按一定配比生成一系列配合物,该类配合物表现出优良的抗炎、抗菌、抗癌、抗氧化等生物活性。咪唑是医药抗真菌药双氯苯咪唑、益康唑、酮康唑、克霉唑的中间体。作为医药原料,用于制造抗真菌药、抗霉剂、低血糖治疗药、人造血浆、滴虫治疗药、支气管哮喘治疗药、防斑疹剂等。针对稀土氧化物或稀土离子对生物体或细胞有氧化损害作用的问题,提高稀土配合物的生物活性。本发明提供一种稀土三元配合物;降低直接利用稀土氧化物或稀土离子对生物体或细胞的氧化损害作用。充分利用当地中药材资源,利用稀土离子的强配位作用,选择具有特定生物活性的配体绿原酸和咪唑,与具有较好生理生化性能的稀土络合,生成稀土-绿原酸-咪唑三元配合物,由于三者之间发生协同作用,使该三元配合物的生物活性得到显著提高。
发明内容
本发明的目的在于提供一种稀土绿原酸咪唑三元抑菌剂及制备方法,本发明的有益效果是该三元配合物表现出优良的抗炎、抗菌、抗癌、抗氧化等生物活性。
本发明所采用的技术方案是本发明稀土绿原酸咪唑三元抑菌剂通式为:
REX-(CA)Y-(IM)Z
其中,X=1~2;Y=0~2;Z=0~5;Y、Z不同时等于0;
式中的稀土RE选取La、Ce、Pr、Nd、Sm、Eu、Gd、Tb、Dy、Ho、Er、Yb、 Y中的任意一种三价离子的盐酸盐或硝酸盐;
式中的第一配体CA为绿原酸,从一些含有绿原酸的中草药中提取。式中的第二配体IM为咪唑;第二配体咪唑由金银花、金银花叶、紫锥菊全草,蒲公英等含有绿原酸的中草药中提取获得。原料组份的摩尔比为稀土:绿原酸:咪唑:酸性溶剂的摩尔比为1~2:0~2:0~5:5~20。其中绿原酸和咪唑含量不同时为0。酸性溶剂为四氢呋喃、甲醇、乙醇和/或二甲亚砜等中的一种或多种。
本发明稀土绿原酸咪唑三元抑菌剂的制备方法,包括下列步骤:
步骤一,绿原酸的提取;
将金银花干燥花蕾、干燥叶、紫锥菊全草等中药材原料打磨成粉,用85%乙醇在60℃条件下回流提取三次,每次提取3h,提取液经冷冻分离出沉淀物,然后减压蒸馏回收乙醇,水浴上蒸发至干得到膏状物,用蒸馏水溶解过滤,滤液用稀H2SO4调节pH=2-3用乙酸乙酯进行萃取,合并萃取液回收溶剂,将所得产品溶于水,用醋酸铅溶液沉淀,沉淀水洗至滤液用稀H2SO4检不出Pb2+为止;再用pH=3的稀H2SO4酸化得到绿原酸水溶液,减压蒸发至干,置于硅胶干燥器中真空干燥至恒重;得到淡黄色绿原酸粉末;
步骤二,稀土硝酸盐或盐酸盐的制备;
称取一定量的稀土氧化物固体,溶于盐酸或硝酸中,让其充分反应并在水浴上缓慢蒸发至干;用丙酮洗涤,放在NaOH干燥器中干燥至恒重制得稀土三价离子的硝酸盐或盐酸盐;
步骤三,称取一定量的稀土三价离子的硝酸盐或盐酸盐水合物、绿原酸和咪唑,分别溶于乙醇溶液中,得到硝酸盐或盐酸盐水合物乙醇溶液、绿原酸乙醇溶液和咪唑乙醇溶液;先在硝酸盐或盐酸盐水合物乙醇溶液中加入绿原酸乙醇溶液,加热搅拌,60℃时加入含有咪唑的乙醇溶液,继续搅拌回流,用稀HCl溶液或者稀NaOH溶液缓慢调节酸度为pH值5,反应约5.0~10h,再将所得反应液旋转蒸发浓缩得到晶体,抽滤,用丙酮洗去过量的稀土盐,用乙醚洗去过量的咪唑,再用蒸馏水重结晶,放入P2O5真空干燥器中干燥至恒重,得稀土绿原酸咪唑三元抑菌剂。
