CN110573520A - 治疗剂及其制备方法 - Google Patents
治疗剂及其制备方法 Download PDFInfo
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- CN110573520A CN110573520A CN201780076841.2A CN201780076841A CN110573520A CN 110573520 A CN110573520 A CN 110573520A CN 201780076841 A CN201780076841 A CN 201780076841A CN 110573520 A CN110573520 A CN 110573520A
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Abstract
本发明整体涉及聚糖及其在用于治疗用途的糖缀合物生产中的应用的领域。本发明还涉及制备糖缀合物的方法。
Description
背景
本申请涉及2016年10月12日提交的、名称为“治疗剂及其制备方法”的美国临时专利申请No.62/407,109并要求其优先权,其全部内容在此通过引用并入本文。
技术领域
本发明整体上涉及多糖领域及,并涉及其在用于治疗用途的糖缀合物的生产中的应用。本发明还涉及制备糖缀合物的方法。
背景技术
本说明书中作者引用的出版物的书目细节在说明书末尾按字母顺序列出。
本说明书中对任何先前出版物(或从其衍生出的信息)或任何已知事实的引用,不是、也不应被视为是承认、接受或以任何形式表明先前出版物(或从其衍生出的信息)或已知事实构成本说明书涉及的研究领域中的公知常识的一部分。
糖胺多糖(GAG)是蛋白多糖的多糖部分,普遍存在于人体内并在许多生物过程中起关键作用。例如,GAG被认为是能够将生物调节剂(如趋化因子、细胞因子、生长因子和趋化剂)固定在细胞外基质和细胞表面上的关键生物结构。然而,就一些细胞因子而言,GAG相互作用会导致生理上不利的过程,如炎症、癌症转移以及具有反作用结果的各种免疫反应。目前,最著名的GAG之一是硫酸化多糖的肝素家族,其与蛋白质上的三维模体结合并且还具有抗凝血活性。
鉴于它们具有与生物调节剂相结合并调节其活性的能力,GAG已被提出作为潜在的治疗剂。
然而,GAG是异质的分子异质组[Conrad(1998)Heparin bindingproteins.Academic Press,San Diego;Lander and Selleck(2000)J.Cell Biol.148(2):227-232],通常是通过对重复糖单元的链的不完全修饰而合成的。此外,特定GAG的蛋白质结合特征特性很大程度上取决于糖链的硫酸化模式。GAG的硫酸化模式是复杂的,尤其是涉及到6-O-硫酸盐的定位。因此,并非所有的GAG分子都是相同的。类似地,在来自一个特定细胞或组织的GAG的制备中,并非所有分子都是相同的,相反,这些制备代表着一个分子家族。因此,GAG本身不代表最理想的治疗剂,特别是在从异质混合物中分离特定GAG或部分GAG方面。
此外,从天然来源获得大量这些复合寡糖需要通过色谱法重复纯化,并且由于这些寡糖中的许多的相似性,难以获得均匀的样品。
GAG合成化学产品生产在商业上也没有吸引力。例如,生产一种对靶蛋白具有选择性的特定合成五糖,需要大约40个化学步骤。
尽管使用相对无毒的GAG调节生物调节剂(如趋化因子、细胞因子、生长因子和趋化剂)活性的概念具有吸引力,但仍需要能够产生替代化合物,其在与生物调节剂结合并调节其活性方面是功能性GAG模拟物。
发明内容
本发明部分基于确定一种糖缀合物的合成方法,所述糖缀合物与所选生物调节剂结合并调节其活性,所述生物调节剂例如但不限于与细胞信号通路相关的趋化因子、细胞因子、生长因子或趋化剂。相应地,糖缀合物是以一种能够快速合成且大规模合成生产的方式进行生产的。生产方式包括模块化方法,其使所需的合成化学步骤数量最少。另外,与先前在本领域中使用的方法相比,糖缀合物生产为高纯度的单一化学实体。如上所述,糖缀合物以模块化方式合成,从而易于生成针对生物调节剂阵列的分子库。本发明的糖缀合物具有与GAG类似的结合特性,并且在本文中被称为“功能性GAG模拟物”,然而,本发明的糖缀合物是均匀的、纯的且易于合成。这是GAG自身合成方面的重大改进。
本文提出了在此实现的糖缀合物可用于:预防和/或治疗疾病病症,例如但不限于包括过敏性疾病、骨关节炎的炎性病症;癌症治疗;病原体感染的治疗,这些病原体包括但不限于结核分枝杆菌,与人流感或禽流感相关的A型流感病毒以及人类免疫缺陷病毒(HIV)。特定的疾病实例包括哮喘、过敏性呼吸道疾病、过敏性鼻炎、气道高反应性的上皮下纤维化、慢性鼻窦炎、常年性过敏性鼻炎、囊性纤维化患者过敏性支气管肺曲霉病、慢性阻塞性肺病、嗜酸粒细胞性支气管炎、支气管扩张、支气管痉挛、支气管收缩、支气管高反应性和支气管肥大。
在一实施方式中,本文教导了式(I)的化合物:
其中,
L是键或任选取代的二价连接基团;
L1和L2各自独立地选自键和任选取代的二价连接基团;
L3和L4各自独立地选自键和任选取代的二价连接基团;
X1和X2各自为封端糖,其中X1和X2各自独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;
Y1和Y2各自为连接糖,其中Y1和Y2各自独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;并且
n是0到3的整数。
本文还教导了制备式(I)化合物的方法,包括:
i)提供二价连接基团,
ii)通过二价连接基团缀合至少两个当量的封端糖,形成式(I)化合物。
本文进一步教导了制备式(I)化合物的方法,包括:
(i)提供二价连接基团,
(ii)通过二价连接基团缀合至少两个当量的连接糖以形成缀合中间体;
(iii)通过缀合中间体与至少两个当量的封端糖缀合,形成式(I)化合物。
本文另外教导了制备式(I)化合物的方法,包括:
(i)提供封端糖,
(ii)将封端糖与连接糖缀合以形成缀合中间体;和
(iii)通过二价连接基团与至少两个当量的缀合中间体缀合,形成式(I)化合物。
这些方法有利地以相对少的化学步骤和高纯度实现了作为单一化学实体的糖缀合物的快速组装。这种快速组装部分归因于产生糖缀合物的模块化合成方法。
本文进一步教导了一种试剂,其在生物调节剂上的结合靶点与本发明方法产生的糖缀合物与生物调节剂相结合的靶点相同。这种试剂可以合成作为化合物库的一部分,或者可以是纯化的天然产物。
“生物调节剂”意指趋化因子、细胞因子、生长因子或趋化剂。生物调节剂可以是肽、多肽或蛋白质。术语“生物介质”包括在术语“生物调节剂”中,并可互换使用。
本文实现的是用于产生糖缀合物库的方法和用于确认与特定生物调节剂结合并调节其活性的糖缀合物的方法。根据本文所述方法产生的糖缀合物可用于治疗与生物调节剂的活性相关或因生物调节剂活性加剧的任何疾病,包括生物调节剂与其受体之间的相互作用、涉及信号通路的活化或病毒与细胞之间的相互作用。如上所述,生物调节剂可以是趋化因子、细胞因子、生长因子或趋化剂。糖缀合物尤其可用于治疗炎性或过敏性疾病病症和转移性癌症以及病原体(如细菌、病毒或寄生虫)的感染。
本文进一步考虑了哺乳动物受试者的治疗方法,包括施用本文定义的糖缀合物或糖缀合物模拟物。
在一实施方式中,哺乳动物是人。
本文进一步教导了药物组合物,其包含本文定义的糖缀合物和一种或多种药学上可接受的载体、稀释剂和/或赋形剂。
本文进一步教导了本文所定义的糖缀合物或糖缀合物模拟物在用于治疗需要治疗的哺乳动物受试者的药物的制备中的应用。在相关的实施方式中,本文实现了本文定义的糖缀合物或糖缀合物模拟物在治疗需要治疗的哺乳动物受试者中的应用。在一实施方式中,哺乳动物是人。
本文进一步实现了用于治疗受试者疾病病症的药物的生产方法,该方法包括根据本发明的方法制备一系列的糖缀合物,以及筛选具有与本文中限定的生物调节剂相互作用或调节其活性的能力的糖缀合物,其中,生物调节剂与疾病或病症有关。确定了与调节剂相互作用的糖缀合物,并将其用于药物制备。
附图简述
图1是显示用重组人IL-13进行TF1生物测定的图示。A:IL-13滴定范围25ng/ml-0.9ng/ml;抑制剂:肝素、硫酸化糖缀合物21及蔗糖八硫酸盐保持在10μg/ml,但糖缀合物25保持在50μg/ml。IL-13依赖性细胞增殖显示为490nm处的吸光度。B:来自5个独立实验的数据以抑制细胞增殖的平均百分数表示出来,其中,IL-13为4ng/ml,抑制剂肝素、蔗糖八硫酸盐和糖缀合物21为2.5μg/ml或10μg/ml,糖缀合物25以12.5μg/ml使用。显示了平均值和标准偏差。
图2是显示用重组人IL-5进行的Ba/F-IL-5生物测定的图示。A:IL-5滴定范围25ng/ml-0.9ng/ml;抑制剂:肝素、硫酸化糖缀合物21及蔗糖八硫酸盐保持在10μg/ml,但糖缀合物25以50μg/ml使用。IL-5依赖性细胞增殖显示为每秒的发光数。B:来自3个独立实验的数据以抑制细胞增殖的平均百分数表示出来,其中,IL-5为1.6ng/ml,抑制剂肝素、蔗糖八硫酸盐和糖缀合物21为2.5μg/ml或10μg/ml,糖缀合物25以12.5μg/ml使用。显示了平均值和标准偏差。
图3是显示用重组人(rh)IL-4进行TF1生物测定的图示。A:IL-4滴定范围25ng/ml-0.9ng/ml;抑制剂:肝素、硫酸化糖缀合物21及蔗糖八硫酸盐保持在10μg/ml,但糖缀合物25以50μg/ml使用。IL-4依赖性细胞增殖显示为490nm处的吸光度。B:来自3个独立实验的数据以抑制细胞增殖的平均百分数表示出来,其中,IL-4为4ng/ml,抑制剂肝素、蔗糖八硫酸盐和糖缀合物21为2.5μg/ml或10μg/ml,糖缀合物25以12.5μg/ml使用。显示了平均值和标准偏差。
图4是显示用重组人(rh)IL-6进行TF1生物测定的图示。IL-6滴定范围25ng/ml-0.9ng/ml;抑制剂:肝素、硫酸化糖缀合物21及蔗糖八硫酸盐保持在10μg/ml,但糖缀合物25以50μg/ml使用。IL-6依赖性细胞增殖显示为490nm处的吸光度。
图5是显示用重组人(rh)IL-1β进行TF1生物测定的图示。A:rhIL-1β滴定范围25ng/ml-0.9ng/ml;抑制剂:肝素、硫酸化糖缀合物21和蔗糖八硫酸盐保持在10μg/ml,但糖缀合物25以50μg/ml使用。IL-1β依赖性细胞增殖显示为490nm处的吸光度。B:来自4个独立实验的数据以抑制细胞增殖的平均百分数表示出来,其中,IL-1β为2ng/ml,抑制剂肝素、蔗糖八硫酸盐和糖缀合物21保持在为2.5μg/ml或10μg/ml,糖缀合物25以12.5μg/ml使用。显示了平均值和标准偏差。
图6是显示U937细胞凋亡TNF-α生物测定的图示。TNF-α始终以1ng/ml使用,抑制剂:肝素、两种硫酸化糖缀合物及蔗糖八硫酸盐以40、10或2.5μg/ml使用。显示了4次重复的平均值和标准误差。
图7是显示用重组人IL-2进行CTL-luc生物测定的图示。IL-2滴定范围25ng/ml-0.09ng/ml;抑制剂:肝素及硫酸化糖缀合物21保持在10μg/ml。IL-2依赖性细胞增殖显示为每秒的发光数。
图8是显示用重组人IL-13进行TF1.8生物测定的图示。来自至少3次重复的数据以抑制细胞增殖的平均百分数表示出来,其中,IL-13为10ng/ml,抑制剂为10μg/ml。A中抑制剂是肝素、蔗糖八硫酸盐和糖缀合物83、85、86、88和91。B中抑制剂为肝素、糖缀合物78-84和87-94。显示了平均值和标准偏差。
图9是显示用重组人IL-5进行Ba/F-IL-5生物测定的图示。来自至少3次重复的数据以抑制细胞增殖的平均百分数表示出来,其中,IL-5为1ng/ml,抑制剂为10μg/ml。A中抑制剂是肝素、蔗糖八硫酸盐及糖缀合物78-88。B中抑制剂为肝素、蔗糖八硫酸盐及糖缀合物89-94。显示了平均值和标准偏差。
图10是显示用重组人IL-4进行TF1.8生物测定的图示。来自至少3次重复的数据显示以抑制细胞增殖的平均百分数表示出来,其中,IL-4为1ng/ml,抑制剂为10μg/ml。图A中抑制剂是肝素、蔗糖八硫酸盐糖缀合物83、85、86、88和91。B中抑制剂是肝素、糖缀合物78-84和87-94。显示了平均值和标准偏差。
图11是显示各种糖缀合物使100nM重组人IL-4与固定于BIAcore生物传感器芯片上的肝素的结合抑制50%所需的IC50浓度的BIAcore数据的图示。抑制剂是肝素、蔗糖八硫酸盐、糖缀合物21、糖缀合物25及糖缀合物78-94。
发明详述
在整个说明书中,除非上下文另有要求,否则词语“包括”或其变体将被理解为暗示包括所述元素或整数或者方法步骤,或者一组元素或整数或方法步骤,但并不排除任何其他的元素或整数或方法步骤或者一组元素或整数或方法步骤。
如在本说明书中使用的,单数形式“一”和“该”包括多个的情况,除非上下文另有明确说明。因此,例如,提及“生物调节剂”则包括单一的生物调节剂,也包括两种或更多种生物调节剂;提及“试剂”包括单一试剂,也包括两种或多种试剂;提及“公开”则包括本发明的单个和多个方面,等等。本文教导和实现的方面由术语“本发明”进行涵盖,所有这些方面都在本发明的范围内实现。本文所考虑的任何变体和衍生物都包括在本发明的“形式”中。
本发明整体上涉及与靶生物调节剂相结合并调节其活性的糖缀合物。此外,本发明涉及一种制备糖缀合物的多糖方法,用该方法可以实现快速合成以及大规模生产,获得糖缀合物的高度均匀制备。
说明书中所用的术语“生物调节剂”,意指趋化因子、细胞因子、生长因子或趋化剂。术语“生物介质”包括在术语“生物调节剂”中,并且可互换使用。
本文实现了制备靶向选定生物调节剂的糖缀合物的方法。生物调节剂可包括肽、多肽或蛋白质。
说明书中所用的术语“糖缀合物”是指复合化合物,包含糖类或通过一个或多个连接基团的连接而由其衍生出的化合物。就功能性而言,糖缀合物可被认为是GAG模拟物。
相应地,本发明的一个方面涉及式(I)的化合物:
其中,
L是键或二价连接基团;
L1和L2各自独立地选自键和二价连接基团;
L3和L4各自独立地选自键和二价连接基团;
X1和X2各自为封端糖,其中X1和X2各自独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;
Y1和Y2各自为连接糖,其中Y1和Y2各自独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;并且
n是0到3的整数。
