CN118084700A - 一种氨基酸型衍生物及应用 - Google Patents
一种氨基酸型衍生物及应用 Download PDFInfo
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- CN118084700A CN118084700A CN202410222005.2A CN202410222005A CN118084700A CN 118084700 A CN118084700 A CN 118084700A CN 202410222005 A CN202410222005 A CN 202410222005A CN 118084700 A CN118084700 A CN 118084700A
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Abstract
本发明属于表面活性剂技术领域,具体涉及一种氨基酸型衍生物及应用。所述氨基酸型衍生物以天冬氨酸或谷氨酸为架构,在两个羧基上分别接有疏水长链,在氨基上连有含亲水性基的基团,所述氨基酸型衍生物具有如下所示的化学结构式。本发明提供的氨基酸型衍生物是一种生物基团表面活性剂,具有良好的生物相容性,可体内代谢,易生物降解。并且该类表面活性剂制备方法简单,可规模化生产。
Description
技术领域
本发明属于表面活性剂技术领域,具体涉及一种氨基酸型衍生物及应用。
背景技术
表面活性剂能够降低液体表面张力,具有增溶、乳化、润湿、去污、絮凝、破乳、渗透、起泡、消泡、缓蚀、杀菌等多种用途,广泛应用于医药、食品、日化、农药、石油开采等领域。传统表面活性剂的广泛使用往往会对环境造成不利影响,因此开发出低毒、可生物降解以及生物相容性好的表面活性剂具有非常重要的意义。。
表面活性剂在药物递送中可作为脂质材料使用。脂质材料是一类包含亲水性头基、连接基和疏水性尾链的两亲分子(J.Nanomed,2018,2:1008-1021)。其结构和理化性质与组成细胞膜的脂质分子相近,因此具有较好的组织相容性和细胞亲和力,可用于制备给药系统制剂,如脂质体(Liposome)、类脂囊泡(niosome)、脂质体复合物(lipoplex,LP)、脂质体聚合物(lipopolyplex,LPR)、质粒-脂质颗粒(stabilizedplasmid-lipidparticle,SPLP)、纳米脂质颗粒(lipidnanoparticle,LNP)等。这些递释系统在药物治疗领域逐渐开始发挥着越来越重要的作用,特别是在递送生物活性药物领域不可或缺。脂质材料的亲水性头基的类型、电性等因素会影响递释效率。连接基可以是醚键、酯键、氨基甲酸酯、酰胺、甘油和氨基酸(例如天冬氨酸和谷氨酸)等,其类型、长度和方向等因素会影响稳定性和递释效率。非极性尾链的数量、长度、化学键特异性、对称性(尾链非单链)对双层囊泡的形成中起着至关重要的作用(J.Nanomed,2018,2:1008-1021.)。鉴于被递送药物具有多样性和特异性,因此开发适用于不同药物递释需求的安全性高,稳定性好,可靶向递送,可控制释药速度和时间的脂质材料仍然具有非常重要的意义。
随着环境保护要求的逐步提高,开发生物表面活性剂和以生物物质为基础的表面活性剂具有非常重要的意义。由于氨基酸是可再生物质,由氨基酸合成的表面活性剂也具有作为可持续和环保物质的巨大潜力(ColloidsandSurfaces A.1997,123-124:49-70)。因此,开发出更多类型的氨基酸型衍生物可以满足不同领域的不同表面活性剂需求。
发明内容
本发明提供一种氨基酸型衍生物及其制备方法和应用,以天冬氨酸或谷氨酸为架构,在两个羧基上分别接有疏水长链,在氨基上连有含亲水性基的基团,将氨基酸与链状醇酯化得氨基酸α,β-二酯(或与链状胺酰胺化得氨基酸α,β-二酰胺)中间体,中间体的氨基连接末端为水溶性基团的化合物。这些化合物安全性好且生物可降解,可用于生物医药、食品、日化、农药及有害生物绿色防治等领域。
本发明是通过以下技术方案解决上述技术问题的。
本发明的第一个目的是提供一种氨基酸型衍生物或其可接受的盐,其特征在于,所述氨基酸型衍生物以天冬氨酸或谷氨酸为架构,在两个羧基上分别接有疏水长链,在氨基上连有含亲水性基的基团,所述氨基酸型衍生物具有如下所示的化学结构式:
其中,n为1或2;
Y、Z各自独立地为氧原子、氮原子或硫原子;
R'为H或烷基;