在步骤二中,对氯化铈和氯化镨的制备分别用以下方法:将350g二氧化铈加入100mL水及680mL36%盐酸,加热溶解,有氯气逸出;反应式2CeO2+8HCl =2CeCl3+4H2O+Cl2↑,反应完毕,溶液应呈中性或弱酸性;经过滤,蒸发滤液至浓稠状并有发泡现象为止;再冷却至室温,吸滤结晶、干燥,即得氯化铈;用一个150mL烧杯称取Pr6O11稀土氧化物2g,加入5mL双氧水,再逐滴滴加 6mol·L-1的HCl直至溶解,80℃℃水浴加热,蒸去过量的双氧水、盐酸及多余的水分,将溶液蒸干,得到氯化镨固体。
具体实施方式
下面结合具体实施方式对本发明进行详细说明。
实施例1
一种生物活性物质稀土绿原酸咪唑三元配合物,由LaCl3、绿原酸、咪唑和溶剂按1:1:0.5:5的摩尔比配制而成。
金银花叶中绿原酸的制备:
三元配合物的合成按一定配比投料。先准确称取一定量的LaCl3·6H2O和绿原酸,分别溶于乙醇溶液中,咪唑溶解时需用1mol/L HCl将溶液调至pH值为3 左右,然后将LaCl3与绿原酸溶液混合,60℃左右水浴搅拌回流1.5~4h。将咪唑溶解于25mL乙醇中,经漏斗逐滴加入到混合液中。调节pH值至5。继续搅拌回流,反应约4~6h,反应完成后,转移至水浴中缓慢蒸发浓缩、真空干燥后,得三元固体配合物。实验表明该三元配合物具有良好的抗炎作用,对由二甲苯诱导的小鼠耳肿胀具有较好的抑制作用。与稀土-绿原酸二元配合物相比,能提高药物的脂溶性,从而促进细胞对药物的吸收,降低细胞毒性,提高药物疗效。
实施例2
一种具有生物活性物质稀土绿原酸咪唑三元配合物,由CeCl3、绿原酸、咪唑和溶剂按2:1:0.5:10的摩尔比配制而成。
实施例3
一种具有生物活性物质稀土绿原酸咪唑三元配合物,由氯化镨、绿原酸、咪唑和溶剂按5:2:2:8的摩尔比配制而成。
本发明的优点还在于:与稀土离子、稀土氧化物、稀土-绿原酸二元配合物相比,由于增加了咪唑作为配体,显著提高了抗菌活性,并且能避免直接利用稀土离子或稀土氧化物对生物体或细胞的氧化损害作用,提高药物的脂溶性,从而促进细胞对药物的吸收,降低细胞毒性,提高药物疗效。三元配合物表现出优良的生物活性和较小的细胞毒性。降低直接利用稀土氧化物或稀土离子对生物体或细胞的氧化损害作用,充分利用当地金银花叶等中草药资源,提高稀土配合物的生物活性,提高咪唑的抗菌活性。
以上所述仅是对本发明的较佳实施方式而已,并非对本发明作任何形式上的限制,凡是依据本发明的技术实质对以上实施方式所做的任何简单修改,等同变化与修饰,均属于本发明技术方案的范围内。
Claims (7)
1.一种稀土绿原酸咪唑三元抑菌剂,其特征在于:抑菌剂通式为:
REX-(CA)Y-(IM)Z
其中,X=1~2;Y=0~2;Z=0~5;Y、Z不同时等于0;
式中的稀土RE选取三价离子的盐酸盐或硝酸盐;
式中的第一配体CA为绿原酸;
式中的第二配体IM为咪唑;