整个说明书中使用的术语“任选取代”,表示该基团可以或可以不进一步被一个或多个非氢取代基取代或稠合(以形成缩合多环体系)。在特定的实施方式中,取代基是独立地选自以下组中的一种或多种基团:卤素、羟基、酰基、氨基、烷基、烯基、炔基、芳基、烷氧基、烷基氨基、烯基氨基、烷基杂环基、环烷基、环烯基、环烷基氨基、环烯基氨基、芳基氨基、杂芳基、杂环基、杂芳基氨基、杂环基氨基、氨基芳基氨基、氨基杂芳基氨基、氨基杂环基氨基、四氢吡啶氨基、氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、氮杂环丁基氨基、吡咯烷基氨基、哌啶基氨基、哌嗪基氨基、氮杂环丁烷基羰基氨基、吡咯烷基羰基氨基、哌啶基羰基氨基、哌嗪基羰基氨基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基、芳氧基、杂芳氧基、杂环氧基、氨基烷氧基、氨基烯氧基、氨基炔氧基、氨基环烷氧基、氨基环烯氧基、氨基芳氧基、氨基杂芳氧基、氮杂环丁烷基氧基、吡咯烷氧基、哌啶基氧基或哌嗪基氧基。
“酰基”意指R-C(=O)-基团,其中R基团可以是本文所定义的烷基、环烷基、杂环烷基、芳基或杂芳基。酰基的实例包括乙酰基和苯甲酰基。
除非另有说明,作为基团或基团一部分的“烷基”是指直链或支链脂族烃基,包括C1-C18烷基、C1-C8烷基及C1-C6烷基。
“亚烷基”是指具有1至10个碳原子(包括1至6个碳原子,且包括1至3个碳原子)的二价烷基基团。这种亚烷基的实例包括亚甲基(-CH2-)、亚乙基(-CH2CH2-)和亚丙基异构体(例如-CH2CH2CH2-和–CH(CH3)CH2-)等。
“烯基”意指含有至少一个碳碳双键且可以是直链或支链的脂族烃基,包括C2-C10烯基,包括C2-C8烯基,优选地包括C2-C6烯基。该基团可以在正链中含有多个双键,并且其取向各自独立地为E或Z。示例性的烯基基团包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基和壬烯基。
“炔基”意指含有碳碳三键且可以是直链或支链的脂族烃基,包括C2-C10炔基、C2-C8炔基及C2-C6炔基。
作为基团或基团一部分的“烷氧基”意指烷基-O-基团,其中烷基如本文所定义。在一实施方式中,烷氧基是C1-C10烷氧基。实例包括但不限于甲氧基和乙氧基。
“芳基”意指具有单环(例如苯基)或多个缩合环(例如萘基或蒽基)的不饱和芳族碳环基团,包括6至14个碳原子。芳基的实例包括苯基、萘基等。
“芳氧基”是指芳基-O-基团,其中芳基如本文所定义。在一实施方式中,芳氧基是C6-C10芳氧基。
除非另有说明,“环烷基”是指饱和的单环、稠合或螺旋多环的碳环,每环包括3至10个碳原子,例如环丙基、环丁基、环戊基、环己基等。它包括单环体系如环丙基和环己基、双环体系如十氢化萘以及多环体系如金刚烷。
“环烯基”意指非芳族单环或多环体系,其含有至少一个碳碳双键且每个环包含5至10个碳原子。示例性的单环环烯基环包括环戊烯基、环己烯基或环庚烯基。
“环烷氧基”意指环烷基-O-基团,其中环烷基如本文所定义。在一实施方式中,环烷氧基是C3-C10环烷氧基。实例包括但不限于环丙氧基和环丁氧基。
除非另有说明,作为基团或基团一部分的“杂烷基”是指直链或支链脂族烃基,包括C1-C10杂烷基、C1-C8杂烷基以及C1-C6杂烷基,其中脂族链中一个或多个碳原子被选自S、O、P和N的杂原子取代。示例性的杂烷基包括烷基醚、仲烷基胺、叔烷基胺、酰胺及烷基硫化物等。
“杂烯基”是指含有至少一个碳碳双键且可以是直链或支链的脂族烃基,包括C2-C10烯基、C2-C8杂烯基及C2-C6杂烯基,其中脂族链中的一个或多个碳原子被选自S、O、P和N的杂原子取代。该基团正链中可含有多个双键,并且取向各自独立地为E或Z。示例性的烯基基团包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基和壬烯基。
“杂炔基”是指含有碳碳三键且可以是直链或支链的脂族烃基,包括C2-C10杂炔基、C2-C8杂炔基及C2-C6杂炔基,其中脂族链中一个或多个碳被选自S、O、P和N的杂原子取代。
独立或作为基团一部分的“杂芳基”是指含有芳环(包括5、6、9、10或11元芳环)的基团,其在芳环中具有一个或多个杂原子作为环原子,其余环原子是碳原子。合适的杂原子包括氮、氧和硫。杂芳基的实例包括三唑、噻吩、呋喃、异吲哚嗪、xantholene、phenoxatine、吡咯、咪唑、吡唑、吡啶、吡嗪、嘧啶、哒嗪、四唑、吲哚、异吲哚、1H-吲唑、嘌呤、喹啉、异喹啉、酞嗪、萘啶、喹喔啉、噌啉、咔唑、菲啶、吖啶、吩嗪、噻唑、异噻唑、吩噻嗪、恶唑、异恶唑、呋咱、吩恶嗪、2-、3-或4-吡啶基、2-、3-、4-、5-或8-喹啉基、1-、3-、4-或5-异喹啉基、1-、2-或3-吲哚基和2-或3-噻吩基,且包括苯并稠合的杂芳基如苯并噻吩、苯并呋喃、苯并咪唑、苯并恶唑、苯并噻唑、苯并异噻唑和萘并[2,3-b]噻吩。
“杂环基”或“杂环”是指含有至少一个选自氮、硫、氧的杂原子的饱和单环、双环或多环,至少一个环中包含1至3个杂原子。每个环包括3至11元环、4至7元环和9至11元环。合适的杂环取代基实例包括氮丙啶基、环氧乙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、thistanyl、吡咯啉基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、哌啶基、噻唑烷基、哌嗪基、四氢吡啶基、吗啉基、硫代吗啉基、1,3-二氮杂环庚烷、1,4-二氮杂环庚烷、1,4-氧氮杂环庚烷和1,4-氧硫杂环庚烷,包括苯并稠合化合物如indiny、异吲哚啉基、氧代异吲哚啉基、异喹啉基和喹啉基。
在一实施方式中,连接糖和封端糖独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自单糖、二糖、三糖、四糖或五糖的化合物。在一实施方式中,连接糖和封端糖选自葡萄糖、果糖、半乳糖、甘露糖、三氯蔗糖、蔗糖、乳糖、乳果糖、海藻糖、麦芽糖、新霉胺、卡那霉素A、异麦芽三糖、黑曲霉三糖、麦芽三糖、阿卡波糖、麦芽四糖、水苏糖、松三糖、麦芽丙酮糖(maltotriulose)、棉子糖、蔗果三糖、葡糖醛酸、艾杜糖醛酸、葡糖胺、庚酮糖、戊糖、半乳糖胺、葡糖胺和由其衍生的化合物。在一实施方式中,连接糖和/或封端糖选自三氯蔗糖或甘露糖。
此外,在一实施方式中,一种或多种连接糖和/或封端糖是衍生自单糖、二糖、三糖、四糖或五糖的化合物,包括氨基糖。本文所用的术语“氨基糖”是指其中至少一个羟基被氨基取代的糖或糖分子。氨基糖可以是天然存在的氨基糖或通过本领域已知的任何恰当方法制备的合成氨基糖。在一实施方式中,氨基糖选自任选取代的半乳糖胺、葡糖胺及其衍生物,如N-乙酰葡糖胺或N-乙酰半乳糖胺。
糖缀合物也可以被“任选地修饰”。例如,连接糖和或封端糖可以在缀合之前或之后被“任选地修饰”。在一实施方式中,连接糖和或封端糖在缀合之前进行修饰以促进缀合。此类修饰的实例包括但不限于缩链、扩链、交换(转糖基作用)、N-乙酰化、官能团保护(例如保护作为苄酯的醇)和官能团相互转化(例如伯醇转化为叠氮化物或烯基部分转化为环氧化物)。尽管一些糖本身可具有促进两种或更多种此类化合物缀合的功能,其他糖也可在缀合之前修饰以促进缀合。即使是那些具有促进缀合功能的糖,也可以通过不同类型的连接基团进行修饰以促进缀合。一个或多个糖苷键水解以露出作为反应性手柄的还原糖的还原末端是促进缀合的修饰的一个实例。
另外或可替代地,在一实施方式中,连接糖和/或封端糖在缀合之前或之后进行修饰,以增强或改变所得糖缀合物对靶蛋白的生物活性和/或结合亲和力。在一实施方式中,连接糖和/或封端糖通过例如硫酸化、磷酸化、氧基化、官能团相互转化和/或侧链的连接来修饰,但不限于此。因此,在一实施方式中,连接糖和/或封端糖是过硫酸化的、非硫酸化的或半硫酸化的、过磷酸化的、非磷酸化的或半磷酸化的。在一实施方式中,连接糖和/或封端糖是过硫酸化或半硫酸化的。在一实施方式中,连接糖和/或封端糖是过硫酸化的。在一实施方式中,连接糖和/或封端糖是过磷酸化的。
化学硫酸化可通过本领域已知的任何合适的硫酸化方法而实现。在一实施式中,硫酸化是选择性的硫酸化。在另一实施式中,硫酸化是通过全面硫酸化来提供过硫酸化产物的。例如,糖缀合物与吡啶三氧化硫的硫酸化提供了过硫酸化产物。相关肝素型寡糖的化学硫酸化已被研究。例如,通过使用不同的反应条件实现了一定程度的选择性,并且已经确定了某些羟基的反应性(参见Ogamo et al.(1989)Carbohydr.Res.193:165-172)。此外,通过先进行硫酸化然后选择性地使某些位置脱硫来实现硫酸化中的某种选择性。例如,在一实施方式中,糖缀合物通过用三氧化硫源(如吡啶三氧化硫复合物)处理糖缀合物来硫酸化。
通过本领域已知的任何合适的磷酸化手段可实现化学磷酸化。在一实施方式中,磷酸化是选择性的磷酸化。在另一实施方式中,磷酸化是通过全面磷酸化来提供过磷酸化产物的。例如,在一实施方式中,糖缀合物通过用磷酸盐源(例如磷酸、磷酰氯、二苯基氯代磷酸酯或无机磷酸盐)处理糖缀合物来磷酸化。或者,糖缀合物可进行酶促磷酸化。
如上所述,此类修饰可用于增强或改变所得糖缀合物的生物活性和/或结合亲和力。在一实施方式中,修饰例如可提供具有净负电荷(阴离子缀合物)、净正电荷(阳离子缀合物)或净中性电荷的糖缀合物。在一实施方式中,糖缀合物是阴离子糖缀合物。
本文所用术语“阴离子”描述材料的净负电荷。应当理解的是,给定的带负电材料可以具有与其相关的一个或多个带正电的平衡离子,反之亦然。在溶液中,带负电荷材料可与一种或多种与其相关的带正电平衡离子解离。本文所用的术语“阴离子”用于描述该材料的一种性质,而不是具有通常使复合物呈中性的一种或多种平衡离子的整体复合物。应理解的是,某些官能团在不同的pH值下带负电、呈中性或带正电。材料是否为阴离子将取决于这些电荷的总和。因此,在给定的pH下,如果材料具有一个带正电的官能团和两个带负电的官能团,则该材料具有净负电荷,并且正如在本发明的上下文中使用术语一样是阴离子的。在一实施方式中,本发明的糖缀合物在pH为5的水溶液中具有净负电荷。改性将提供具有净负电荷的糖缀合物,改性包括例如连接糖和/或封端糖的硫酸化和/或磷酸化和/或氧化。
本文所用的术语“连接基团”是指共价连接两种或更多种材料的多价基团。在一实施方式中,所述或每个连接基团L、L1、L2、L3和L4可以是任何合适的多价基团。在一实施方式中,所述或每个连接基团L、L1、L2、L3和L4各自独立地为二价连接基团。在一实施方式中,所述或每个连接基团独立地为二价基团,该二价基团选自亚烷基、亚烯基、亚炔基、亚芳基、酰基、亚碳环基、亚杂环基、亚杂芳基、烷氧基、烯氧基、炔氧基、芳氧基、酰氧基、碳环氧基、杂环氧基、杂芳氧基、烷硫基、烯硫基、炔硫基、芳硫基、酰硫基、碳环硫基、杂环硫基、杂芳硫基、烷基烯基,烷基炔基、烷基芳基、烷基酰基、烷基碳环基、烷基杂环基、烷基杂芳基、烷氧基烷基、烯氧基烷基、炔氧基烷基、芳氧基烷基、烷基酰氧基、烷基碳环氧基、烷基杂环氧基、烷基杂芳氧基、烷硫基烷基、烯硫基烷基、炔硫基烷基、芳硫基烷基、烷基酰基硫基、烷基碳环硫基、烷基杂环硫基、烷基杂芳硫基、烷基烯基烷基、烷基炔基烷基、烷基芳基烷基、烷基酰基烷基、芳基烷基芳基、芳基烯基芳基、芳基炔基芳基、芳基酰基芳基、芳基酰基、芳基碳环基、芳基杂环基、芳基杂芳基、烯氧基芳基、炔氧基芳基、芳氧基芳基、芳基酰基氧基、芳基碳环氧基、芳基杂环氧基、芳基杂芳氧基、烷基硫基芳基、烯基硫基芳基、炔基硫基芳基、芳基硫基芳基、芳基酰基硫基、芳基碳环基硫基、芳基杂环基硫基和芳基杂芳基硫基。
在一实施方式中,所述或每个连接基团L、L1、L2、L3和L4各自独立地为二价连接基团,该二价连接基选自C1-C18亚烷基、C2-C18亚烯基、C2-C18亚炔基、C6-C18亚芳基、C1-C18亚酰基、C3-C18亚碳环基、C2-C18亚杂环基、C3-C18亚杂芳基、C1-C18烷氧基、C2-C18烯氧基、C2-C18炔氧基、C6-C18芳氧基、C1-C18酰氧基、C3-C18碳环基氧基、C2-C18杂环氧基、C3-C18杂芳氧基、C1-C18烷硫基、C2-C18烯硫基、C2-C18炔硫基、C6-C18芳硫基、C1-C18酰基硫基、C3-C18碳环硫基、C2-C18杂环硫基、C3-C18杂芳硫基、C3-C18烷基烯基、C3-C18烷基炔基、C7-C24烷基芳基、C2-C18烷基酰基、C4-C18烷基碳环基、C3-C18烷基杂环基、C4-C18烷基杂芳基、C2-C18烷氧基烷基、C3-C18烯氧基烷基、C3-C18炔氧基烷基、C7-C24芳氧基烷基、C2-C18烷基酰氧基、C4-C18烷基碳环氧基、C3-C18烷基杂环氧基、C4-C18烷基杂芳氧基、C2-C18烷硫基烷基、C3-C18烯硫基烷基、C3-C18炔硫基烷基、C7-C24芳硫基烷基、C2-C18烷基酰硫基、C4-C18烷基碳环基硫基、C3-C18烷基杂环硫基、C4-C18烷基杂芳基硫基、C4-C18烷基烯基烷基、C4-C18烷基炔基烷基、C8-C24烷基芳基烷基、C3-C18烷基酰基烷基、C13-C24芳基烷基芳基、C14-C24芳基烯基芳基、C14-C24芳基炔基芳基、C13-C24芳基酰基芳基、C7-C18芳基酰基、C9-C18芳基碳环基、C8-C18芳基杂环基、C9-C18芳基杂芳基、C8-C18烯基氧基芳基、C8-C18炔基氧基芳基、C12-C24芳氧基芳基、C7-C18芳酰基氧基、C9-C18芳基碳环氧基、C8-C18芳基杂环氧基、C9-C18芳基杂芳氧基、C7-C18烷基硫基芳基、C8-C18烯基硫基芳基、C8-C18炔基硫基芳基、C12-C24芳硫基芳基、C7-C18芳酰基硫基、C9-C18芳基碳环基硫基、C8-C18芳基杂环硫基和C9-C18芳基杂芳基硫基。
在一实施方式中,所述或每个连接基团L、L1、L2、L3和L4各自独立地选自C1-C12亚烷基、C2-C12亚烯基、C2-C12亚炔基、C5-C18亚芳基、C3-C18亚杂芳基、C3-C12碳环基、C2-C18亚杂环基、C6-C18烷基亚芳基、C4-C12烷基亚杂芳基、C4-C18烷基亚碳环基、C3-C18烷基亚杂环基、C6-C18芳基酰基、C1-C12烷氧基、C2-C18烯氧基、C2-C18炔氧基、C5-C18芳氧基、酰基、酰氧基、C1-C18烷硫基、C2-C18烯硫基、C2-C18炔基硫基、C5-C18芳硫基、酰基硫基、磺酰基、亚砜基、C1-C18烷基氨基、C2-C18链烯基氨基、C2-C18炔基氨基、C5-C18芳基氨基和酰氨基。
在上文定义的所述或每个连接基团可选的多价基团列表中,每个亚烷基、亚烯基、亚炔基、亚芳基、亚碳环基、亚杂芳基和亚杂环基部分可以如上所述地任选取代。为避免任何疑问,当给定的连接基团含有两个或多个这样的部分(例如烷芳基)时,这些部分中的每一个可被本文所定义的一个、两个、三个或更多个任选取代基任选取代。