R1和R2各自独立地为H、末端连有亲水基团的C1-C6烃基、杂环基、磺酸基、磷酸基、2-羟基乙酰基、己酰基、樟脑酸基、氨基酸基、维生素基、单糖基、二糖基、2-10个氨基酸构成低聚肽基、糖醛酸基、聚乙二醇及衍生物基、聚丙二醇及衍生物基、衣康酸基、琥珀酸基、甘草酸基或甘草次酸基;
R3和R4各自独立地为胆固醇基及其衍生物、维生素A基及其衍生物、维生素D基及其衍生物、维生素E基及其衍生物、金刚烷醇基、腰果酚基及其衍生物、C6-30的饱和或不饱和烷烃基。
优选的,所述R1和R2为各自独立地为H、磺酸基、磷酸基、2-羟基乙酰基、己酰基、氨基酸基、维生素基、单糖基、聚乙二醇基、其中x为1-6;
R3和R4各自独立地为H、胆固醇基、维生素A基、维生素D基、维生素E基、金刚烷醇基、腰果酚基、C6-30的疏水碳链或含有支链的疏水碳链,所述疏水碳链中包括含0-8个的-CH=CH-、-C≡C-、-O-、-S-、-C(O)O-、-OC(O)-、-C(O)N-、-NC(O)-、-S-S-、-OC(O)O-、-O-N=C-、-C=N-O-、-OC(O)N-、-NC(O)N-、-NC(O)C-、-C(O)S-、-C(S)O-或-C=N-O-C(O)-。
优选的,R1和R2各自独立地为H、磺酸基、(2R,3R,4R,5R)-2,3,4,5,6-五羟基己酰基、琥珀酸基、乙醇酸基、其中x为1-6;
R3和R4各自独立地为胆固醇基、维生素A基、维生素D基、维生素E基、金刚烷醇基、腰果酚基、C6-C18的疏水碳链或含有支链的疏水碳链,所述疏水碳链中包括含0-6个的-CH=CH-、-C≡C-、-O-、-S-、-C(O)O-、-OC(O)-、-C(O)N-、-NC(O)-、-S-S-、-OC(O)O-、-O-N=C-、-C=N-O-、-OC(O)N-、-NC(O)N-、-NC(O)C-、-C(O)S-、-C(S)O-或-C=N-O-C(O)-。
优选的,R3和R4各自独立地为H、胆固醇基、维生素A基、维生素D基、维生素E基、金刚烷醇基、腰果酚基、C10-C18的疏水碳链或含有支链的疏水碳链,所述疏水碳链中包括含0-6个的-CH=CH-、-C(O)O-、-OC(O)-、-C(O)N-、-NC(O)-、-OC(O)O-、-C=N-O-、-OC(O)N-、-NC(O)C或-C(O)S-,所述支链为C3-C8的烷基。
本发明的第二个目的是提供上述氨基酸型衍生物的制备方法,包括以下步骤:
将氨基酸和长链醇或长链胺溶于溶剂中,在催化剂和保护气体下或酰胺缩合剂下反应得到中间体氨基酸α,β-二酯或中间体氨基酸α,β-二酰胺;
将中间体氨基酸α,β-二酯或中间体氨基酸α,β-二酰胺溶于溶剂中,加入卤磺酸、酸酐和DMAP、羧酸化合物和酸胺缩合试剂或葡萄糖酸内酯反应得到氨基酸型衍生物。
优选的,当合成中间体氨基酸α,β-二酯时,将氨基酸和长链醇溶于溶剂中,在催化剂和保护气体下进行回流分水反应得到中间体氨基酸α,β-二酯;氨基酸和长链醇的摩尔比为1:2~1:2.4,所述氨基酸为天冬氨酸或谷氨酸;所述催化剂用量为氨基酸摩尔量的1-1.5倍,所述催化剂为对甲苯磺酸一水合物;所述回流分水反应的温度为90-140℃,时间为6-18h;
当合成中间体氨基酸α,β-二酰胺时,将氨基酸和长链胺溶于溶剂中,在酰胺缩合剂下反应得到氨基酸α,β-二酰胺,在冰水浴条件下加入脱保护试剂经脱保护反应得中间体氨基酸α,β-二酰胺;氨基酸和长链胺的摩尔比为1:2~1:2.4,所述氨基酸为Boc-天冬氨酸或Boc-谷氨酸;所述酰胺缩合剂的用量为氨基酸摩尔量的1:2~1:2.4,酰胺缩合剂为HOAT和EDCI,HOAT和EDCI的摩尔比1:0.8-1.2,Boc-氨基酸为Boc-天冬氨酸或Boc-谷氨酸;反应的温度为20-30℃,时间为6-18h;脱保护试剂为三氟乙酸,三氟乙酸的用量为Boc-氨基酸α,β-二酰胺摩尔量的8-12倍,脱保护反应的温度为20-30℃,时间为6-18h。
优选的,当氨基酸型衍生物为氨基酸α,β-二酯N-磺酰化产物时,制备方法包括以下步骤:将中间体氨基酸α,β-二酯溶于二氯甲烷中,冰水浴条件下滴加卤磺酸溶液和DIPEA为缚酸剂,反应得到氨基酸α,β-二酯N-磺酰化产物;中间体氨基酸α,β-二酯和卤磺酸的摩尔比为1:1-1:1.1,DIPEA用量为氨基酸α,β-二酯摩尔量的3-5倍,反应的温度为20-30℃,时间为6-18h;
当氨基酸型衍生物为氨基酸α,β-二酯N-氧代羧酸产物时,制备方法包括以下步骤:将中间体氨基酸α,β-二酯溶于二氯甲烷中,加入酸酐和DMAP,反应得到氨基酸α,β-二酯N-氧代羧酸;中间体氨基酸α,β-二酯和酸酐的摩尔比为1:1-1:1.4,DMAP用量为氨基酸α,β-二酯摩尔量的1.5-2.5倍,反应的温度为20-30℃,时间为6-18h;