原料组份的摩尔比为稀土:绿原酸:咪唑:酸性溶剂的摩尔比为1~2:0~2:0~5:5~20;其中绿原酸和咪唑含量不同时为0。
2.按照权利要求1所述一种稀土绿原酸咪唑三元抑菌剂,其特征在于:所述稀土RE选取La、Ce、Pr、Nd、Sm、Eu、Gd、Tb、Dy、Ho、Er、Yb、Y中的任意一种三价离子。
3.按照权利要求1所述一种稀土绿原酸咪唑三元抑菌剂,其特征在于:所述第一配体绿原酸从含有绿原酸的中草药中提取。
4.按照权利要求1所述一种稀土绿原酸咪唑三元抑菌剂,其特征在于:所述第二配体咪唑由金银花、金银花叶、紫锥菊全草,蒲公英中提取获得。
5.按照权利要求1所述一种稀土绿原酸咪唑三元抑菌剂,其特征在于:所述酸性溶剂为四氢呋喃、甲醇、乙醇和/或二甲亚砜等中的一种或多种。
6.一种稀土绿原酸咪唑三元抑菌剂的制备方法,其特征在于按照以下步骤进行:
步骤一,绿原酸的提取;
将金银花干燥花蕾、干燥叶、紫锥菊全草等中药材原料打磨成粉,用85%乙醇在60℃条件下回流提取三次,每次提取3h,提取液经冷冻分离出沉淀物,然后减压蒸馏回收乙醇,水浴上蒸发至干得到膏状物,用蒸馏水溶解过滤,滤液用稀H2SO4调节pH=2-3用乙酸乙酯进行萃取,合并萃取液回收溶剂,将所得产品溶于水,用醋酸铅溶液沉淀,沉淀水洗至滤液用稀H2SO4检不出Pb2+为止;再用pH=3的稀H2SO4酸化得到绿原酸水溶液,减压蒸发至干,置于硅胶干燥器中真空干燥至恒重;得到淡黄色绿原酸粉末;
步骤二,稀土硝酸盐或盐酸盐的制备;
称取一定量的稀土氧化物固体,溶于盐酸或硝酸中,让其充分反应并在水浴上缓慢蒸发至干;用丙酮洗涤,放在NaOH干燥器中干燥至恒重制得稀土三价离子的硝酸盐或盐酸盐;
步骤三,称取一定量的稀土三价离子的硝酸盐或盐酸盐水合物、绿原酸和咪唑,分别溶于乙醇溶液中,得到硝酸盐或盐酸盐水合物乙醇溶液、绿原酸乙醇溶液和咪唑乙醇溶液;先在硝酸盐或盐酸盐水合物乙醇溶液中加入绿原酸乙醇溶液,加热搅拌,60℃时加入含有咪唑的乙醇溶液,继续搅拌回流,用稀HCl溶液或者稀NaOH溶液缓慢调节酸度为pH值5,反应约5.0~10h,再将所得反应液旋转蒸发浓缩得到晶体,抽滤,用丙酮洗去过量的稀土盐,用乙醚洗去过量的咪唑,再用蒸馏水重结晶,放入P2O5真空干燥器中干燥至恒重,得稀土绿原酸咪唑三元抑菌剂。
7.按照权利要求6所述一种稀土绿原酸咪唑三元抑菌剂的制备方法,其特征在于:所述步骤二中稀土三价离子的盐酸盐为氯化铈和氯化镨,对氯化铈和氯化镨的制备分别用以下方法:将350g二氧化铈加入100mL水及680mL36%盐酸,加热溶解,有氯气逸出;反应式2CeO2+8HCl=2CeCl3+4H2O+Cl2↑,反应完毕,溶液应呈中性或弱酸性;经过滤,蒸发滤液至浓稠状并有发泡现象为止;再冷却至室温,吸滤结晶、干燥,即得氯化铈;用一个150mL烧杯称取Pr6O11稀土氧化物2g,加入5mL双氧水,再逐滴滴加6mol·L-1的HCl直至溶解,80℃℃水浴加热,蒸去过量的双氧水、盐酸及多余的水分,将溶液蒸干,得到氯化镨固体。
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