在上文定义的可能的连接基团列表中,当给定的连接基团包含两个或更多个亚基团时,例如,亚基团可以以[亚基团A][亚基团B]的格式列出,如烷基芳基,或者以[亚基团A][亚基团B][亚基团C]的格式列出,如芳基氧基烷基,上面列出的亚基团顺序并不是为了限于它们的呈现顺序。因此,具有定义为[亚基团A][亚基团B](如烷基芳基)的两个亚基团的连接基团,也旨在作为具有定义为[亚基团B][亚基团A](如芳基烷基)的两个亚基团的连接基团的参照。
所述或每个连接基团可以是支链的和/或任选取代的。当所述或每个连接基团包含任选取代的烷基部分时,任选的取代基包括烷基链中-CH2-基团被选自-O-、-S-、-NRa、-C(O)-(即羰基)、-C(O)O-(即酯)和-C(O)NRa-(即酰胺)的基团取代的情况,其中Ra选自氢、烷基、烯基、炔基、芳基、碳环基、杂芳基、杂环基、芳基烷基和酰基。
连接基团优选地不与GAG受体相互作用。连接基团可影响糖缀合物的几何形状、大小、柔韧性或刚性、亲水性和疏水性,而不会不利地影响其结合靶蛋白的能力。因此,连接基团包括选择用于增强或改进给定生物效应的那些基团。在这方面,连接基团可以被认为是“框架”,在其上排列连接糖和封端糖以使糖缀合物取向产生多结合剂。待模拟的GAG和/或同源物之间的结构-活性关系的知识、关于配体-受体复合物的结构信息(例如来自X射线晶体学,NMR)可以影响连接基团的选择。
通过选择连接基团可实现本发明的糖缀合物的不同取向。
例如,在一实施方式中,糖缀合物的所需取向可通过使用包括芳基和杂芳基的单环或多环连接基团或者包含一个或多个不饱和碳碳键的结构(即烯类和炔类)来实现。在一实施方式中,包含环状基团(例如芳基、杂芳基、环烷基、杂环等)赋予了糖缀合物刚性。在一实施方式中,环状基团是六元或十元环。环状基团可以是芳族基团(例如苯基或萘基)或杂芳基(三唑)。在另一实施方式中,连接基团包含烯烃或炔烃。
在另一实施方式中,通过包含刚性和/或大体积的辅助基团来降低连接基团的柔性。刚性或大体积基团的存在可阻碍连接基团中围绕键的自由旋转。刚性基团的实例是其构象柔性受到环和/或多键存在限制的那些基团,例如芳基、杂芳基、环烷基和/或杂环。也可以通过内部氢键来赋予刚性。大体积基团的实例包括大的原子和/或离子(例如碘、硫、金属离子等)、多环基团(包括芳族基团和非芳族基团)以及包含一个或多个烯键和/或炔键的基团。
可替代地,例如可能需要刚性较小的糖缀合物。在一实施方式中,通过使用柔性连接基团实现柔性取向,例如包含一个或多个饱和碳碳键(即烷基、杂烷基)的结构。在一实施方式中,连接基团包含C1-C18烷基或C1-C18杂烷基。
在构建本发明的糖缀合物时,确定合适的框架几何形状是一个重要的考虑因素。体系空间搜索策略可用于帮助识别GAG模拟物的所需框架。因此,分子设计可有助于本发明糖缀合物的设计。
合适的连接基团实例如下所示:
上面所示的连接基团可进一步形成较大连接基团的一部分,使得配体域的空间排列基本上由例如上述连接基团中的亚苯基的取代模式决定。
与连接糖和/或封端糖相类似,连接基团可在缀合之前或之后“任选地修饰”。可以在缀合之前修饰连接基团,包括式(I)化合物的L、L1、L2、L3和L4,以促进缀合。当L1、L2、L3和L4中的任何一个独立地为连接基团时,这些可以是与一个或多个连接糖或封端糖和/或式(I)中一个或多个L缀合的独立化学实体。例如,在一实施方式中,连接基团L1和L2衍生自二醇。
可替代地,L1、L2、L3和L4各自独立地例如通过一个或多个封端糖和/或连接糖的缀合形成。具体地,缀合前每个封端糖和/或连接糖上的官能团可形成式(I)化合物中任何一个连接基团(L1至L4)。例如,在一实施方式中,连接基团L1和L2是各自通过炔烃与叠氮化物反应形成的三唑。在一实施方式中,封端糖X1和/或X2被修饰为包含炔烃官能团,且连接糖Y1和/或Y2被修饰为包含叠氮官能团。随后通过炔烃与叠氮化物反应将封端糖(X1)与连接糖(Y1)缀合,以形成三唑连接基团(L1)。类似地,随后通过炔烃与叠氮化物的反应将封端糖(X2)与连接糖(Y2)缀合,以形成三唑连接基团(L2)。在另一实施方式中,封端糖X1和/或X2反而被修饰为包含叠氮官能团,连接糖Y1和/或Y2被修饰为包含炔烃官能团,其可以类似地由获得的三唑连接基团(L1和/或L2)缀合。
例如,在一实施方式中,式(I)的糖缀合物包含衍生自聚乙二醇的连接基团L,L1和L2各自是衍生自三唑的连接基团,连接糖衍生自甘露糖(顶部)或三氯蔗糖(底部),然后进一步与另外的连接糖和/或)封端糖(由下面的R’表示)缀合。
R=SO3M(其中M为Li、Na、K等)
R’=单糖、二糖、三糖
连接基团还可以包含一个或多个辅助基团,其例如可调节多结合剂(在水、脂肪、脂质、生物流体等中)的溶解度、疏水性、亲水性、连接基团柔性、抗原性、分子大小、分子量、体内半衰期、体内分布、生物相容性、免疫原性、稳定性等。
增强连接基团水溶性/亲水性的基团实例是聚(乙二醇)、醇、多元醇(例如甘油、丙氧基甘油和如单糖、寡糖和多糖的糖类)、羧酸盐、聚羧酸盐(例如聚谷氨酸、聚丙烯酸等)、胺、聚胺(例如聚赖氨酸、聚次乙亚胺等)。在一实施方式中,用于改善水溶性/亲水性的辅助基团是聚醚。在一实施方式中,辅助基团是聚(乙二醇)。
亲脂性辅助基团可结合到连接基团中以增强阴离子缀合物的亲脂性和/或疏水性。这类基团的实例是任选取代的烷基、芳基和杂芳基。
糖缀合物的实例包括但不限于以下含二醇连接基团(L)、甘露糖连接糖和三氯蔗糖封端糖的八聚体:
如上所述,在这些实例中,R还包括基团SO3M,其中M是Li、Na、K等。其他实例包括但不限于以下六聚体,其包含二醇连接基团或烷基连接基团(L)、甘露糖连接糖和三氯蔗糖封端糖。
其他实例包括但不限于以下糖缀合物,其包含芳基连接基团(L)、甘露糖连接糖和三氯蔗糖封端糖。
另一方面,本发明提供了制备任选取代的单糖、二糖、三糖、四糖和/或五糖作为糖缀合物的结构单元。如前所述,单糖、二糖、三糖、四糖和/或五糖可进行修饰以用作封端和/或连接糖来促进缀合。在一实施方式中,设想了包含至少一个反应位置或缀合手柄的封端糖和连接糖。例如,在一实施方式中,连接糖选自修饰的单糖和二糖,例如甘露糖和三氯蔗糖衍生物,其包含炔烃和/或叠氮官能团和/或可以转化为叠氮官能团的基团。
在一实施方式中,封端糖选自修饰的单糖和二糖,例如以下包含炔烃官能团的甘露糖和三氯蔗糖衍生物。
相对于本文公开的式(I)化合物,构想了以下(i)至(x)的任意一种或多种的组合:
(i)L是亚苯基;或者
L是亚甲基;或者
L是亚乙基;
L是二亚甲基醚;或者
L是乙二醇;或者
L是三甘醇;或者
L是双(三唑基)二甲醚;
(ii)L1是二亚甲基醚;或者
L1是三唑基;或者
L1是亚甲基三唑基;或者
L1是亚乙基三唑基;或者
L1是甲氧基三唑基;或者
L1是甲氧基亚甲基三唑基;或者
L1是甲氧基亚甲基(三唑基)亚甲基(三唑基);或者
L1是双(三唑基)二甲醚;或者
L1是双(亚甲基)三唑基;或者
L1是双(甲氧基)三唑基;
(iii)L2是二亚甲基醚;或者
L2是三唑基;或者
L2是亚甲基三唑基;或者
L2是亚乙基三唑基;或者
L2是甲氧基三唑基;或者
L2是甲氧基亚甲基三唑基;或者
L2是甲氧基亚甲基(三唑基)亚甲基(三唑基);或者
L2是双(三唑基)二甲醚;或者
L2是双(亚甲基)三唑基;或者
L2是双(甲氧基)三唑基;
(iv)L3是亚甲基;或者
L3是三唑基;或者
L3是亚甲基三唑基;或者
L3是亚乙基三唑基;或者
L3是双(亚甲基)三唑基;
(v)L4是亚甲基;或者
L4是三唑基;或者
L4是亚甲基三唑基;或者
L4是亚乙基三唑基;或者
L4是双(亚甲基)三唑基;
(vi)X1是三氯蔗糖或其衍生物;或者
X1是甘露糖或其衍生物;
(vii)X2是三氯蔗糖或其衍生物;或者
X2是甘露糖或其衍生物;
(viii)Y1是三氯蔗糖或其衍生物;或者
Y1是甘露糖或其衍生物;
(ix)Y2是三氯蔗糖或其衍生物;或者
Y2是甘露糖或其衍生物;
(x)n为0;或者
n为1;或者
n为2;或者
n为3。
另一方面,本发明提供了制备式(I)化合物的方法,包括:
i)提供二价连接基团,
ii)通过二价连接基团缀合至少两个当量的封端糖,
形成式(I)化合物。
例如,在一实施方式中,至少两个当量的封端糖,如三氯蔗糖或其衍生物,通过二价连接基团缀合,从而提供式(I)的糖缀合物。
在另一方面,本发明提供了制备式(I)化合物的方法,包括:
(i)提供二价连接基团,
(ii)通过二价连接基团缀合至少两个当量的连接糖,以形成缀合物中间体;和
(iii)通过缀合物中间体与至少两当量的封端糖缀合,形成式(I)化合物。
例如,在一实施方式中,通过二价连接基团缀合至少两个当量的连接糖(如甘露糖或其衍生物),以提供中间缀合物。随后,通过中间缀合物缀合至少两个当量的封端糖(如三氯蔗糖或其衍生物),以提供式(I)的糖缀合物。
在其他方面,本发明提供了制备式(I)化合物的方法,包括:
(i)提供封端糖,
(ii)将封端糖与连接糖缀合以形成缀合物中间体;
(iii)通过二价连接基团与至少两个当量的缀合物中间体缀合,形成式(I)化合物。
例如,在一实施方式中,将至少两个当量的封端糖(例如三氯蔗糖或其衍生物)与连接糖(例如甘露糖或其衍生物)缀合,以提供缀合物中间体。随后,通过二价连接基团缀合至少两个当量的缀合物中间体,以提供式(I)的糖缀合物。
缀合可通过本领域已知的任何方法实现。本文所用的术语“缀合”是指两个或多个分子或组分的共价或其他形式的连接。例如,封端、连接和/或连接基团的缀合可以通过本领域已知的标准化学反应来实现,包括但不限于叠氮化物-炔烃点击化学、复分解(包括交叉复分解和闭环复分解)、取代(包括亲核取代和亲电取代)、加成(包括环加成、亲电加成和亲核加成)、烷基化、胺化、酯化、酰胺化及其组合。
本发明的方法便利地提供了作为单一化学实体的糖缀合物的快速组装。在一实施方式中,该方法可以认为是模块合成,其可以规模化并且以相对较少的化学步骤和/或以高的纯度和均匀性制备糖缀合物。
在一实施方式中,制备糖缀合物的方法是模块化的“由内向外”合成方法。用于制备糖缀合物的“由内而外”合成方法提供的是,在每个步骤,糖缀合物在至少两个方向上组装。这种方法可提高糖缀合物的制备速度和/或容易度。这种方法还可以减少组装糖缀合物所需的合成步骤总数。
在一实施方式中,“由内向外”合成方法提供了相对中心连接基团(L)对称的式(I)的糖缀合物。例如,在一实施方式中,糖缀合物被认为是回文,其中封端糖X1和X2各自是相同的单糖、二糖、三糖、四糖、五糖或其衍生物。此外,在一实施方式中,连接糖Y1和Y2各自是相同的单糖、二糖、三糖、四糖、五糖或其衍生物。X1、X2、Y1和Y2还可包含一个或多个硫酸酯基团、磷酸酯基团、氧化物基团或其组合。
在一实施方式中,制备糖缀合物的方法是模块化的“由外向内”合成方法。用于制备糖缀合物的“由外向内”合成方法提供了模块化的会聚合成。即首先制备目标糖缀合物的各部分。随后,各个部分围绕中心连接基团(L)缀合以形成目标糖缀合物。这种方法可以提高糖缀合物的制备速度和/或容易度。这种方法还可以减少组装糖缀合物所需的合成步骤总数。
在一实施方式中,“由外向内”合成方法提供了相对中心连接基团(L)对称的式(I)的糖缀合物。例如,在一实施方式中,糖缀合物被认为是回文,其中封端糖X1和X2各自是相同的单糖、二糖、三糖、四糖、五糖或其衍生物。此外,在一实施方式中,连接糖Y1和Y2各自是相同的单糖、二糖、三糖、四糖、五糖或其衍生物。X1、X2、Y1和Y2还可包含一个或多个硫酸酯基团、磷酸酯基团、氧化物基团或其组合。
在另一实施方式中,“由外向内”合成方法提供了式(I)的糖缀合物,其关于中心连接基团(L)是非对称的,例如,其中封端糖X1和X2是不同的单糖、二糖、三糖、四糖、五糖或其衍生物。此外,在一实施方式中,连接糖Y1和Y2是不同的单糖、二糖、三糖、五糖或其衍生物。“从外到内”合成方法的模块收敛性质提供了非对称糖缀合物的有效制备。如上所述,X1、X2、Y1和Y2还可包含一个或多个硫酸酯基团、磷酸酯基团、氧化物基团或其组合。
在另一实施方式中,通过“由内向外”和“由外向内”合成方法的组合制备了糖缀合物。这种方法可以提高糖缀合物的制备速度和/或容易性,并且还可以减少组装糖缀合物所需的合成步骤总数。
在一实施方式中,连接糖和封端糖通过炔烃与叠氮化物反应形成的三唑连接基团L1和L2缀合。如前所述,在一实施方式中,封端糖X1和/或X2在缀合之前进行修饰以包含炔烃官能团,连接糖Y1和/或Y2在缀合之前进行修饰以包含叠氮官能团。随后通过炔烃与叠氮化物反应以形成三唑连接基团(L1和L2),将封端糖(X1和/或X2)与连接糖(Y1和/或Y2)缀合。也要考虑逆反应性,这种反应性适用于“由内向外”的合成方法和“由外向内”的合成方法。
在一实施方式中,连接糖和封端糖通过烯基连接基团缀合,所述烯基连接基团包括含有至少一个碳碳双键的脂族烃基,如乙烯基连接基。在此类实施方式中,烯基连接基团L1和L2通过交叉复分解形成。例如,在缀合之前,封端糖和连接糖X1、X2、Y1和/或Y2各自被修饰以包含烯烃官能团。随后通过交叉复分解将封端糖(X1和/或X2)与连接糖(Y1和/或Y2)缀合以形成烯基连接基团(L1和L2)。这种反应性适用于“由内向外”的合成方法和“由外向内”的合成方法。
本领域技术人员将理解本文中关于该方法使用的术语“当量”。除非另有定义,否则关于该方法的术语“当量”是表明给定物质以摩尔数计的近似相对量的测量单位。
在一实施方式中,任意一种封端糖、连接糖和/或连接基团上的官能团可任选地用一个或多个保护基团进行保护以促进缀合。术语“保护基团”是指当与化合物的一个或多个羟基、硫醇、氨基或羧基结合时能够防止在这些基团上发生反应的基团,其可以通过常规化学或酶促步骤除去以重建羟基、硫代、氨基或羧基。所用的特定可除去的保护基团并不重要,可除去的羟基保护基团的实例包括常规取代基,如烯丙基、苄基、乙酰基、氯乙酰基、硫代苄基、亚苄基、苯甲酰甲基、叔丁基二苯基甲硅烷基和任何其他可以化学引入到羟基官能团上并随后在与产品性质相容的温和条件下通过化学方法或酶促方法选择性地除去的基团。保护基团更详细地公开在Greene and Wuts(1991),"Protective Groups in OrganicSynthesis"2nd Ed.,John Wiley and Sons,N.Y。术语“阻断基团”被认为在功能上等同于保护基团,并且任一术语可在上下文中使用。
在一实施方式中,封端糖和/或连接糖的一个或多个羟基可以用乙酸酯保护基团保护。在另一实施方式中,封端糖和/或连接糖的一个或多个羟基可以用苄基保护基保护。
本文中使用的糖缀合物可与涉及各种生理过程的生物调节剂(例如趋化因子、细胞因子、生长因子或趋化剂)结合并调节其活性,因此可用于治疗或预防疾病如炎性疾病,如过敏性疾病、骨关节炎、过敏性反应、哮喘、过敏性呼吸系统疾病、过敏性鼻炎、气道高反应性上皮下纤维化、慢性鼻窦炎、常年性过敏性鼻炎、囊性纤维化患者的过敏性支气管肺曲霉病、慢性阻塞性肺病、ARDS/ALI、嗜酸粒细胞性支气管炎、支气管扩张、支气管痉挛、支气管收缩、支气管高反应性、支气管肥大和支气管炎症、转移性癌症,病原体感染,包括但不限于作为导致结核病的病原体的结核分枝杆菌、作为引起艾滋病的病原体的人类免疫缺陷病毒(HIV)。