当氨基酸型衍生物为氨基酸α,β-二酯N-酰胺化产物时,制备方法包括以下步骤:将中间体氨基酸α,β-二酯溶于二氯甲烷中,加入羧酸化合物和酸胺缩合试剂,反应得到氨基酸α,β-二酯N-酰胺化产物;中间体氨基酸α,β-二酯与乙醇酸的摩尔比为1:1-1:1.5,酸胺缩合试剂的用量为氨基酸α,β-二酯摩尔量的1.0-1.5倍,酸胺缩合试剂为HOAT和EDCI,HOAT和EDCI的摩尔比1:0.8-1.2,反应的温度为20-30℃,时间为6-18h;
当氨基酸型衍生物为氨基酸α,β-二酯N-葡萄糖酸酯产物时,制备方法包括以下步骤:将中间体氨基酸α,β-二酯溶于水中,加入葡萄糖酸内酯,在保护气体下反应得到氨基酸α,β-二酯N-葡萄糖酸酯产物;中间体氨基酸α,β-二酯和葡萄糖酸内酯的摩尔比为1:0-1:1.2,反应温度为60-100℃,时间为6-18h,保护气体为氮气或氦气。
本发明的第三个目的是提供上述氨基酸型衍生物在表面活性剂中的应用,所述表面活性剂作为药物、增溶剂、乳化剂、润湿剂、分散剂、絮凝剂、发泡剂、洗涤剂、稳定剂、促渗透剂、抗微生物试剂、基因转染载体、药物转运载体、药物缓控释材料、脂质体材料、微球材料或脂质纳米颗粒材料在生物医药中的应用。
作为生物化学物质递送物质,包括但不限于核酸、质粒DNA、DNA疫苗、蛋白质、疫苗、免疫球蛋白、免疫调节剂(如免疫刺激剂、免疫抑制剂、抗体和细胞因子)、寡核苷酸、反义寡核苷酸、反义核酸、siRNA、miRNA、snRNA、mRNA、核酸适配体、肽、激素、毒素、酶、多糖、微生物药物(如灭活疫苗、减毒活疫苗)、甾体、萜类。
所述表面活性剂作为乳化剂、增稠剂、保鲜剂、分散剂或起泡剂在食品中的应用。
所述表面活性剂作为乳化剂、渗透剂、洗涤剂、柔软剂、润湿剂、杀菌剂、分散剂、增溶剂、抗静电剂或染发剂在日化产品中的应用。
所述表面活性剂作为农药分散剂、增溶剂、润湿剂、乳化剂、抗微生物剂、蚊蝇阻飞剂、化肥抗结块剂或水分蒸发抑制剂在农药中的应用。
本发明与现有技术相比具有如下有益效果:
本发明提供的氨基酸型衍生物是一种生物基团表面活性剂,具有良好的生物相容性,可体内代谢,易生物降解。并且该类氨基酸型衍生物制备方法简单,可规模化生产。其中,(S)-4-((1,4-二氧代-1,4-双(十二烷氧基)丁-2-基)氨基)-4-氧代丁酸制备空白脂质体,结果显示制得的空白脂质体粒径平均为79.78nm,PDI平均为0.188,表面电位平均为-50.14mV,具有较好稳定性。并选取了部分化合物进行溶血性试验,结果显示溶血率较吐温80溶血率低;选取了部分化合物进行进行细胞毒性试验,显示出大部分化合物较小细胞毒性,本发明提供的氨基酸型衍生物是一类可再生物质来源的新型绿色表面活性剂,其结构特点是含有氨基酸基团或氨基酸残基。对人类和环境(特别是海洋生物)的低毒性或无毒性,对皮肤温和且无刺激性,使其适合作为食品成分、药物和化妆品。
附图说明
图1为本发明实施例1L-天冬氨酸α,β-二肉豆蔻醇酯对甲苯磺酸盐的质谱图;
图2为本发明实施例1L-天冬氨酸α,β-二肉豆蔻醇酯对甲苯磺酸盐的核磁氢谱图;
图3为本发明实施例2L-谷氨酸α,β-二肉豆蔻醇酯对甲苯磺酸盐的质谱图;
图4为本发明实施例2L-谷氨酸α,β-二肉豆蔻醇酯对甲苯磺酸盐的核磁氢谱图;
图5为本发明实施例3(S)-(1,4-双(十四氨基)-1,4-二氧丁-2-基)氨基的质谱图;
图6为本发明实施例3(S)-(1,4-双(十四氨基)-1,4-二氧丁-2-基)氨基的核磁氢谱图;
图7为本发明(S)-4-((1,4-二氧代-1,4-双(十二烷氧基)丁-2-基)氨基)-4-氧代丁酸制备的空白脂质体粒径分布图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
需要说明的是,本发明中所使用的专业术语只是为了描述具体实施例的目的,并不是旨在限制本发明的保护范围,除非另有特别说明,本发明以下各实施例中用到的各种原料、试剂、仪器和设备均可通过市场购买得到或者通过现有方法制备得到。
一种氨基酸型衍生物,所述氨基酸型衍生物以天冬氨酸或谷氨酸为架构,在两个羧基上分别接有疏水长链,在氨基上连有含亲水性基的基团,所述基酸型表面活性剂具有如下所示的化学结构式:
其中,n为1或2;
Y为氧原子、氮原子或硫原子;
Z为氧原子、氮原子或硫原子;
R'为H、烷基或不存在;