在一实施方式中,所治疗的疾病包括炎性疾病,例如过敏性疾病、骨关节炎、转移性癌症,病原体感染,包括但不限于作为导致结核病的病原体的结核分枝杆菌、与人或禽流感相关的A型流感病毒、作为引起艾滋病的病原体的人类免疫缺陷病毒(HIV)。疾病的实例包括哮喘、过敏性呼吸道疾病、过敏性鼻炎、气道高反应性的上皮下纤维化、慢性鼻窦炎、常年性过敏性鼻炎、囊性纤维化患者的过敏性支气管肺曲霉病、慢性阻塞性肺病、嗜酸粒细胞性支气管炎、支气管扩张、支气管痉挛、支气管收缩、支气管高反应性和支气管肥大。
本文所用的术语“支气管痉挛”是指患者呼吸管的不自愿痉挛。支气管收缩既是术语也是医学病症,在其用于本申请目的时可与“支气管痉挛”互换。本文所用的术语“支气管炎症”是指患者呼吸管的炎症。此外,过敏综合征,例如哮喘,可由普通感冒病毒引发,尤其是鼻病毒,所公开的化合物可用于治疗上呼吸道感染,例如感冒和流感,以及来自鼻病毒和冠状病毒的感染。支气管收缩也是过敏性反应的症状,所公开的化合物可用于治疗过敏性反应。
过敏性反应是一种严重的、快速发作的过敏反应,可引起死亡。危及生命的上气道阻塞、支气管痉挛和/或低血压是严重过敏性反应的特征。美国每年约有10万发病案例,其中约1%导致死亡,约66%是新病例。在大多数情况下,可以描述出特定引发源,但约20%的病例被指定为特发的。肾上腺素多年来已被接受作为选择疗法,但有人认为其未被充分利用且并非总是有效(Golden(2007)Curr.Opin.Allergy Clin.Immunol.,7:331-336)。医生们倾向于使用皮质类固醇和抗组胺进行治疗,尽管没有证据证明它们在急性疾病中的效力。抗组胺可能有助于组胺介导的病理学,但无助于其他介质产生的作用,并且在预防持续的肥大细胞和嗜碱性粒细胞活化方面具有有限的功效。与抗组胺一样,皮质类固醇已被认为在疾病管理中发挥着作用,尽管几乎没有临床试验证据证明其有效性,但其建议使用的基础是早期给予急性哮喘患者皮质类固醇是有益的(El-Shanawany et al.(2008)Clin.Exp.Immunol.153:1-9)。皮质类固醇在急性疾病期间不会有效,因为它们的作用需要蛋白质合成,从而延迟了它们的活性。
过敏性反应涉及肥大细胞和嗜碱性粒细胞的活化。通常大部分通过涉及IgE和肥大细胞及嗜碱性粒细胞上IgE的高亲和力受体的机制,接触昆虫毒液、食物、药物和过敏原免疫疗法注射来引发。响应于过敏原接触而合成的IgE,固定于肥大细胞和嗜碱性粒细胞表面上的IgE受体(FcεRI)之上。IgE受体聚集导致细胞活化,预形成的介质释放(包括组胺、类胰蛋白酶(包括β-类胰蛋白酶)、羧肽酶A、TNF-α和糜酶)并引发即时超敏反应。在几分钟内通过胞吐作用释放预先形成的颗粒介质。类似地,包括前列腺素和白三烯的花生四烯酸代谢物以及血小板活化因子(PAF)的合成在几分钟内发生。而生物调节剂、炎性细胞因子和趋化因子的合成和释放可能需要数小时,并且这些介质有助于双相过敏反应的后期。释放的生物调节剂包括IL-5、IL-4、IL-13、粒细胞(G)集落刺激因子(CSF)、巨噬细胞(M)-CSF、GM-CSF、IL-1β、IL-3、IL-6、IL-8、IL-10、IL-16、1L-18和IL-22。通常,这些调节剂引起其他细胞的集聚和活化,包括嗜碱性粒细胞、嗜酸性粒细胞和Th2细胞(Ogawa and Grant(2007)Immunol.Allergy Clin.N.Am.,27:249-260)。在一些描述为具有特发性过敏性反应的患者中,FcεRI受体可以在不存在IgE的情况下通过自身免疫机制聚集(Simons(2008)J.AllergyClin.Immunol.121:S402-7),并且存在涉及IgG和IgG受体的替代途径的证据。后一种途径不会引发组胺释放,相反,PAF是主要的早期介质(Peavy and Metcalfe(2008)Curr.Opin.Allergy Clin.Immunol.,8:310-314)。
在过敏性反应的早期阶段,组胺刺激血管舒张,提高血管通透性、心率、心脏收缩和腺分泌。前列腺素D2是支气管收缩剂、肺和冠状血管收缩剂以及外周血管扩张剂。白三烯也会促进支气管收缩,提高血管通透性,以及促进气道重塑。PAF同样引起支气管收缩和血管通透性提高。TNF-α激活中性粒细胞,聚集其他效应细胞并增强趋化因子合成,这导致进一步的炎性细胞聚集。这些重叠和协同作用有助于过敏性反应的整体病理生理学,其可变地表现为全身性荨麻疹和血管性水肿、支气管痉挛和其他呼吸系统症状、低血压、心血管症状(包括昏厥)、恶心以及其他胃肠道症状(Peavy and Metcalfe(2008)同上)。IL-4是过敏性反应后期的关键细胞因子,也是刺激和维持Th2细胞增殖并将B细胞转换为IgE合成的关键细胞因子,这种细胞因子对过敏性反应最快速和最显著的作用是显著增强靶细胞对血管活性介质(包括组胺、血清素、PAF和半胱氨酰白三烯)的反应性(Ogawa and Grant(2007)同上)。
过敏性鼻炎和过敏性哮喘是涉及炎症反应的疾病。它们具有相似的潜在病因,其特征在于显著的炎性细胞浸润,包括嗜酸性粒细胞、肥大细胞、T淋巴细胞和单核细胞谱系的细胞。黏附分子P-选择蛋白、MAC-1(CD11b/CD18)和PECAM-1在白细胞外渗中起重要作用,并且可能参与炎症过程。此外,趋化因子中的嗜酸性粒细胞趋化因子家族(即CCL11、CCL24和CCL26)在这些疾病中起关键作用,因为它们是刺激嗜酸性粒细胞和CD4+T淋巴细胞浸润的主要趋化因子。人们越来越认识到哮喘和过敏性鼻炎是单一炎性气道疾病的组成部分,这一结论得到了流行病学数据的支持,该数据显示超过80%的过敏性哮喘患者患有过敏性鼻炎,高达50%的过敏性鼻炎患者患有哮喘(Gelfand(2004)J.Allergy Clin.Immunol,114:S135-138;Passalacqua et al.(2004)Curr.Opin.Allergy Clin.Immunol.4:177-183)。此外,纵向和随访研究表明,鼻炎通常发生在哮喘之前,是哮喘的危险因素。过敏性鼻炎使患哮喘的风险增加至少三倍,使用鼻内类固醇对过敏性鼻炎进行正确治疗对支气管症状有良好影响,显著降低了急性哮喘发作的入院率和急诊率(Passalacqua et al.(2004)同上)。
过敏性疾病被认为是由活化的Th2细胞和抗原特异性IgE介导的“获得型过敏症”,或者是在未激活获得性免疫系统的情况下诱导的“先天性过敏症”。气道上皮细胞的贡献越来越多地涉及过敏性疾病,因为它们通过模式识别受体(PRR)感知到接触病原体或过敏原,并且可以激活树突细胞(DC)。在气道上皮细胞上触发这些PRR导致上皮细胞和一些免疫细胞释放pro-Th2细胞因子,例如胸腺基质淋巴细胞生成素(TSLP)、GM-CSF、IL-1α、IL-25、IL-18和IL-33。这些细胞因子不仅激活DC以启动Th2应答,而且刺激Th2细胞以增强Th2免疫。此外,它们还刺激先天性2型细胞,包括嗜碱性粒细胞、肥大细胞、嗜酸性粒细胞和第2组先天淋巴样细胞(ILC2)。IL-25、IL-33和TSLP强有力的触发ILC2以产生IL-5和IL-13。而IL-18和IL-33刺激肥大细胞和嗜碱性粒细胞以分泌IL-4、IL-6、IL-9和IL-13,而不交联IgE受体及Fcε受体I(FcεRI)。因此,Th2细胞因子是在不存在过敏原和IgE抗体的情况下产生的,并且这些细胞因子会引发“先天型过敏”(Yoshimoto(2014)Allergol.Internat.63Suppl 1:3-11)。
“获得型过敏”的发展发生在抗原特异性IgE使嗜碱性粒细胞和肥大细胞上的FcεRI交联之后。这导致包括组胺和细胞因子IL-4及IL-13的炎性生物调节剂(在本文中也称为“介质”)的释放。IL-4引发Th2应答,并且这些Th2细胞分泌更多IL-4以及其他Th2细胞因子如IL-5、IL-9、IL-13和GM-CSF(Yoshimoto(2014)同上)。IL-13与IL-4一起导致B淋巴细胞转变为产生IgE。IL-13还通过触发粘液形成、气道重塑和嗜酸性粒细胞趋化因子产生而促成过敏响应。后者对于嗜酸性粒细胞浸润到组织中是重要的,所述组织包括发生哮喘的肺和发生过敏性鼻炎的鼻粘膜。IL-5是细胞因子,其对于嗜酸性粒细胞分化、存活和活化是关键的,而IL-9在动物哮喘模型中促成气道嗜酸性粒细胞增多、肥大细胞积聚和粘液产生。应理解,ILC2是过敏原诱导的上皮细胞因子产生和Th2细胞介导的应答开始之间的纽带(Martinez-Gonalez et al.(2015)Trends Immunol.36:189-195)。
靶向IL-33的药物减轻/减弱:哮喘中的气道高反应性(AHR)、气道炎症(嗜酸性粒细胞和中性粒细胞)、粘液分泌和气道重塑(Nabe(2014)J.Pharmacol.Sci.126:85-91;Lloyd(2015)Curr Opin Immunol.34:52-58)。类似地阻断IL-25活性显著降低了过敏性哮喘中的IL-5、IL-13和IgE分泌水平,减少了嗜酸性粒细胞浸润和杯状细胞增生(Ballantyne(2007),J.Allergy Clin.Immunol.120:1324-1331)。还有很好的证据表明,三种细胞因子IL-25、IL-33和TSLP在过敏性鼻炎中同样具有关键重要性,对于特应性皮炎也是如此(Matsushita et al.(2015)Allergol.Internat.64:235e240)。小鼠模型表明来自表皮角质细胞的IL-33诱导皮肤中的ILC2并刺激它们产生IL-5,IL-5诱导具有嗜酸性粒细胞浸润的特应性皮炎。虽然特应性皮炎经常与血清中过敏原特异性IgE增加有关,但约有20%的特应性皮炎患者没有过敏原特异性IgE,这表明先天性特应性皮炎也可能由于通过促过敏细胞因子的ILC2刺激而发生(Yoshimoto(2014)同上)。
这些过敏性疾病是病理的复杂混合物,至少涉及上述各种细胞因子、趋化因子和细胞粘附分子。
慢性阻塞性肺病(COPD)的潜在病因与过敏性炎性疾病的潜在病因不同(Sutherland and Martin(2003)J Allergy Clin.Immunol.112:819-27)。慢性阻塞性肺病涉及影响外周气道和肺实质的慢性炎症过程,并且在恶化期间炎症更严重。慢性阻塞性肺病发展的主要促成因素是对香烟烟雾的炎症反应。慢性阻塞性肺病的病理指标是肺实质的破坏(肺气肿)、小外周气道的炎症(呼吸道支气管炎)和中央气道的炎症。大多数慢性阻塞性肺病患者具有表现出不同炎症模式的所有三种病理状况(慢性阻塞性支气管炎、肺气肿和粘液塞)(Adcock and Ito(2005),Proc.Am.Thorac.Soc.2:313-319)。稳定的慢性阻塞性肺病中的炎症的特征在于中性粒细胞、巨噬细胞、T淋巴细胞、树突细胞和B淋巴细胞。在慢性阻塞性肺病恶化期间,特别是在病毒诱导的严重慢性阻塞性肺病恶化期间,还存在嗜酸性粒细胞的募集。肺泡巨噬细胞在慢性阻塞性肺病中起关键作用,它们定位于肺泡破坏部位,其数量与肺气肿的疾病严重程度、气道阻塞和肺泡壁损伤程度呈正相关。在恶化期间、严重慢性阻塞性肺病期间或感染期间,慢性阻塞性肺病患者的大气道和小气道中的气道组织中性粒细胞增加。慢性阻塞性肺病的患者还表现出CD8+/CD4+T细胞比率的增加,或气道壁中CD8+和CD4+T细胞总数的增加(MacNee(2005)Proc.Am.Thorac.Soc.2:258-266)。细支气管受纤维化阻塞,并被巨噬细胞和T淋巴细胞浸润。
在T淋巴细胞中,特征在于干扰素(IFN)-γ的产生的T辅助(Th)-1和T细胞毒性(Tc)-1亚型占优势。许多炎症介质参与与慢性阻塞性肺病相关的炎症。TNFα、IL-1β、粒细胞-巨噬细胞集落刺激因子(GM-CSF)和CXCL8(IL-8)由暴露于香烟烟雾的气道上皮细胞释放。除白三烯B4和氧化剂(活性氧物质)之外,香烟烟雾激活肺泡巨噬细胞以释放细胞因子,包括TNFα、CXCL8、CCL2(MCP-1)。慢性阻塞性肺病中,痰和细支气管灌洗中的中性粒细胞数量及其数量与疾病严重程度相关。中性粒细胞募集的趋化信号包括白三烯B4、CXCL1、CXCL2、CXCL3、CXCL5和CXCL8(IL-8),其在慢性阻塞性肺病中的表达增加,并且可能源自肺泡巨噬细胞和上皮细胞。GM-CSF和粒细胞CSF(G-CSF)可以增加中性粒细胞的存活率。越来越多的证据表明,炎性体参与慢性阻塞性肺病以及炎性体与促炎细胞因子、特别是IL-1β和IL-18的活化有关联(Caramori et al.(2014)Internat.J.COPD 9:397–412)。
许多生物调节剂已经涉及慢性阻塞性肺病发病机理方面。这些疾病过程的促炎介质包括白三烯-B4、IL-8和其他趋化因子(如MIP-1α、MCP-1)、TNF-α、IL-13和IL-4(Barnes(2004),Pharmacol.Rev.56:515-548)。已经表明TNF-α和IL-4对通过支气管上皮细胞的调节性细胞因子TGF-β的产生的抑制作用可能有助于炎症反应的进展。此外,已经在痰中测量到IL-6、IL-1β、TNF-α和IL-8水平的增加,并且在恶化期间进一步增加。其他重要的促炎生物调节剂包括IFNγ、IL-5、IL-17、IL-18、IL-22、IL-23、IL-25、IL-32、IL-33和胸腺基质淋巴细胞生成素(TSLP)。有人认为,IL-5可能参与慢性阻塞性肺病恶化,因为在暴露于鼻病毒后,慢性阻塞性肺病的动物模型中IL-5的肺表达增加了(Caramori et al.(2014)同上),尽管在一般患者群体中没有在恶化期间检测到用于IL-4或IL-5的mRNA的实际增加。然而,将慢性阻塞性肺病群组分为由烟草烟雾引起疾病(TS-COPD)的患者和生物质烟雾诱发疾病(BE-COPD)的患者,可以揭示这些Th2细胞因子对慢性阻塞性肺病发病机理的贡献,这是因为发现了TS-COPD患者中Th17细胞的频率显著高于BE-COPD患者和健康对照。相比之下,BE-COPD患者的Th2细胞水平高于TS-COPD患者和健康对照,并且BE-COPD患者血清IL-4浓度高于TS-COPD患者(Solleiro-Villavicencio et al.(2015)Clin Immunol.doi:10.1016/j.clim.2015.07.009)。IL-17主要由Th17和Tc17细胞产生,它诱导气道上皮细胞和平滑肌细胞释放CXCL1、CXCL8和GM-CSF,以诱导中性粒细胞浸润。此外,它诱导支气管上皮细胞和成纤维细胞中的IL-6表达,并且关联IL-6的IL-17诱导气道上皮细胞中粘蛋白MUC5AC和MUC5B的产生。慢性阻塞性肺病患者的痰液中CXCL8水平显著升高,其与疾病严重程度相关(Caramori et al.(2014)同上)。针对CXCL8的单克隆抗体改善了慢性阻塞性肺病患者的呼吸困难,但未改善肺功能、健康状况或6分钟步行距离。可能对多种中性粒细胞趋化剂以及对其他细胞因子(例如IL-17)的抑制对于慢性阻塞性肺病患者的肺功能临床效果的显现是必需的。