R1和R2各自独立地为H、末端连有亲水基团的C1-C6烃基、杂环基、磺酸基、磷酸基、2-羟基乙酰基、樟脑酸基、氨基酸基、维生素基、单糖基、二糖基、2-10个氨基酸构成低聚肽基、糖醛酸基、聚乙二醇及衍生物基、聚丙二醇及衍生物基、衣康酸基、琥珀酸基、甘草酸基或甘草次酸基;
R3和R4各自独立地为H、胆固醇基及其衍生物、维生素A基及其衍生物、维生素D基及其衍生物、维生素E基及其衍生物、金刚烷醇基、腰果酚基及其衍生物、C6-30的饱和或不饱和烷烃基。
所述氨基酸型衍生物包含亲水头基、氨基酸骨架、疏水基团,如下所示:
在一些具体的实施例中,亲水头基即R'、R1和R2各自独立地为如下基团:
m=0~6M=Na,K,Li,1/2Ca,1/2Mg,1/2Zn,1/2Fe,1/3AlX=Cl,Br,I在一些具体的实施例中,R3和R4各自独立地为如下基团:
本发明氨基酸型衍生物的实例包括上述结构任意连接于天冬氨酸或谷氨酸所得的表面活性剂和脂质及其盐(包括其药学上可接受的盐),更具体的,氨基酸型衍生物的结构如下所示。
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n=1,2;m=0-6;Y,Z=O/S/NH
以下通过具体的实施例进行进一步说明。
实施例1
中间体L-天冬氨酸α,β-二肉豆蔻醇酯对甲苯磺酸盐(化合物1)的制备方法,包括以下步骤:
取250ml圆底烧瓶,称取L-天冬氨酸1.34g(10mmol),肉豆蔻醇4.72g(22mmol),对甲苯磺酸一水合物2.28g(12mmol),甲苯150ml,安装好分水器和冷凝管,氮气保护下130℃分水回流过夜。反应完毕,将反应液冷至室温,减压回收溶剂,向残留物中加入乙酸乙酯30ml,加热溶解完全,室温静置重结晶。次日进行抽滤,得到的固体用适量的乙酸乙酯洗涤,最终收集得到白色絮状固体6.29g,产率90.13%;合成反应式如下:
ESI-MS:m/z526.4857[M+H]+(C32H64NO4)(理论值526.4835),如图1所示;
1H NMR(600MHz,CDCl3)δ:1H NMR(600MHz,Chloroform-d)δ8.32(d,J=5.6Hz,2H),7.73(d,J=8.1Hz,2H),7.12(d,J=7.9Hz,2H),4.41(q,J=4.9Hz,1H),4.13-4.02(m,2H),4.01-3.93(m,2H),3.16(dd,J=18.1,4.7Hz,1H),3.04(dd,J=18.1,4.9Hz,1H),2.78(s,1H),2.34(s,3H),1.52(d,J=6.5Hz,4H),1.32-1.20(m,44H),0.88(t,J=7.0Hz,6H),如图2所示。
实施例2
中间体L-谷氨酸α,β-二肉豆蔻醇酯对甲苯磺酸盐(化合物2)的制备方法,包括以下步骤:
取250ml茄形瓶,称取L-谷氨酸1.47g(10mmol),肉豆蔻醇4.72g(22mmol),对甲苯磺酸一水合物2.28g(12mmol),甲苯150ml,安装好分水器和冷凝管,氮气保护下130℃分水回流过夜。反应完毕,将反应液冷至室温,减压回收溶剂,向残留物中加入乙酸乙酯30ml,加热溶解完全,室温静置重结晶。次日进行抽滤,得到的固体用适量的乙酸乙酯洗涤,得白色固体5.34g,产率75.11%;合成反应式如下:
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ESI-MS:m/z540.5032[M+H]+(C33H66NO4)(理论值540.4992),如图3所示;
1HNMR(600MHz,Chloroform-d)δ:8.27(s,2H),7.74(d,J=7.4Hz,2H),7.12(d,J=7.8Hz,2H),4.13-4.07(m,1H),4.05-4.00(m,1H),3.98-3.94(m,2H),2.74(s,2H),2.55-2.47(m,1H),2.45-2.38(m,1H),2.34(s,3H),2.25-2.11(m,2H),1.61-1.44(m,4H),1.36-1.14(m,44H),0.88(t,J=7.0,2.0Hz,6H),如图4所示。
实施例3
(S)-(1,4-双(十四氨基)-1,4-二氧丁-2-基)氨基(化合物3)的制备方法,包括以下步骤:
称取Boc-L-天冬氨酸2.33g(10mmol),十四胺4.69g(22mmol),HOAT 2.99g(22mmol),无水二氯甲烷40ml,搅拌至全溶。加入EDCI3.41g(24mmol),室温搅拌过夜。反应完毕,抽滤,滤液柱层析,得白色固体产物5.48g,产率87.82%;