结核病(TB)是一个主要的健康问题,每年约有130万人死亡,900万新病例。结核病是一种由含有结核分枝杆菌的气溶胶传播的传染病。结核分枝杆菌不会产生毒素,相反,过度旺盛的炎症反应导致组织损伤和疾病,并且可导致死亡以及驱动内源性再感染(Cardona,(2010)Archiv Immunol Et Therap Experimental.58:7-14)。控制炎症有助于减轻疾病进程。活动性肺结核的特征在于破坏性炎症和使个体感染的气道上皮细胞感染的扩散。在活动性肺结核中,中性粒细胞和参与中性粒细胞募集到肺部的过程的趋化因子/受体对(CXCL5/CXCR2)对破坏性炎症至关重要,因为阻断CXCL5的活性可消除炎症。CXCL5被认为约导致60%的中性粒细胞募集。在小鼠模型中,CXCL5或CXCR2的丧失对结核病及其相关的消耗性疾病和死亡具有保护作用(Nouailles et al.(2014)J.Clin.Invest.124:1268-1282)。尽管结核分枝杆菌在吞噬细胞内繁殖,但当感染毒性菌株时,这些细胞迅速成为会导致更多感染的坏死的释放杆菌。当中性粒细胞和巨噬细胞发生坏死时,它们释放出细胞外陷阱(NET),导致组织破坏。在细胞外陷阱中,组蛋白是细胞毒性的有效诱导剂,杀死肺泡上皮细胞和内皮细胞。已知,阻断组蛋白介导的细胞毒性显著降低炎性肺病中的组织损伤(Wildhagen et al.(2014)Blood 123:1098-1101)。设计用于模拟免疫活性的患者的活动性结核的小鼠模型也显示出大量的肺泡内中性粒细胞浸润。当用抗炎药物治疗时,记录了较低水平的促炎介质、较低的杆菌负荷、减轻的病状和增加的存活率。肝素是该模型中的有效抗炎药物(Marzo et al.(2014)Tuberculosis 94:55-64)。
在结核病中,含有坏死细胞碎片(和杆菌)的活化巨噬细胞随着肺泡液排出到上支气管。结果,杆菌进入气溶胶并通过上支气管的气道上皮引起再次感染。由于结核分枝杆菌在肺泡的丰富上皮细胞中生长,这些细胞可能是复制杆菌的重要位点。由结核分枝杆菌表达的HBHA(肝素结合血细胞凝集素)对于杆菌到上皮细胞的粘附是必需的。HBHA的富含赖氨酸的C末端域结合上皮硫酸乙酰肝素(HS)以介导粘附,而其卷曲螺旋域聚集杆菌。两个HBHA域共同使杆菌有效进入气道上皮(Pethe et al.(2001)Nature 412:190-4)。破坏HBHA-HS结合主要可减少内源性再感染,但初始感染也可能受到影响。
急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)是与高死亡率相关的呼吸道炎症症状。急性肺损伤和急性呼吸窘迫综合征的发病机制涉及导致炎症、内皮损伤、凝血增强、纤维蛋白溶解和纤维增生减少的不受控制的宿主防御反应。病理性急性呼吸窘迫综合征的特征是弥漫性肺泡损伤、肺泡毛细血管渗漏和富含蛋白质的肺水肿,其导致的临床表为肺顺应性差、严重低氧血症和胸片上双侧浸润。最常见的危险因素是严重的败血症,其可具有肺部或非肺部来源。其他危险因素有毒性吸入、肺挫伤、急性胰腺炎、肺炎、误吸、肺栓塞、溺水、再灌注肺水肿、创伤、手术、烧伤、药物过量和心肺旁路手术(Han and Mallampalli(2015)J.Immunol.194:855-860)。该疾病的发病率与日俱增,在美国每年增加约20万例,并且38.5%的死亡率几十年来没有改善。该疾病有三个重叠阶段:渗出期(前4至7天)、增殖期(≥7至14或21天)和纤维化期(≥14或21天)(MacLaren and Stringer(2007)Pharmacotherapy,27:860-873)。
初始早期阶段(渗出期)的特征在于肺的内皮和上皮屏障的渗透性增加,肺间质及肺泡中富含蛋白质和富含细胞的水肿液的积聚。水肿液含有透明膜和各种炎症细胞,但中性粒细胞占优势。因此,病理相关性定义为:弥漫性肺泡损伤,由透明膜及下列中的至少一种组成:肺泡I型或内皮细胞坏死、水肿、间质纤维化或突出的肺泡细胞II型增殖。一些患者在疾病的第一周恢复,其他患者在该阶段死亡,但一些患者发展成在发病后存在7天左右的急性肺损伤/急性呼吸窘迫综合征的亚急性阶段。在这个亚急性阶段,肺泡腔充满了间充质细胞、它们的产物和新血管。有证据表明,间质和肺泡纤维化伴有II型细胞增殖和肺部微循环部分的破坏。在一些患者中,呼吸衰竭持续超过14天,并且该慢性阶段的特征在于广泛的肺纤维化、正常肺泡结构的丧失和肺中肺气肿区域的逐渐发展(Cepkova and Matthay(2006)J.Intensive Care Med.,21:119-143)。
急性呼吸窘迫综合征是一种炎性疾病,其特征在于中性粒细胞和巨噬细胞浸润以及肺泡腔中过度的促炎细胞因子和蛋白酶活性,所有这些都与肺泡上皮和毛细血管内皮损伤有关(Boyle et al.(2014)Expert.Opin.Biol.Ther.,14:969-981)。最初的炎症损伤(败血症、创伤、输血等)触发了Toll样受体(TLR)和核苷酸结合寡聚化结构域样受体(NOD样受体)信号通路,以激活肺泡巨噬细胞。这些活化细胞释放促炎细胞因子,包括IL-1β、TNF-α、IL-6和IL-8,其募集循环巨噬细胞和中性粒细胞。过多的中性粒细胞数和持续激活的巨噬细胞会损害肺泡-毛细血管屏障,使富含蛋白质的流体进入肺泡,引起肺水肿并干扰表征该疾病的气体交换(Han and Mallampalli(2015)同上)。中性粒细胞流入肺部与急性呼吸窘迫综合征的严重程度相关。生物调节剂,特别是由白细胞和体细胞产生的CXCL8(IL-8),在中性粒细胞募集和随后的组织损伤中起关键作用。特别地,气道上皮细胞可以从其顶面释放CXCL8,从而刺激中性粒细胞的跨上皮迁移(Shen et al.(2011)Expert.Opin.Biol.Ther.5:107-114)。中性粒细胞胞外陷阱(NET)由这些活化细胞产生,并直接诱导肺上皮细胞和内皮细胞的死亡,部分通过酶(弹性蛋白酶、基质金属蛋白酶-8(MMP-8))、活性氧类(ROS)以及NET中包含的组蛋白。
急性呼吸窘迫综合征的特征还在于泛素蛋白酶体系统的激活(其中泛素在肺泡(II型)上皮细胞中的表达增加)以及泛素蛋白酶体组分释放到肺液中。据报道,泛素化在急性呼吸窘迫综合征期间调节Na、K-ATP酶和上皮Na+通道功能中起重要作用。Na、K-ATP酶位于肺泡2型上皮细胞的基底外侧表面,其有助于肺液的清除。在缺氧期间,Na、K-ATP酶被内化并通过泛素化由内吞作用降解,导致肺泡液清除率降低。针对泛素蛋白酶体系统已被提议作为急性呼吸窘迫综合征的治疗靶标(Han and Mallampalli(2015)同上)。
用于急性呼吸窘迫综合征治疗的生物调节剂靶标包括CXCL8、IL-1β、IL-17和TNF-α。动物研究表明,用靶向这些分子的单克隆抗体阻断CXCL8或TNF-α可以减弱急性呼吸窘迫综合征的发展并减少中性粒细胞浸润(Boyle et al.(2014)同上)。IL-1β是中性粒细胞的有效募集者且可增加肺泡-毛细血管通透性。此外,IL-1β依赖性的IL-6诱导启动成纤维细胞活性,因此有助于急性呼吸窘迫综合征的纤维化重塑期。IL-17将中性粒细胞吸引到肺部并与TNF-α协同作用以增加内皮细胞的选择素表达,从而进一步增加中性粒细胞募集。
在急性肺损伤/急性呼吸窘迫综合征中,凝血的局部激活和纤维蛋白翻转的扰动发生,导致过度的肺泡纤维蛋白沉积,这也损害了肺的完整性和功能。在这些条件下观察到的肺泡内纤维蛋白积聚起因于血浆蛋白(包括纤维蛋白原)泄漏到肺泡腔中。与因子VIIa相关的组织因子和纤溶酶原激活物抑制剂-1对尿激酶的抑制是导致急性肺损伤/急性呼吸窘迫综合征中促凝血状态和抗纤维蛋白溶解状态的主要因素(Wygrecka et al.(2008)Thromb.Haemost.99:494-501)。纤维蛋白本身可以增加血管通透性,影响炎症介质的表达并改变各种细胞类型的迁移和增殖。另外,纤维蛋白可使肺表面活性剂失活,并提供成纤维细胞可在其上迁移并产生胶原的基质。凝血抑制剂如组织因子途径抑制剂、活性位点失活因子VIIa、活化蛋白C、抗凝血酶、肝素或水蛭素的应用看起来在急性和慢性肺损伤的实验模型中是有益的,因此作为可能的疗法引起了人们的兴趣。
骨关节炎(OA)是一种退行性关节疾病,其特征在于关节软骨退化,其可影响身体中的许多关节,但在诸如膝盖和髋部的负重关节中尤其常见。软骨的损失可导致关节间隙变窄、疼痛和功能丧失,最终导致需要全关节置换。已经研究了促炎细胞因子和抗炎细胞因子与人和动物模型中骨关节炎的发展和进展的关联(Mabey and Honsawek(2015)World JOrthop.6:95-105)。除了促炎和抗炎作用(例如,白介素(IL)-6、IL-1β、肿瘤坏死因子(TNF)-α、IL-10、IL-13和IL-4),细胞因子还通过血管生成和趋化性对骨关节炎的病理生理学有所贡献。IL-1β、IL-6和TNF-α是参与骨关节炎的主要促炎细胞因子(Mabey andHonsawek(2015)同上),但该组中还包括IL-15、IL-17和IL-18。所有这些细胞因子都会促进导致软骨退化的分解代谢和破坏性过程。IL-1β影响软骨细胞合成金属蛋白酶(MMP)家族的酶,主要是间质胶原酶(MMP-1)、溶基质素-1(MMP-3)胶原酶3(MMP-13),其降解软骨。此外,IL-1β可以影响软骨细胞的ADAMTS金属蛋白酶的产生,其负责软骨中聚集蛋白聚糖分子的蛋白水解。主要作用归因于ADAMTS-4,其产生受IL-1β和TNFα的刺激,而ADAMTS-5是组成型产生的。TNF-α是诱导骨关节炎病理的另一种主要细胞因子,TNFα的作用通常与IL-1β的作用一致,并且在骨关节炎中两种细胞因子之间存在显著的协同作用。因此,TNFα影响软骨细胞合成蛋白多糖、结合蛋白多糖的蛋白质和II型胶原的能力。它还激活软骨细胞以产生MMP-1、MMP-3、MMP-13和ADAMTS-4。OA关节组织中IL-6的产生通常是响应IL-1β和TNFα及其对软骨细胞、成骨细胞、巨噬细胞和脂肪细胞的作用。与IL-1β和TNFα一样,IL-6引起II型胶原产生的减少,并且增加各种NMP的产生(Nasi et al.(2015)Ann Rheum Dis doi:10.1136/annrheumdis-2015-207487)。IL-6是引起软骨下骨层的变化的主要细胞因子,它促进破骨细胞的形成,从而促进骨再吸收。由IL-1β、TNFα和IL-6激发的成骨细胞也可以产生NMP,因此对关节中骨骼附近的软骨产生不利影响。除了影响软骨细胞和滑膜细胞外,这些炎性细胞因子还会影响迁移到炎症部位的免疫系统细胞。由于这些细胞因子,免疫细胞以自分泌方式产生过量的炎性PGE2、COX-2、磷脂酶A2、NO、自由基、IL-8、CCL5、更多IL-1β、TNFα和IL-6(Wojdasiewicz(2014)Mediators Inflamm.561459doi:10.1155/2014/561459)。
根据本发明,糖缀合物与许多生物调节剂相互作用,所述生物调节剂部分或全部是上述讨论的病症的原因。在一实施方式中,调节剂是趋化因子、细胞因子、生长因子或趋化剂,且包括肽、多肽、蛋白质或糖蛋白。合适的生物调节剂靶标包括已被描述为GAG结合蛋白(例如肝素、硫酸肝素、软骨素和透明质酸)的那些。实例包括但不限于:组胺、白介素(例如IL-1、IL-1α、IL-1β、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-19、IL-20、IL-21、IL-22、IL-23、IL-24、IL-25、IL-26、IL-27、IL-28、IL-29、IL-30、IL-31、IL-32、IL-33、IL-34、IL-35、IL-36、IL-37、IL-38)、干扰素(例如α-干扰素、β-干扰素、γ-干扰素)、胸腺基质蛋白(TSLP)、趋化因子类分子(CCL1、CCL2、CCL3、CCL4、CCL5、CCL6、CCL7、CCL8、CCL9、CCL10、CCL11、CCL12、CCL13、CCL14、CCL15、CCL16、CCL17、CCL18、CCL19、CCL20、CCL21、CCL22、CCL23、CCL24、CCL25、CCL26、CCL27、CCL28、CXCL1、CXCL2、CXCL3、CXCL4、CXCL5、CXCL6、CXCL7、CXCL8、CXCL9、CXCL10、CXCL11、CXCL12、CXCL13、CXCL14、CXCL15、CXCL16、CXCL17、XCL1、XCL2、CX3CL1、白三烯B4、MIP-1α、MCP-1)、生长因子(包括但不限于TSLP、G-CSF、M-CSF、GM-CSF、BDNF、CNTF、EGF、EPO、FGF1、FGF2、FGF3、FGF4、FGF5、FGF6、FGF7、FGF8、FGF9、FGF10、FGF11、FGF12、FGF12、FGF13、FGF14、FGF15、FGF16、FGF17、FGF18、FGF19、FGF20、FGF21、FGF22、FGF23、LIF、M-CSF、NGF、NT3、NT4、NT5、NT6、NT7、OSM、PBP、PBSF、PDGF、PECAM-1、SCF、TGFα、TGFβ1、TGFβ2、TGFβ3、TNFα、TNFβ、TPO、VEGF、GH、胰岛素等)、酶(例如超氧化物歧化酶、嗜酸性阳离子蛋白、主体碱性蛋白、类胰蛋白酶、糜酶、弹性蛋白酶、选择蛋白、解聚素和金属蛋白酶4(ADAM4)、ADAM5、磷脂酶A2或前列腺素内过氧化物)、可溶性或细胞或病毒结合的受体(例如肌醇三磷酸受体)、补体级联的成员(例如C1、C1q、C1-抑制剂、C2、C4、C4b、C4bp、MASP-1、MASP-2、C3、C3b、D因子、H因子、B因子、备解素、C6、C8、C9)、组蛋白或肝素结合血细胞凝集素(HBHA)。
本文实现了用于确定与一种或多种生物调节剂结合并调节其活性的糖缀合物的测定或筛选,所述测定包括以下步骤:
(a)使生物调节剂与糖缀合物接触;和
(b)量化糖缀合物对生物受体的作用;所述糖缀合物具有下式(I):
其中,
L是连接键或连接基团;
L1和L2各自独立地选自键和连接基团;
L3和L4各自独立地选自键和连接基团;
X1和X2各自为封端糖,其中,X1和X2各自独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;
Y1和Y2各自为连接糖,其中,Y1和Y2独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;和
n是0到3的整数。
X1、X2、Y1和Y2还可包含一个或多个硫酸酯基团、磷酸酯基团、氧化物基团或其组合。
在一实施方式中,生物调节剂是趋化因子、细胞因子、生长因子或趋化剂,且包括肽、多肽、蛋白质或糖蛋白。在识别与生物调节剂结合或调节其活性的糖缀合物的方法中,糖缀合物可基于一种或多种物理化学、药代动力学、生物学和/或生理学特性进行选择。此类性质的实例包括但不限于:结合亲和力、选择性、毒性、效力、稳定性、亲脂性和/或活性(如激动、拮抗、抑制)。在另一实施方式中,糖缀合物结合到生物调节剂的受体链上,这样来调节调节剂的活性。例如,糖缀合物可通过抑制调节剂与受体的结合来调节生物调节剂的活性。
在一实施方式中,使生物调节剂与糖缀合物接触的步骤可以原位、体外或体内进行。例如,生物调节剂与糖缀合物的接触步骤可以在细胞或动物体内进行。
与生物调节剂的相互作用可以通过任何方便的手段检测,例如核磁共振(NMR)、质谱(MS)、等温滴定量热法(ITC)、动态光散射(DLS)、表面等离子体共振(SPR)、双极化干涉测量(DPI)、微尺度热泳(MST)、凝胶阻滞、滤器延迟、亲和共电泳、生物发光共振能量转移(BRET)测定、荧光共振能量转移(FRET)测定、荧光偏振(FP)测定、闪烁接近测定、固定到生物芯片或其它表面(包括与质谱检测相结合的那些)上。
后者可通过首先将糖缀合物固定到芯片上,然后添加生物调节剂来实现。或者,调节剂可被固定在芯片上并用于筛选糖缀合物与其结合的能力。
另一种替代方法是将GAG(如肝素)固定在固体支持物上,然后筛选糖缀合物抑制受体与固定的肝素结合的能力。
因此,本文考虑的测定包括混合生物调节剂和糖缀合物,并筛选糖缀合物抑制调节剂与结合到芯片上的GAG(例如肝素或硫酸乙酰肝素)结合的能力。
在一实施方式中,糖缀合物结合生物调节剂,这样抑制生物调节剂与其受体之间的相互作用。在另一实施方式中,糖缀合物结合生物调节剂的受体链,这样抑制调节剂结合和信号传导。
当然,存在任意数量的其他测定,其可用于筛选糖缀合物和生物调节剂或调节剂受体链之间的相互作用,或用于筛选调节剂与其受体之间的相互作用的抑制。另一种测定是过滤结合测定。在该测定中,糖缀合物或生物调节剂之一用能够提供可识别信号(如荧光染料)的报道分子标记,并使得两种分子在溶液中相互作用。然后使得到的混合物通过能够延迟糖缀合物、趋化因子或糖缀合物-调节剂复合物之一的过滤器。
例如,在一实施方式中,过滤器是延迟蛋白质的硝酸纤维素过滤器。在这种情况下,如果用报道分子标记的糖缀合物不能通过过滤器,那么过滤器中报道信号的存在表明糖缀合物与趋化因子结合。
在另一实施方式中,GAG用报道分子标记,并在不同糖缀合物存在下与生物调节剂反应。肝素或硫酸乙酰肝素通过过滤器表明糖缀合物抑制了肝素或硫酸乙酰肝素和调节剂之间的相互作用。
不同的糖缀合物将与不同的生物调节剂相互作用,不同的调节剂将与不同的糖缀合物相互作用,或两者均可。此外,不同的糖缀合物可以与不同的生物调节剂受体链相互作用。因此,另一种测定涉及使用携带固定趋化因子的亲和柱。使糖缀合物通过所述柱并测定糖缀合物的延迟的存在。盐梯度方便地用于洗脱结合的糖缀合物。
本发明考虑的测定的其他实例包括功能测定,例如评估细胞增殖的全细胞测定(例如实施例22-28中所示)。与纯结合测定相比,此类功能测定可提供关于测试糖缀合物效果的更有用的信息。
一旦确定出与特定配体结合的糖缀合物,糖缀合物本身可用作抑制生物调节剂与细胞表面GAG(例如肝素或硫酸乙酰肝素)或生物调节剂受体之间相互作用的治疗剂。调节剂由细胞分泌,它们可以处于可溶性相中、固定在细胞外基质上或附着于细胞表面GAG。糖缀合物也可用作治疗剂,以调节分泌的细胞产物和细胞外基质组分之间、细胞表面蛋白质和细胞外基质组分之间或生物调节剂与其受体之间(它们的双方或一方与细胞表面相关)的相互作用。或者,糖缀合物可用作靶标,以确定天然产物或在结合生物调节剂方面模拟糖缀合物、或抑制或促进糖缀合物与调节剂之间的相互作用的化学品库中的产物。这些分子可以是糖缀合物的拮抗剂或激动剂或化学类似物。因此,“类似物”延伸到并涵盖功能上等同(它以类似的方式结合和/或调节趋化因子)的任何结构。
本文提及的“调节”延伸到并涵盖抑制和(或)促进相互作用。
另一方面,本发明提供了治疗或预防哺乳动物受试者中与生物调节剂活性相关或因其加剧的任何疾病的方法,包括调节剂与其受体之间的相互作用(例如或涉及信号通路的活化),或病毒和细胞之间的相互作用,该方法包括向受试者施用本文定义的糖缀合物、一种糖缀合物或糖缀合物模拟物。糖缀合物尤其可用于治疗炎性或过敏性疾病病症、转移性癌症以及病原体(如细菌、病毒或寄生虫)引起的感染。
在一实施方式中,本文实现了预防和/或治疗受试者疾病病症的方法,所述疾病病症来自所述宿主的细胞表面上的GAG与生物调节剂之间的相互作用,或者来自宿主细胞外基质中的GAG与可能与细胞相关或不相关的调节剂之间的相互作用,或者宿主中可被GAG破坏的生物调节剂受体的相互作用,其中蛋白质可能与细胞相关,可溶配体或者调节剂和受体都是与细胞相关的,该方法包括给受试者施用治疗有效量的糖缀合物,该糖缀合物如本文所述制备并确定,且与调节剂相互作用。
本文考虑的“受试者”是人和非人的哺乳动物,包括实验室或技术上接受的试验或载体动物。“受试者”包括需要治疗或预防的人类受试者。
本文还考虑了用于生产治疗受试者疾病病症的药物的方法,该方法包括根据本文定义的方法来生产糖缀合物或一系列糖缀合物,并筛选具有与生物调节剂相互作用或调节其的能力的每种糖缀合物。确定能与生物调节剂相互作用或调节生物调节剂的糖缀合物,并在药物制备中使用所述糖缀合物或其模拟物。
在一实施方式中,调节是指抑制。
本文考虑的生物调节剂类型包括上面列出的那些。
有用地,本发明还提供了包含本文所述糖缀合物的组合物。术语“化合物”包括“药物”、“试剂”、“治疗剂”、“药理学上可接受的化合物”和“药物组合物”等。在另一实施方式中,组合物包含药学上或生理学上可接受的载体或稀释剂。包含一种或多种(被术语“糖缀合物”所涵盖的)糖缀合物的“组合物”包括单一组合物或多种独立的组合物,每种组合物包含相同或不同的糖缀合物,同时或顺序给药,或给药之前混合在一起。在一实施方式中,糖缀合物用于治疗或预防由生物调节剂促进或加剧的病症或症状。
根据常规药物配制技术方便地制备药物组合物。例如,参见Remington'sPharmaceutical Sciences(1990)18th Ed.,Mack Publishing,Company。除了一种活性物质(本文所述的糖缀合物或其模拟物)之外,这些组合物还可包含药学上可接受的赋形剂、载体、缓冲剂、稳定剂或本领域熟知的其他材料。这些材料应无毒,且不应干扰活性成分的功效。载体可以采取多种形式,这取决于给药(例如静脉内、口腔或肠胃外)所需的制剂形式。
本文所述的糖缀合物或包含其的组合物以有效量施用。术语“有效量”包括“治疗有效量”和“预防有效量”,并且意指在单剂量下或者作为系列的一部分或对一些受试者提供所需治疗、预防或生理效果的缓释体系,有足够量的活性。不良效果(例如副作用)有时可能随着所需的治疗效果而出现,因此,从业者在确定适当的“有效量”时需平衡潜在利益与潜在风险。所需组合物的确切量将因受试者而异,取决于受试者的种属、年龄、一般状况和给药方式等。因此,可能无法指定确切的“有效量”。然而,本领域普通技术人员可以使用常规技能或实验来确定任何单独情况下的适当“有效量”。术语“治疗”是指受试者在与所治疗病症相关的病症的一种或多种症状中任何可测量或统计学上显著的改善。该化合物的预防性给药用于预防或减轻需要预防的病症症状的发作。
在一实施方式中,所述疾病或病症选自炎性疾病,包括过敏性疾病、骨关节炎、转移性癌症;病原体感染,所述病原体包括但不限于引起结核病的结核分枝杆菌、与人或禽流感相关的A型流感病毒和引起艾滋病的人类免疫缺陷病毒(HIV)。特定疾病包括哮喘、过敏性呼吸道疾病、过敏性鼻炎、气道高反应性的上皮下纤维化、慢性鼻窦炎、常年性过敏性鼻炎、囊性纤维化患者的过敏性支气管肺曲霉病、慢性阻塞性肺病、嗜酸细胞性支气管炎、支气管扩张、支气管痉挛、支气管收缩、支气管高反应性和支气管肥大。
“药理学上可接受的”组合物是受体患者耐受的组合物。“药学上可接受的载体和/或稀释剂”是药物载体,其由需要的材料组成,即它不可能单独或与活性组合物引起显著的不良反应。载体可包括所有溶剂,分散介质,包衣,抗细菌和抗真菌剂,用于调节紧张性、增加或降低吸收或清除速率的试剂,用于维持pH的缓冲剂,螯合剂,膜或屏障交叉剂。药学上可接受的盐是希望的盐。试剂或包含所述试剂的组合物可以以药学上可接受的无毒盐的形式(例如酸加成盐或金属络合物)给药。
当糖缀合物被适当保护时,可以口服给药。对于口服给药,可将组合物配制成固体或液体制剂,例如胶囊、丸剂、片剂、锭剂、粉末、悬浮液或乳液。在制备口服剂型的组合物时,可以使用任何常用的药物介质,在口服液体制剂(例如悬浮液、酏剂和溶液)的情况下,例如水、二醇、油、醇、调味剂、防腐剂、着色剂、悬浮剂等;或载体,在口服固体制剂(例如粉末、胶囊和片剂)的情况下,如淀粉、糖、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。由于它们易于给药,片剂和胶囊代表着最有利的口服剂量单位形式,这种情况下显然要使用固体药物载体。片剂可含有粘合剂,例如黄蓍胶、玉米淀粉或明胶;崩解剂如海藻酸;润滑剂如硬脂酸镁。如果需要,可以通过标准技术将片剂糖包衣或肠溶包衣。将活性组合物包封以使其稳定通过胃肠道,例如参见国际专利公开号WO 96/11698。
对于肠胃外给药,可将组合物溶解在载体中并以溶液或悬浮液形式给药。对于透膜或经皮(包括贴剂)传送,使用本领域已知的适当渗透剂来传送组合物。对于吸入,传送使用任何方便的系统,例如干粉气溶胶、液体输送系统、空气喷射雾化器、推进系统。例如,制剂可以以气溶胶或雾的形式给药。组合物还可以以持续传送或持续释放形式传送。例如,可生物降解的微球或胶囊或能够持续传送的其他聚合物构型可包括在该制剂中。可以修改制剂以改变药代动力学和生物分布。关于药代动力学的一般性讨论,例如参见Remington'sPharmaceutical Sciences(1990)(同上)。在一些实施方式中,制剂可以掺入脂质单层或双层,例如脂质体或胶束。本领域已知的靶向疗法可用于更特异性地传送药剂至特定类型的细胞或组织。
适于注射使用的药物形式包括无菌水溶液(水溶性的),以及用于临时制备无菌可注射溶液和可吸入形式的无菌粉末。这些形式在制造和储存条件下通常是稳定的。载体可以是溶剂或稀释介质,包括例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等)及其合适的混合物和植物油。例如通过使用表面活性剂可以保持适当的流动性。在许多情况下,优选包括等张剂,例如糖或氯化钠。通过在组合物中使用延迟吸收的试剂,例如单硬脂酸铝和明胶,可以实现可注射组合物的延长吸收。
通过将所需量的糖缀合物和载体/稀释剂加入适当的溶剂中,然后灭菌或至少将污染的病毒、细菌或其他生物实体减少至人或动物受试者给药可接受的的水平的方法来制备无菌可注射溶液。在用于制备无菌可注射溶液的无菌粉末的情况下,合适的制备方法包括真空干燥和冷冻干燥技术,其产生活性成分加上任何另外所需的成分的粉末。
在一实施方式中,制备了根据本发明的组合物或制剂,使得口服剂量单位形式含有约0.1μg至200mg的活性糖缀合物。替代剂量包括约1μg至约1000mg和约10μg至约500mg。这些剂量可以是每个个体或每千克体重。可以按每秒、每分钟、每小时、每天、每周、每月或每年给药。
还可以配制组合物用于局部给药。技术配方和给药可以在"Remington'sPharmaceutical Sciences(1990)(同上)”中找到。因此,对于局部给药,主体组合物可以以任何合适的方式配制,包括但不限于乳膏、凝胶、油、软膏、溶液、悬浮液、粉末、薄雾或气溶胶。对于透膜给药,在制剂中使用适合于要渗透的屏障的渗透剂。这些渗透剂通常是本领域已知的,包括但不限于苯扎氯铵、洋地黄皂苷、二氢细胞松弛素B5和癸酸。
组合物可以是洗剂、乳膏或凝胶的形式,可以含有可接受的稀释剂或载体,以获得所需的质地、稠度、粘度和外观。可接受的稀释剂和载体是本领域技术人员熟悉的,包括但不限于乙氧基化和非乙氧基化的表面活性剂、脂肪醇、脂肪酸、烃油(如棕榈油、椰子油和矿物油)、可可油蜡、硅油、缓冲剂、纤维素衍生物、乳化剂(如非离子有机和无机碱)、防腐剂、蜡酯、甾醇、甘油三酸酯、磷脂(如卵磷脂和脑磷脂)、多羟基醇酯、脂肪醇酯、亲水性羊毛脂衍生物和亲水性蜂蜡衍生物。
在一实施方式中,本文中使用的是吸入药物组合物。包含一种或多种本发明的糖缀合物的组合物可作为鼻或肺吸入气溶胶、或雾化器溶液、或作为微细粉末(在一实施方式中,1至10微米级别或更小的尺寸的颗粒)给药到呼吸道,以供单独地或与惰性载体(如乳糖)或与其它药学上可接受的赋形剂一起吸入。
气溶胶制剂包括其中糖缀合物提供在具有合适推进剂的加压包装(例如加压定量吸入器(pMDI))中的那些。虽然推进剂可以是氯氟烃(CFC),例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷,但推进剂更优选是非氯氟烃推进剂,例如二氧化碳、氢氟烷烃(例如HFA-134a)或其他合适的气体。气溶胶还可方便地含有表面活性剂,例如卵磷脂。糖缀合物的剂量可以通过提供计量阀来控制。已经发现,大约2到3μm的颗粒尺寸可用于治疗哮喘,因为小于1μm的颗粒通常在没有传送到肺部的情况下呼出,大于10μm的颗粒大多被口咽沉积物困住,无法到达肺部。由HFA-134a推动的装置递送更小的液滴,其更容易渗透到支气管气道中。在一实施方式中,使用如上概述的pMDI可期望并实现将大约40%的吸入液滴传送到肺中。对于过敏性鼻炎的治疗,通过鼻腔通道的药物传送的优选粒径为20μm至80μm,较小的颗粒(小于10μm)被带入气管支气管区域,而较大的颗粒(大于100μm)从鼻腔通道迅速清除。
糖缀合物还可以以在鼻腔中形成凝胶的药物制剂形式提供。糖缀合物也可以配制成粉末组合物,其可以单位剂量呈现,例如胶囊或例如明胶小桶或粉末可从其通过吸入器给药的泡罩包装。
本文所用的术语“药学上可接受的盐”是指给定化合物的盐,其中所述盐适合作为药物给药。例如,这些盐可以分别通过酸或碱与氨基或羧基反应形成。
药学上可接受的碱加成盐可以由无机碱和有机碱制备。衍生自无机碱的盐包括但不限于钠、钾、锂、铵、钙和镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺、仲胺和叔胺;取代胺,包括天然存在的取代胺;环胺,包括异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二甲基氨基乙醇、氨丁三醇、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、hydrabamine、胆碱、甜菜碱、乙二胺、葡糖胺、N-烷基葡糖胺、可可碱、嘌呤、哌嗪、哌啶和N-乙基哌啶。还应该理解的是,其它羧酸衍生物可用于实施本发明,例如羧酸酰胺,包括甲酰胺、低级烷基甲酰胺、二(低级烷基)甲酰胺等。