取上一步产物1.62g(2.6mmol),溶于10ml二氯甲烷。冰水浴条件下,缓慢滴加三氟乙酸2ml,自然升至室温,过夜反应。反应完毕,减压蒸除溶剂和三氟乙酸,加二氯甲烷溶解,用1M碳酸氢钠溶液洗涤,有机层干燥,蒸干,柱层析得白色固体产物720mg,产率52.9%;合成反应式如下:
ESI-MS:m/z524.5174[M+H]+(C32H66N3O2)(理论值524.5155),如图5所示;
1HNMR(600MHz,Chloroform-d)δ:7.52(s,1H),6.30-6.18(m,1H),3.65(s,1H),3.20-3.18(m,4H),2.62-2.60(m,1H),2.57-2.52(m,1H),1.98(s,2H),1.50-
1.43(m,4H),1.31-1.21(m,44H),0.87(t,J=6.9Hz,6H),如图6所示;
13CNMR(151MHz,Chloroform-d)δ:173.83,171.03,52.80,40.95,39.56,39.39,31.94,29.72,29.71,29.68,29.64,29.59,29.56,29.38,29.34,26.97,22.71,14.13。
实施例4
(S)-(1,4-双(十四烷氧基)-1,4-二氧丁-2-基)氨基磺酸(化合物4)的制备方法,包括以下步骤:
称取L-天冬氨酸α,β-二肉豆蔻醇酯526mg(1mmol),加入无水二氯甲烷6ml,搅拌至全溶。冰水浴条件下,缓慢滴加氯磺酸66μL(1mmol)溶于2ml无水二氯甲烷的溶液,再缓慢滴加DIPEA0.66ml(3.8mmol),自然升至室温反应过夜。反应完毕,蒸除溶剂,残留物硅胶柱层析(乙酸乙酯:甲醇=12:1),得白色固体产物296mg,产率48.8%;合成反应式如下:
ESI-MS:m/z604.4268[M-H]-(C32H62NO7S)(理论值604.4247);
1HNMR(600MHz,Chloroform-d)δ:5.44(s,1H),4.42-4.37(m,1H),4.16(dd,J=11.8,5.8Hz,1H),4.08-3.98(m,3H),2.98-2.84(m,2H),2.07(s,1H),1.63-1.53(m,4H),1.32-1.23(m,44H),0.88(t,J=6.9Hz,6H);
13CNMR(151MHz,Chloroform-d)δ:175.46,174.79,69.16,66.48,65.76,33.11,33.10,31.16,30.82,30.77,30.72,30.52,30.50,30.45,30.43,29.77,29.70,29.63,27.10,27.07,23.77,14.48。
实施例5
(S)-N-((2R,3R,4R,5R)-2,3,4,5,6-五羟基己酰基)-天冬氨酸α,β-二肉豆蔻醇酯(化合物5)的制备方法,包括以下步骤:
称取L-天冬氨酸α,β-二肉豆蔻醇酯526mg(1mmol),葡萄糖酸内酯194mg(1.1mmol),加入纯净水8ml,氮气保护,80℃反应过夜。反应完毕,蒸除水分,残留物硅胶柱层析(乙酸乙酯:甲醇=12:1),得白色固体产物388mg,产率55.2%;合成反应式如下:
ESI-MS:m/z704.5322[M+H]+(C38H74NO10)(理论值704.5313);
1HNMR(600MHz,Chloroform-d)δ:7.88(d,J=8.6Hz,1H),4.86(dt,J=9.4,4.9Hz,1H),4.37(s,1H),4.30(q,J=8.7,7.7Hz,1H),4.16(dd,J=17.3,7.2Hz,3H),4.07(tt,J=16.8,7.2Hz,4H),3.86-3.69(m,4H),3.12-2.94(m,2H),2.85(dd,J=17.4,4.9Hz,2H),1.65-1.57(m,4H),1.33-1.24(m,44H),0.88(t,J=6.9Hz,6H);
13CNMR(151MHz,Chloroform-d)δ:173.07,171.11,171.06,73.90,71.84,70.62,66.37,65.48,63.72,48.52,36.07,31.99,29.80,29.75,29.68,29.43,28.59,28.48,25.96,25.91,22.74,14.15。
实施例6
(S)-N-((2R,3R,4R,5R)-2,3,4,5,6-五羟基己酰基)-谷氨酸α,β-二肉豆蔻醇酯(化合物6)的制备方法,包括以下步骤:
称取L-谷氨酸α,β-二肉豆蔻醇酯540mg(1mmol),葡萄糖酸内酯194mg(1.1mmol),加入纯净水8ml,氮气保护,80℃反应过夜。反应完毕,蒸除水分,残留物硅胶柱层析(乙酸乙酯:甲醇=12:1),得白色固体产物392mg,产率54.6%;合成反应式如下:
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ESI-MS:m/z718.5466[M+H]+(C39H76NO10)(理论值718.5469);
1HNMR(600MHz,Chloroform-d)δ:7.91(d,J=7.8Hz,1H),5.40(d,J=5.2Hz,1H),4.51(d,J=4.9Hz,1H),4.42(d,J=5.3Hz,1H),4.36-4.29(m,3H),4.09-4.03(m,2H),3.99(m,5.3Hz,3H),3.89(m,1H),3.60-3.56(m,1H),3.47(s,2H),3.36(m,1H),2.37-2.30(m,2H),2.02(m,1H),1.92(m,1H),1.55(q,J=7.4Hz,4H),1.23(m,44H),0.85(t,J=6.9Hz,6H);
13CNMR(151MHz,Chloroform-d)δ:172.70,172.05,171.44,73.40,72.31,71.56,70.20,64.65,63.90,63.44,51.00,31.44,29.81,29.22,29.18,28.87,28.20,28.10,26.49,25.47,22.19,13.87.
实施例7
(S)-4-((1,4-二氧代-1,4-双(十二烷氧基)丁-2-基)氨基)-4-氧代丁酸(化合物7)的制备方法,包括以下步骤:
称取L-天冬氨酸α,β-二月桂醇酯470mg(1mmol),无水二氯甲烷8ml,搅拌至全溶,加入丁二酸酐120mg(1.2mmol),加入DMAP244mg(1.92mmol),室温反应过夜。反应完毕,蒸除溶剂,残留物硅胶柱层析(乙酸乙酯:甲醇=12:1),得白色固体产物319mg,产率56.0%;合成反应式如下:
ESI-MS:m/z570.4357[M+H]+(C32H60NO7)(理论值570.4370);
1H NMR(600MHz,Chloroform-d)δ:6.75(d,J=7.9Hz,1H),4.82(m,1H),4.18-4.10(m,2H),4.06(m,2H),3.02(m,1H),2.83(m,1H),2.75-2.64(m,2H),2.62-2.52(m,2H),1.61m,4H),1.36-1.19(m,44H),0.87(t,J=6.9Hz,6H);
13C NMR(151MHz,Chloroform-d)δ:176.4,171.6,171.2,170.7,66.2,65.4,48.8,36.2,32.0,30.6,29.7,29.7,29.7,29.6,29.6,29.4,29.3,29.3,29.23,28.6,28.5,25.9,25.8,22.7,14.14。
实施例8
(R)-4-(((1,5-双(十四烷氧基)-1,5-二氧代戊烷-2-基)氨基)-4-氧代丁酸(化合物8)的制备方法,包括以下步骤:
称取S-谷氨酸α,β-二肉豆蔻醇酯540mg(1mmol),无水二氯甲烷8ml,搅拌至全溶,加入丁二酸酐120mg(1.2mmol),加入DMAP244mg(1.92mmol),室温反应过夜。反应完毕,蒸除溶剂,残留物硅胶柱层析(乙酸乙酯:甲醇=12:1),得白色固体产物344mg,产率53.8%;合成反应式如下:
ESI-MS:m/z640.5200[M+H]+(C37H70NO7)(理论值640.5152);
1H NMR(600MHz,Chloroform-d)δ:6.57(d,J=7.7Hz,1H),4.62-4.58(m,1H),4.13(t,J=6.8Hz,2H),4.06(t,J=6.9Hz,2H),2.76-2.65(m,2H),2.57(d,J=6.4Hz,2H),2.46-2.39(m,1H),2.39-2.32(m,1H),2.24-2.15(m,1H),2.03-1.97(m,1H),1.66-1.59(m,4H),1.25(s,44H),0.88(t,J=7.0Hz,6H).;