药学上可接受的酸加成盐可以由无机酸和有机酸制备。衍生自无机酸的盐包括盐酸、氢溴酸、硫酸、硝酸、磷酸等。衍生自有机酸的盐包括乙酸、丙酸、乙醇酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。
术语“保护基团”是指当与化合物的一个或多个羟基、硫醇基、氨基或羧基结合时防止反应在这些基团上发生的任何基团,且该保护基团可以通过常规化学或酶促步骤除去,以重建羟基、硫基、氨基或羧基。所用的特定可除去的封闭基团并不重要,优选可除去的羟基封端基团包括常规的取代基,如烯丙基、苄基、乙酰基、氯乙酰基、硫代苄基、亚苄基、苯甲酰基、叔丁基二苯基甲硅烷基和任何其他可化学引入到羟基官能团上并随后在与产品性质相容的温和条件下通过化学或酶促方法选择性地除去的基团。在Greene and Wuts(1991)(同上)中更详细地公开了保护基团。
可除去的氨基封闭(保护)基团的实例包括常规取代基,例如叔丁氧羰基(t-BOC)、苄氧羰基(CBZ)、芴甲氧羰基(FMOC)、烯丙氧羰基(ALOC)等,其可通过与产品性质相容的常规条件除去。
“选择性”或“特异性”通常是一个配体对不同受体的结合偏好的度量和/或不同配体对一个受体的结合偏好的度量。配体关于其靶受体相对于另一种受体的选择性由各自Kd值(即每种配体-受体复合物的解离常数)的比确定,或者在低于Kd值时观察到生物学效应的情况下,通过各EC50值(即产生与两种不同受体相互作用的配体的最大响应50%时的浓度)的比给出选择性。
术语“治疗有效量”是指当施用于受试者(如哺乳动物,包括需要这种治疗的人)时,足以实现如上定义的治疗的量。治疗有效量将根据受试者和所治疗的疾病状态、痛苦的严重程度和给药方式而变化,且可由本领域普通技术人员常规确定。
本文所用的术语“治疗”包括动物(优选哺乳动物,更优选人)的病症或疾病的任何治疗,包括:(i)预防可能易患这种疾病但尚未被诊断为患有该疾病的受试者发生疾病或病症;(ii)抑制疾病或病症,即阻止其发展;(iii)缓解疾病或病症,即使病症消退;(iv)缓解由疾病引起的病症,即疾病的症状。
应理解的是,本发明化合物可以以一种或多种立体异构形式(例如对映异构体、非对映异构体)存在。本发明在其范围内包括所有这些立体异构形式,或分离(例如对映体分离)或组合(包括外消旋混合物)。
本文所用的术语“预防”是指预先施用药物,以避免或预防出现疾病或病症的一种或多种症状。医学领域的普通技术人员认识到,术语“预防”不是绝对术语。在医学领域中,应理解为意指预防性施用药物,以从实质上减少病症的可能性、严重性或病症症状,这是本公开的目的所在。如本领域的标准文本(医师桌上参考手册)中使用的,关于疾病或病症的术语“预防”,是指在疾病或病症完全显现之前,避免疾病或病症的原因、影响、症状或发展。
关于本发明的化合物、组合物或制剂的术语“施用”或“给药”是指将化合物引入需要治疗的动物系统中。当本发明化合物与一种或多种其它活性试剂组合提供时,“给药”及其变体各自应理解为包括同时和/或顺序引入所述化合物和其它活性剂。
实施例
通过以下非限制性实施例进一步描述本文公开的方面。
通用化学过程
除非另有说明,否则所有反应均在氮气氛中进行。使用Bruker Ultraspin 400MHz光谱仪(1H 400MHz,13C 100MHz)收集NMR光谱。使用配有通用ATR采样附件的Perkin ElmerSpectrum 100FT-IR光谱仪记录FT-IR光谱。使用Barnstead 9100电热熔点仪测量熔点。使用Rudolph Research Analytical Autopol I自动旋光仪测量光学活性。使用60μm Merck硅胶进行快速色谱。通过薄层色谱法(TLC)监测反应,使用具有铝背衬并含有F254荧光指示剂的Merck硅胶的60μm TLC板。使用紫外线在TLC板上观察化合物,然后使用去离子水稀释至200mL的含有KMnO4(1.5g)、K2CO3(10g)、10%NaOH溶液(1.25mL)的高锰酸钾溶液染色,或用含有10%H2SO4的乙醇溶液染色。
除非另有说明,所有有机提取物都用无水硫酸镁干燥,并在减压除去溶剂之前过滤。使用的缩略词如下:DMF(N,N-二甲基甲酰胺)、Ac2O(乙酸酐)、DMSO(二甲基亚砜)、MeOH(甲醇)、THF(四氢呋喃)、PPh3(三苯基膦)、NBS(N-溴代琥珀酰亚胺)、DCM(二氯甲烷)。
实施例1
6'-叠氮基-6'-脱氧三氯蔗糖(1)
将三氯蔗糖(4.069g,10.23mmol)溶于DMF(10mL)中,并加入叠氮化钠(1.48g,22.77mmol)。将反应混合物在120℃下加热60小时,减压除去溶剂。将剩余物溶于热的2-丙醇中,过滤以除去不需要的盐。减压浓缩滤液,得到棕色粘稠油状物。通过快速色谱法(洗脱液,95:1的乙酸乙酯/甲醇)纯化油状物,得到浅黄色粘稠油状物的6'-叠氮基-6'-脱氧三氯蔗糖1(1.227g,29%)。化合物不能通过1H NMR完全表征。
1H NMR(D2O,400MHz):5.51(d,1H,J=4Hz,H-1)、4.57(m,1H,H-4)、4.41-4.48(m,2H,H-3',H-5)、4.09-4.25(m,3H)、3.93-4.06(m,2H)、3.77-3.88(m,4H)、3.61-3.67(dd,1H)。
13C NMR(D2O,100MHz);103.4、92.64、80.0、76.0、74.4、71.6、71.2、70.9、61.7、60.6、52.6、43.5。
Rf=0.76(95:5的乙酸乙酯/甲醇)。
实施例2
2,3,3’,4’,6-五-O-乙酰三氯蔗糖(2)
将三氯蔗糖(6.125g,15.40mmol)溶解在吡啶(80mL)中并加入乙酸酐(30mL)。将反应混合物在室温、氮气氛下搅拌18小时。减压除去吡啶,将剩余的反应混合物溶于乙酸乙酯(50mL)中。将其用HCl(1M,3×30mL)、盐水溶液(30mL)、氨溶液(30%,1×60mL)和盐水溶液(30mL)洗涤。弃去水性洗涤液。减压浓缩有机提取物,得到2,3,3’,4’,6-五-O-乙酰三氯蔗糖2(8.616g,92%),其为白色结晶粉末。化合物对于后续步骤而言是足够纯的。
1H NMR(CDCl3,400MHz):5.69(d,1H,J=6.4Hz,H-3')、5.67(m,1H,H-1)、5.41(t,1H,J=6.4Hz,H-4')、5.30(t,2H,J=1.9Hz,H-2,H-3)、4.54-4.59(m,2H,H-4,H-5)、4.36-4.42(m,1H,H-5')、4.22-4.28(m,3H,H-6a,H-6b,H-5')、3.77(dd,2H,J=0.8,6Hz,H-6'a,H-6'b)3.69-3.73(d,1H,J=12.0Hz,H-1'a)3.57-3.61(d,1H,J=12Hz,H-1'b)2.00-2.15(5xAcO)。
1H NMR(d6-丙酮,400MHz):4.99-5.02(m,2H,H-1,H-3')、4.68-4.75(m,2H,H-4',H-3)、4.52-4.57(dd,J=3.6,10.8Hz,H-2)、4.03-4.06(dd,1H,J=1.6、3.6Hz,H-4)、3.96-4.01(m,1H,H-5)、3.54-3.60(m,1H,H-5')、3.51(d,2H,J=6Hz,H-6a,H-6b)、3.16-3.20(m,3H,H-6’a,H-6’b,H-1’a)3.08-3.13(d,1H,J=12Hz,H-1’b)、1.30-1.37(5xOAc)。
13C NMR(d6-丙酮,100MHz):169.8-169.3(5xC=O)、104.3(C,C-2')、90.9(CH,C-1)、80.9(CH,C-5')、75.8(CH)、75.7(CH)、67.9(CH,C-5)、67.6(CH,C-3)、66.7(CH,C-2)、63.5(CH2,C-6)、60.1(CH,C-4)、44.5(2xCH2)、19.9-19.6(5xCH3)。
ATR-FTIR:2940(C-H)、1730(C=O)、1365(C-C-C)、1215(C-C(=O)-O)、1055(C-O-C)
Rf=0.42(1:1的乙酸乙酯/石油精40-60)。lit.+66.8(c 0.9)M.P.86-90℃;lit.92-94℃
实施例3
2,3,3’,4’,6-五-O-乙酰基-6'-叠氮基-6'-脱氧三氯蔗糖(3)
将三氯蔗糖五乙酸酯2(4.025g,6.62mmol)溶于DMF(15mL)中,并加入叠氮化钠(0.489g,7.52mmol),将反应混合物在120℃下加热24小时。减压除去溶剂。将剩余物溶于DCM/水(1:1,100mL)的混合物中。用DCM(3×50mL)提取水相。合并有机提取物,用硫酸铜溶液(3×30mL)和盐水溶液(30mL)洗涤。经硫酸镁干燥有机提取物,减压浓缩,得到黄色粘稠油状粗产物。通过快速色谱法(洗脱液,1:1乙酸乙酯/石油精40-60)纯化剩余物,得到2,3,3',4',6-五-O-乙酰基-6'-叠氮基-6'-脱氧三氯蔗糖3(1.784g,44%),其为淡黄色粘稠油状物。
1H NMR(CDCl3,400MHz):5.70(d,1H,J=6.8Hz,H-3'),5.66(d,1H,J=3.6Hz,H-1),5.31-5.36(m,2H,J=6.8Hz,H-3,H-4'),5.25-5.30(dd,1H,J=3.6,10.8Hz,H-2),4.53-4.88(m,2H,H-4,H-5),4.20-4.26(m,2H,H-6a H-6b),4.10-4.17(td,1H,J=4.0,6.8Hz H-5')3.68-3.73(d,1H,J=12.0Hz,H-1'a)3.57-3.65(m,2H,H-1'b,H-6'a)3.49-3.55(dd,1H,J=4,13.2H-6'b)2.06-2.13(5x AcO)。
13C NMR(CDCl3,100MHz):170.3-169.6(5x C=O),104.2(C,C-2'),90.8(CH,C-1),79.6(CH,C-5'),75.6(CH,C-3'),75.1(CH,C-4'),67.9(CH),67.7(CH),67.0(CH),63.5(CH2,C-6),58.9(CH),52.5(CH2,C-6'),44.5(CH2,C-1'),20.4-21.0(5x CH3).
ATR-FTIR:2961(C-H),2103(N3),1742(C=O),1370(C-C-C),1215,(C-C(=O)-O),1040(C-O-C)cm-1
Rf=0.55(1:1的乙酸乙酯/石油精40-60)。
实施例4
炔丙基三甘醇(4)
在氮气氛下,将叔丁醇钾(5.098g,45.4mmol)溶解在无水THF(30mL)中。通过在减压下与甲苯(15mL)共蒸发来干燥三甘醇(2.251g,14.99mmol)。将干燥的三甘醇溶解在无水THF(5mL)中,并将其加入到反应混合物中。使混合物在室温下反应1小时。将炔丙基溴(80%,4.8mL,50.68mmol)溶解在无水THF(30mL)中,并逐滴加入到反应混合物中。将其在室温下搅拌过夜。将混合物用盐水:水(4:1,100mL)稀释,并用乙酸乙酯(3×50mL)提取。合并有机提取物并用盐水:水(1:1,40mL)和盐水(80mL)洗涤。将有机提取物经硫酸镁干燥,减压浓缩,得到黄色油状物。通过快速色谱法(洗脱液,40:60的乙酸乙酯/石油精40-60)纯化油状物,得到炔丙基三甘醇4,其为黄色油状物(778mg,22%)。
1H NMR(CDCl3,400MHz):4.15(d,2H,J=2.4Hz,H-3a,H-3b),3.60-3.67(m,6H,H-4a,H-4b,H-5a,H-5b,H-6a,H-6b),2.4(t,1H,J=2.4Hz,H-1).
13C NMR(CDCl3,100MHz):79.6(CH,C-1),74.7(C,C-2),70.6(CH2),70.5(CH2),69.0(CH2),58.3(CH2,C-3).
ATR-FTIR:3257(C≡C-H),2871(C-H),1089(C-O-C)cm-1
Rf=0.25(3:7的乙酸乙酯/石油精40-60)。
实施例5
苯甲酰化炔丙基甘露糖(5)的合成
将甘露糖(1.8g,10mmol)、炔丙醇(2.3ml,40mmol)和对甲苯磺酸(172mg,1mmol)的混合物加热至80℃,保持4小时。除去挥发物。将剩余物用乙酸乙酯(125ml)稀释并剧烈搅拌过夜。滗析溶剂,干燥剩余物,得到油状物(1.3g,60%)。
将上述炔丙基甘露糖(1.283g,5.9mmol)的无水吡啶(10ml)溶液在氮气下冷却至0℃。向其中分批加入2,4,6-三异丙基苯磺酰氯(2.68g,8.85mmol)。将溶液加热至室温并搅拌2天。将反应冷却至0℃并滴加苯甲酰氯(2.26ml,13.4mmol)。加入少量4-(二甲基氨基)吡啶晶体,将反应混合物搅拌3天。除去吡啶。将剩余物用乙酸乙酯(30ml)稀释,并用1M HCl溶液(3×30ml)、NaHCO3溶液(3×30ml)和NaCl溶液(3×30ml)洗涤。经无水硫酸镁干燥有机层,减压浓缩,得到深色油状物,其在高真空下变成红糖状固体。使用石油精和乙酸乙酯(4:1)对固体进行快速色谱,得到标题化合物5(465mg,10%)。
1H NMR(CDCl3,400MHz):8.09(dd,2H,J=1.5,8.3Hz,H-Bz),7.92(dd,2H,J=1.5,8.3Hz,H-Bz),7.79(dd,2H,J=1.5,8.3Hz,H-Bz),7.63-7.33(m,6H,H-Bz),7.25(bt,3H,J=7.9Hz,H-Bz),7.14(s,2H,H-TIPBS Ar),5.88(dd,1H,J=3.0,10.2,Hz,H-3),5.75(t,1H,J=10.5Hz,H-4),5.68(dd,1H,J=1.5,3.0Hz,H-2),5.27(d,1H,J=1.5Hz,H-1),4.44(m,1H,H-5),4.34(dd,2H,J=2.3,3.8Hz,H-炔丙基CH2),4.27(m,2H,H-6),4.08(m,2H,J=6.8Hz,H-TIPBS CH),2.87(m,1H,J=7.2Hz,H-TIPBS CH),2.49(t,1H,J=2.3Hz,H-炔丙基CH),1.23(d,6H,J=7.3Hz,H-TIPBS CH3),1.20(d,6H,J=7.3Hz,H-TIPBS CH3),1.17(d,6H,J=6.8Hz,H-TIPBS CH3).