13C NMR(151MHz,Chloroform-d)δ:176.39,173.16,171.97,171.86,65.99,65.12,51.94,31.94,30.58,30.31,29.72,29.70,29.67,29.62,29.56,29.53,29.38,29.30,29.23,28.59,28.50,27.38,25.91,25.82,22.70,14.12.。
实施例9
双十四烷基(2-羟基乙酰基)-D-天冬氨酸(化合物9)的制备方法,包括以下步骤:
称取D-天冬氨酸α,β-二肉豆蔻醇526mg(1mmol),乙醇酸91mg(1.2mmol),HOAT163mg(1.2mmol),EDCI230mg(1.2mmol),无水二氯甲烷10ml,室温反应过夜。反应完毕,蒸除溶剂,残留物硅胶柱层析(石油醚:乙酸乙=4:1),得白色固体产物429mg,产率73.5%;合成反应式如下:
ESI-MS:m/z584.4881[M+H]+(C34H66NO6)(理论值584.4890);
1H NMR(600MHz,Chloroform-d)δ:7.31(d,J=8.3Hz,1H),4.90-4.87(m,1H),4.19-4.12(m,4H),4.09-4.04(m,2H),3.05(dd,J=17.2,4.5Hz,1H),2.85(dd,J=17.2,4.5Hz,1H),2.71(s,1H),1.64-1.58(m,4H),1.32-1.25(m,44H),0.88(t,J=7.0Hz,6H).;
13C NMR(151MHz,Chloroform-d)δ:171.70,171.00,170.65,66.22,65.43,62.16,48.19,36.36,31.95,29.73,29.71,29.69,29.63,29.56,29.39,29.29,29.25,28.55,28.47,25.89,25.82,22.72,14.14.。
实施例10
双十四烷基(2-羟基乙酰基)-L-谷氨酸(化合物10)的制备方法,包括以下步骤:
称取L-谷氨酸α,β-二肉豆蔻醇酯540mg(1mmol),乙醇酸91mg(1.2mmol),HOAT163mg(1.2mmol),EDCI230mg(1.2mmol),无水二氯甲烷10ml,室温反应过夜。反应完毕,蒸除溶剂,残留物硅胶柱层析(石油醚:乙酸乙=4:1),得白色固体产物433mg,产率72.4%;合成反应式如下:
ESI-MS:m/z598.5038[M+H]+(C35H68NO6)(理论值598.5047);
1H NMR(600MHz,Chloroform-d)δ:7.09(d,J=8.0Hz,1H),4.66(q,J=8.0Hz,1H),4.13(d,J=5.2Hz,4H),4.06(t,J=6.8Hz,2H),2.45-2.34(m,2H),2.26-2.21(m,1H),2.06-2.00(m,1H),1.66-1.58(m,4H),1.35-1.23(m,44H),0.87(t,J=6.9Hz,6H).;
13C NMR(151MHz,DMSO-d6)δ:172.92,171.91,171.87,66.03,65.10,62.16,51.34,31.94,30.40,29.72,29.70,29.68,29.61,29.55,29.53,29.38,29.29,29.23,28.59,28.50,27.47,25.91,25.83,22.71,14.13.。
应用例1
将实施例7制备的表面活性剂化合物(S)-4-((1,4-二氧代-1,4-双(十二烷氧基)丁-2-基)氨基)-4-氧代丁酸制备脂质体试验,包括以下步骤:
称取100mg大豆磷脂,50mg受试化合物和15mg胆固醇溶解于3mL二氯甲烷中,于40℃水浴中减压蒸发至二氯甲烷完全挥干,使脂质在圆底烧瓶壁上形成薄膜。加入5mL的水于40℃旋转水化,水化时间为30min,使脂质体均匀地分散在水中,冰浴超声5min,再经探头超声处理3min(功率为200w),经0.45μm的滤膜过滤,即得空白脂质体。重复制备3份,结果如表1所示,制得的空白脂质体粒径平均为79.78nm,PDI平均为0.188,表面电位平均为-50.14mV,显示该脂质体具有较好稳定性。
三批空白脂质体重现性试验粒径分布图谱见附图7。
表1空白脂质体重现性试验结果数据
氨基酸表面活性剂化合物4-10溶血性试验
将0.1mL小鼠红细胞悬浮液(2%V/V)依次加入到0.9mL含有不同浓度样品(400-50μM)的生理盐水、0.9mL蒸馏水和0.9mL生理盐水中,作为实验组、阳性对照组和阴性对照组。轻轻摇动后,混合物在37℃下孵育3小时。将所有样品以10000rpm离心1分钟并拍照,然后将获得的上清液转移到新的96孔透明板上,用微孔板读取器测量541nm处的吸光度,计算溶血率,实验重复三次。
结果如表2所示,所选化合物4-10的溶血率较吐温80溶血率低,说明其溶血性安全性好。
表2化合物4-10溶血率
氨基酸表面活性剂化合物4-10细胞毒性试验
将生长至对数生长期的HePG2细胞以1×105细胞/孔的密度接种到96孔板中,37℃培养24h后将细胞分为空白组(完全培养基)、给药组(1-8号化合物,400、200、100、50μM),加入含有相应药物浓度的培养基,培养24h后,MTT法测定细胞活力,实验重复三次。
结果表3所示,所选化合物细胞毒性较小。
表3化合物4-10的细胞毒性
需要说明的是,本发明中涉及数值范围时,应理解为每个数值范围的两个端点以及两个端点之间任何一个数值均可选用,由于采用的步骤方法与实施例相同,为了防止赘述,本发明描述了优选的实施例。尽管已描述了本发明的优选实施例,但本领域内的技术人员一旦得知了基本创造性概念,则可对这些实施例做出另外的变更和修改。所以,所附权利要求意欲解释为包括优选实施例以及落入本发明范围的所有变更和修改。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (9)
1.一种氨基酸型衍生物,其特征在于,所述氨基酸型衍生物具有如下所示的化学结构式:
其中,n为1或2;
Y、Z各自独立地为氧原子、氮原子或硫原子;
R'为H或烷基;
R1和R2各自独立地为H、末端连有亲水基团的C1-C6烃基、杂环基、磺酸基、磷酸基、乙酰基、己酰基、樟脑酸基、氨基酸基、维生素基、单糖基、二糖基、2-10个氨基酸构成低聚肽基、糖醛酸基、聚乙二醇及衍生物基、聚丙二醇及衍生物基、衣康酸基、琥珀酸基、甘草酸基或甘草次酸基;
R3和R4各自独立地为胆固醇基及其衍生物、维生素A基及其衍生物、维生素D基及其衍生物、维生素E基及其衍生物、金刚烷醇基、腰果酚基及其衍生物、C6-30的饱和或不饱和烷烃基。
2.根据权利要求1所述的氨基酸型衍生物,其特征在于,所述R1和R2各自独立地为H、磺酸基、磷酸基、2-羟基乙酰基、己酰基、氨基酸基、维生素基、单糖基、聚乙二醇基、其中x为1-6。
3.根据权利要求1所述的氨基酸型衍生物,其特征在于,所述R3和R4各自独立地为H、胆固醇基、维生素A基、维生素D基、维生素E基、金刚烷醇基、腰果酚基、C6-30的疏水碳链或含有支链的疏水碳链,所述疏水碳链中包括含0-8个的-CH=CH-、-C≡C-、-O-、-S-、-C(O)O-、-O C(O)-、-C(O)N-、-NC(O)-、-S-S-、-OC(O)O-、-O-N=C-、-C=N-O-、-OC(O)N-、-NC(O)N-、-NC(O)C-、-C(O)S-、-C(S)O-或-C=N-O-C(O)-。
4.根据权利要求2所述的氨基酸型衍生物,其特征在于,R1和R2各自独立地为H、磺酸基、(2R,3R,4R,5R)-2,3,4,5,6-五羟基己酰基、琥珀酸基、乙醇酸基、其中x为1-6。
5.根据权利要求3所述的氨基酸型衍生物,其特征在于,R3和R4各自独立地为H、胆固醇基、维生素A基、维生素D基、维生素E基、金刚烷醇基、腰果酚基、C6-C18的疏水碳链或含有支链的疏水碳链,所述疏水碳链中包括含0-6个的-CH=CH-、-C≡C-、-O-、-S-、-C(O)O-、-O C(O)-、-C(O)N-、-NC(O)-、-S-S-、-OC(O)O-、-O-N=C-、-C=N-O-、-OC(O)N-、-NC(O)N-、-NC(O)C-、-C(O)S-、-C(S)O-或-C=N-O-C(O)-。
6.根据权利要求5所述的氨基酸型衍生物,其特征在于,R3和R4各自独立地为H、胆固醇基、维生素A基、维生素D基、维生素E基、金刚烷醇基、腰果酚基、C10-C18的疏水碳链或含有支链的疏水碳链,所述疏水碳链中包括含0-6个的-CH=CH-、-C(O)O-、-O C(O)-、-C(O)N-、-NC(O)-、-OC(O)O-、-C=N-O-、-OC(O)N-、-NC(O)C或-C(O)S-,所述支链为C3-C8的烷基。
7.根据权利要求1所述的氨基酸型衍生物,其特征在于,所述氨基酸型衍生物具体为以下化合物:
其中,n为1或2;m为0-6;Y,Z为O、S或NH。
8.根据权利要求1所述的氨基酸型衍生物,其特征在于,所述氨基酸型衍生物具体为以下化合物:
9.一种权利要求1所述的氨基酸型衍生物在表面活性剂中的应用。
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