13C NMR(CDCl3,100MHz):165.56(1C,C=O),165.37(1C,C=O),165.30(1c,C=O),153.79(1C,Ar),150.39(1C,Ar),133.57(2CH,Bz),133.20(1CH,Bz),130.59(1C,Ar),129.94(2CH,Bz),129.84(2CH,Bz),129.72(2CH,Bz),129.28(1C,Ar),129.71(1C,Ar),128.98(1C,Ar),128.89(1C,Ar),128.64(2CH,Bz),128.44(2CH,Bz),128.28(2CH,Bz),123.79(2CH,TIPBS-Ar),95.96(1CH,C-1),77.93(1C,炔丙基-C),75.83(1CH,炔丙基-CH)70.21(1CH,C-2),69.72(1CH,C-3),69.61(1CH,C-5),67.85(1CH,C-6),67.04(1CH,C-4),55.13(1CH2,炔丙基-CH2),34.20(1CH,TIPBS-CH),29.69(2CH,TIPBS-CH),24.96(2CH3,TIPBS-CH3),24.65(2CH3,TIPBS-CH3),23.50(2CH3,TIPBS-CH3)。
实施例6
苯甲酰化炔丙基甘露糖(5)的替代合成
1,2,3,4,6-五-O-乙酰基-D-吡喃甘露糖(6)
将乙酸酐(20.7mL,160mmol)加入到D-甘露糖(3.0g,10.6mmol)和乙酸钠(1.6g,20mmol)的混合物中。然后将反应混合物在80℃下搅拌4小时并倒入冷的饱和NaHCO3溶液(100mL)中。然后将混合物搅拌1小时,用DCM(2×100mL)提取,干燥(MgSO4)并减压浓缩。得到五乙酸酯6(3.5g,85%,α/β1:0.4),其为无色油状物。粗产物无需进一步纯化即可用于后续步骤。1H NMR(CDCl3,400MHz):6.06(d,1H,J=1.1Hz),5.84(d,0.4H,J=1.3Hz),5.46(dd,0.4H,J=1.1Hz,J=3.3Hz),5.34-5.32(m,2H),5.28(d,0.4H,J=9.9Hz),5.25-5.22(m,1H),5.11(dd,0.4H,J=3.3Hz,J=10.0Hz),4.28(dd,0.4H,J=5.4Hz,J=12.5Hz),4.26(dd,1H,J=4.9Hz,J=12.3Hz),4.15-3.98(m,2.4H),3.78(ddd,0.4H,J=2.4Hz,J=5.3Hz,J=7.8Hz),2.19(s,1.2H,OCH3),2.16(s,3H,OCH3),2.15(s,3H,OCH3),2.08(s,1.3H,OCH3),2.07(s,4H,OCH3),2.03(s,4H,OCH3),1.99(s,4H,OCH3)。
丙炔基2,3,4,6-四-O-乙酰基-β-D-吡喃甘露糖苷(7)
将丙炔醇(1.1mL,19.2mmol)加入到搅拌的1,2,3,4,6-五-O-乙酰基-D-吡喃甘露糖6(1.5g,3.8mmol)的无水DCM(20mL)溶液中。将混合物冷却至0℃并滴加BF3.OEt2(4.9mL,38.4mmol)。将所得混合物搅拌15分钟,使其回到室温,继续搅拌24小时。将反应混合物用DCM(100mL)稀释并倒入冰冷的饱和NaHCO3(100mL)溶液中。搅拌所得混合物直至冒泡,然后分离有机相并用饱和NaHCO3溶液(3×50mL)、水(100mL)洗涤,干燥(MgSO4)并减压浓缩。然后通过用石油精/EtOAc(8:1)重结晶纯化粗物质,得到7(1.2g,85%),其为无色针状晶体。1HNMR(CDCl3,400MHz):5.33(dd,1H,J2,3=3.2Hz,J3,4=9.8Hz,H-3),5.29(d,1H,J3,4=J4,5=9.3Hz,H-4),5.26(dd,1H,J1,2=1.8Hz,J2,3=3.2Hz,H-2),5.01(d,1H,J1,2=1.8Hz,H-1),4.30-4.24(m,3H,H-6a,CH2C≡CH),4.09(B-ABq,J5,6b=2.5Hz,J6a,6b=12.3Hz,H-6b),4.00(ddd,1H,J4,5=9.2Hz,J5,6b=2.5Hz,J5,6a=5.3Hz,H-5),2.45(t,1H,J=2.4Hz,CH2C≡CH),2.14(s,3H,CH3),2.09(s,3H,CH3),2.02(s,3H,CH3),1.97(s,3H,CH3);13C NMR(CDCl3,100MHz):170.6,169.9,169.8,169.7(4×CH3CO),96.3(C-1),77.9(OCH2C≡CH),75.6(OCH2C≡CH),69.3(C-2),69.0(C-3),68.8(C-5),66.1(C-4),62.3(C-6),55.0(OCH2C≡CH),20.9,20.7(2×),20.6(4×CH3CO);HRMS(ESI);m/z[M+Na]+针对C17H22O18Na计算;得到409.1121。
丙炔基2,3,4-三-O-苯甲酰基-6-2,4,6-三异丙基苯磺酰基-β-D-吡喃甘露糖苷(5)
向甘露吡喃糖苷7(5.0g,13mmol)的MeOH(50mL)溶液中加入催化量的金属钠(约4mg),并在室温下搅拌混合物2小时,然后用预洗涤的酸性离子交换树脂(IR-120H+)中和反应混合物,过滤并减压浓缩。将粗物质溶于无水吡啶(50mL)中并冷却至0℃。将2,4,6-三异丙基苯磺酰氯(4.7g,16mmol)加入到反应混合物中并使其加热至室温,搅拌18小时。然后将反应混合物冷却至0℃,加入苯甲酰氯(5.0mL,47mmol),在室温下搅拌24小时。通过与甲苯共蒸发吡啶,在减压下浓缩反应混合物。将获得的粗剩余物溶于EtOAc(100mL)中并用1MHCl(2×50mL)、饱和NaHCO3(50mL)洗涤,干燥(MgSO4)并减压浓缩。通过快速柱色谱法(Pet.Sp./EtOAc 3:1)在硅胶上纯化粗物质,得到甘露吡喃糖苷5(7.3g,70%),其为无色油状物。1H NMR(CDCl3,400MHz):8.06(dd,2H,J=1.1Hz,J=8.1Hz,H-OBz),7.90(dd,2H,J=0.9Hz,J=8.1Hz,H-OBz),7.78(dd,2H,J=1.2Hz,J=8.3Hz,H-OBz),7.62-7.18(m,8H,H-OBz),7.13(s,2H,H-OTPS),5.87(dd,1H,J2,3=3.3Hz,J3,4=10.0Hz,H-3),5.75(dd,1H,J3,4=J4,5=10.0Hz,H-4),5.67(dd,1H,J1,2=1.8Hz,J2,3=3.3Hz,H-2),5.26(d,1H,J1,2=1.8Hz,H-1),4.47-4.40(m,1H,H-5),4.32(t,2H,J=2.9Hz,CH2C≡CH),4.29-4.25(m,2H,H-6),4.08(h,2H,J=6.9Hz,J=13.3Hz,J=20.1Hz,CH-i-pr),2.86(p,1H,J=6.9Hz,J=13.3Hz,J=20.1Hz,CH-i-pr),2.48(t,1H,J=2.4Hz,CH2C≡CH),1.22(s,3H,CH3),1.19(s,3H,CH3),1.18(s,3H,CH3),1.17(s,3H,CH3),1.15(s,3H,CH3);13C NMR(CDCl3,100MHz):165.5,165.3,165.2(3×C=O),153.8,150.9,133.5,129.9,129.8,129.7,128.6,128.4,128.2,123.7(Ar-OTPS),95.9(C-1),77.9,77.2(OCH2C≡CH),75.8(OCH2C≡CH),70.2(C-2),69.7(C-3),69.6(C-5),67.8(C-6),67.0(C-4),55.1(OCH2C≡CH),34.1(CH-i-pr),29.6(CH-i-pr),24.6,24.5,23.4(6×CH3);HRMS(ESI);m/z[M+Na]+针对C44H48O11NaS计算;得到819.2844。
实施例7
乙酰化炔丙基甘露糖(8)的合成
丙炔基2,3,4-三-O-乙酰基-6-2,4,6-三异丙基苯磺酰基-β-D-吡喃甘露糖苷(8)
向甘露吡喃糖苷7(12.9g,33mmol)的MeOH(200mL)溶液中加入催化量的金属钠(约10mg),并在室温搅拌混合物2小时,然后用预洗涤的酸性离子交换树脂(IR-120H+)中和反应混合物,过滤并减压浓缩。将粗物质溶于无水吡啶(200mL)中并冷却至0℃。将2,4,6-三异丙基苯磺酰氯(15g,50mmol)加入到反应混合物中并使其加热至室温,搅拌48小时。然后将反应混合物冷却至0℃,加入乙酸酐(12.5mL),在室温下搅拌24小时。通过与甲苯共蒸发吡啶,在减压下浓缩反应混合物。将获得的粗剩余物溶于EtOAc(500mL)中并用1M HCl(3×500mL)、饱和NaHCO3,(500mL)洗涤,干燥(MgSO4)并减压浓缩。通过快速柱色谱法(Pet.Sp./EtOAc 3:1)在硅胶上纯化粗物质,得到甘露吡喃糖苷8(13.8g,70%),其为无色油状物。1HNMR(CDCl3,400MHz):7.19(s,2H,Ar-OTPS),5.32(dd,1H,J2,3=3.5Hz,J3,4=9.8Hz,H-3),5.24(dd,1H,J1,2=1.7Hz,J2,3=3.5Hz,H-2),5.13(t,1H,J3,4=J4,5=9.8Hz),4.97(d,1H,J1,2=1.7Hz,H-1),4.20(dd,J=2.5Hz,J=3.3Hz,CH2C≡CH),4.14-4.07(m,5H,H-5,H-6,CH-i-pr),2.91(h,1H,J=6.9Hz,J=13.6Hz,J=20.1Hz,CH-i-pr),2.43(t,1H,J=2.3Hz,CH2C≡CH),2.11(s,3H,OCH3),1.99(s,3H,OCH3),1.97(s,3H,OCH3),1.27(2×s,6H,CH3),1.25(2×s,6H,CH3);13C NMR(CDCl3,100MHz):169.9,169.8,169.7(3×C=O),153.9,150.9,129.2,123.8(Ar-OTPS),95.8(C-1),77.2(OCH2C≡CH),78.8(d,J=214Hz,OCH2C≡CH),69.3(C-5),69.2(C-2),68.7(C-3),67.6(C-6),66.4(C-4),54.8(OCH2C≡CH),34.2(CH-i-pr),29.7(CH-i-pr),24.7(×2),23.5(6×CH3),20.8,20.6(×2)(3×OCH3)。
实施例8
2,3,3’,4’,6-五-O-乙酰三氯蔗糖(9)
向搅拌的三氯蔗糖(6.1g,15mmol)的吡啶(80mL)溶液中加入乙酸酐(15mL,100mmol)。然后将混合物在室温下搅拌24小时,通过与甲苯共蒸发吡啶浓缩。将粗物质溶于EtOAc(100mL)中并用1M HCl(2×100mL)、5%NaHCO3(100mL)、盐水(50mL)洗涤,干燥(MgSO4)并减压浓缩,得到玻璃状固体。将粗物质从甲苯中重结晶,得到五乙酸酯9(8.5g,97%),其为针状晶体。1H NMR(CDCl3,400MHz):δ=5.67(d,1H,J3’,4’=6.4Hz,H-3’),5.65(d,J1,2=2.0Hz,H-1),5.29-5.27(m,2H,H-2,H-3),4.58-4.52(m,2H,H-4,H-5),4.27-4.19(m,3H,H-5’,H-6a,H-6b),3.75(dd,2H,J5’,6’=6.2Hz,J6’a,6’b=0.7Hz,H-6’a,H-6’b),3.69,3.57(ABq,2H,J=12.1Hz,H-1’),2.12(s,3H,CH3),2.11(s,3H,CH3),2.09(s,3H,CH3),2.08(s,3H,CH3),2.07(s,3H,CH3);13C NMR(CDCl3,100MHz):δ=170.4,170.2,170.0,169.8,169.6(5×COCH3),104.4(C-2’),90.7(C-1),80.8(C-5’),77.2,76.1(C-4’),75.9(C-3’),68.0(C-2),67.8(C-4),66.9(C-3),63.6(C-6),59.0(C-5),44.5(C-1’),43.9(C-6’),20.8,20.7(×2),20.5(5×COCH3)。
实施例9
2,3,3’,4’,6-五-O-乙酰基-6'-叠氮基三氯蔗糖(10)
向9(3.8g,6.4mmol)的无水DMF(20mL)溶液中加入NaN3(1.3g,20mmol),将混合物在100℃下搅拌24小时。然后滗析反应混合物,将留在烧瓶中的剩余物用EtOAc(3×5mL)洗涤。然后将组合的有机层减压浓缩。将粗物质溶于1:1的DCM/H2O(100mL)中。提取有机层,用DCM(2×10mL)反提取水层。将组合的有机层用饱和CuSO4溶液(100mL)、盐水(50mL)洗涤,干燥(MgSO4)并减压浓缩。通过快速柱色谱法(Pet.sp./EtOAc 1:1)纯化粗物质,得到叠氮化物10(3.1g,78%),其为无色油状物。1H NMR(CDCl3,400MHz):δ=5.68(d,1H,J3’-4’=6.9Hz,H-3’),5.64(d,1H,J1,2=3.6Hz,H-1),5.32(dd,1H,J2,3=10.7Hz,H-3),5.32-5.29(m,1H,H-4’),5.25(dd,1H,H-2),4.58-4.49(m,2H,H-4,H-5),4.24-4.20(m,2H,H-6a,H-6b),4.15-4.08(m,1H,H-5’),3.69,3.58(ABq,2H,J=12.1Hz,H-1’),3.64-3.56(m,1H,H-6’a),3.50(dd,1H,J6a’,6b’=4.1Hz,J5,6b’=13.3Hz,H-6b’),2.10(s,3H,CH3),2.09(s,3H,CH3),2.08(s,3H,CH3),2.06(s,3H,CH3),2.05(s,3H,CH3);13C NMR(CDCl3,100MHz):δ=170.3,170.1,170.0,169.9,169.7(5×COCH3),104.1(C-2’),90.8(C-1),80.0(C-5’),75.6(C-3’),75.1(C-4’),67.9(C-3),67.7(C-5),67.0(C-2),63.4(C-6),58.9(C-4),52.5(C-6’),44.5(C-1’),20.7,20.6,20.6,20.6,20.4(5×COCH3);HRMS(ESI);m/z[M+Na]+针对C22H29Cl2N3O13Na计算;得到636.0994。
实施例10
6-2,4,6-三异丙基苯磺酰基-6'-叠氮基三氯蔗糖(11)
将含有30%NH3水溶液(3mL)和三氯蔗糖叠氮化物10(1.7g,2.8mmol)的混合物的MeOH(20mL)溶液在室温下搅拌24小时。减压浓缩反应混合物,得到玻璃状固体的多元醇。然后将粗物质溶于吡啶(10mL)中,并将2,4,6-三异丙基苯磺酰氯(0.8g,2.7mmol)加入混合物中,在室温下搅拌3天。通过与甲苯共蒸发吡啶,在减压下浓缩反应混合物。通过快速柱色谱(EtOAc)在硅胶上纯化粗物质,得到化合物11(0.25g,25%),其为无色油状物。
实施例11
2,3,3’,4’-四-O-乙酰基-6-2,4,6-三异丙基苯磺酰基-6'-叠氮基三氯蔗糖(12)
将乙酸酐(0.3mL,3.1mmol)加入到化合物11(250mg,0.6mmol)和吡啶(10mL)的混合物中。然后将混合物在室温下搅拌24小时,并在减压下浓缩。将粗物质溶于EtOAc(50mL)中并用1M HCl(3×50mL)、饱和NaHCO3(50mL)洗涤,干燥(MgSO4)并减压浓缩,得到化合物12(310mg,98%),其为黄色油状物。1H NMR(CDCl3,400MHz):δ=7.19(s,2H,Ar-H),5.74-5.68(m,2H,H-1,H-3’),5.40-5.34(m,2H,H-3,H-4’),5.25(dd,1H,J=3.8Hz,J=10.7Hz,H-2),4.69(dd,1H,J=1.1Hz,J=6.2Hz,H-4),4.57(dd,1H,J=1.4Hz,J=3.6Hz,H-5’),4.29-4.01(m,5H,H-6,H-5,CH-i-Pr),3.72,3.58(ABq,2H,J=12.1Hz,H-1’),3.63-3.58(m,2H,H-6’),2.91(p,1H,J=6.9Hz,J=13.7Hz,CH-i-pr),2.16(s,3H,OCH3),2.11(s,3H,OCH3),2.10(s,3H,OCH3),2.08(s,3H,OCH3),1.27,1.25(s,18H,6×CH3);13C NMR(CDCl3,100MHz):δ=170.1,170.0,169.8,169.7,154.1,151.0,128.8,123.9,104.5,90.7,80.3,75.7,75.0,67.9,67.7,66.9,66.8,58.7,52.3,44.5,34.2,24.7,23.5,20.7,20.6,20.5。
实施例12
乙酰化的炔丙基麦芽三糖(13)
在0℃,将三氟化硼二乙基醚合物(46mL)滴加到在无水DCM(500mL)中的过乙酸麦芽三糖(13.3g,13.8mmol)和炔丙醇(8.5mL,137mmol)的混合物中,然后将混合物在室温下搅拌48小时。将饱和NaHCO3(10mL)加入到反应混合物中,再搅拌10分钟。提取有机层,干燥(MgSO4)并减压浓缩。获得的粗物质通过快速柱色谱法(3:1EtOAc/Pet.Sp.)纯化,得到乙酰化的炔丙基麦芽三糖13(6.0g,45%),其为玻璃状固体。1H NMR(CDCl3,400MHz):δ=5.43-5.22(m,6H),5.04(t,1H,J=10.0Hz),4.86-4.76(m,3H),4.71(dd,1H,J=4.1Hz,J=10.4Hz),4.51-4.39(m,2H),4.33(d,2H,J=2.3Hz),4.32-4.13(m,4H),4.06-3.87(m,6H),3.77-3.69(m,1H),2.44(t,1H,J=2.4Hz),2.15,2.13,2.07,2.02,2.02,2.00,1.98,1.97(×2)(s,3H,9×CH3);13C NMR(CDCl3,100MHz):δ=170.6(×2),170.5(×2),170.3,170.1,169.8,169.7(×2),169.4,97.5,95.7(×2),77.2,75.5,75.2,73.7,72.5,72.2,71.8,71.7,70.4,70.1,69.4,68.9,68.5,67.9,62.8,62.3,61.4,60.4,55.8,20.9,20.8,20.6,20.5,14.2;HRMS(ESI);m/z[M+Na]+针对C41H54O26Na计算;得到385.2792。
实施例13
乙酰化炔丙基阿卡波糖(14)
在0℃,将三氟化硼二乙基醚合物(0.6mL,5mmol)滴加到过乙酸阿卡波糖(0.6g,0.5mmol)和炔丙醇(35μL,0.6mmol)在无水DCM(20mL)的混合物中,然后将混合物在室温下搅拌续5小时。将饱和NaHCO3(10mL)加入到反应混合物中,再搅拌10分钟。提取有机层,干燥(MgSO4)并减压浓缩。获得的粗物质通过快速柱色谱法(3:1EtOAc/Pet.Sp.)纯化,得到炔丙基阿卡波糖14(0.1g,17%),其为玻璃状固体。1H NMR(CDCl3,400MHz):δ=5.95(d,1H,J=5.3Hz),5.60-5.51(m,2H),5.40-5.31(m,1H),5.31-5.18(m,3H),5.10(t,1H,J=10.2Hz),4.92(dd,1H,J=4.3Hz,J=10.0Hz),4.85-4.69(m,4H),4.67-4.60(m,1H),4.49(dd,1H,J=2.9Hz,J=12.3Hz),4.47-4.34(d,2H),4.33(d,2H,J=2.3Hz),4.29(dd,1H,J=4.0Hz,J=12.4Hz),4.20-4.14(m,1H),3.99(t,1H,J=9.3Hz),3.94-3.88(m,2H),3.77-3.67(m,2H),3.57-3.46(m,1H),2.46(t,1H,J=2.4Hz),2.39(t,1H,J=9.9Hz),2.16,2.13,2.09,2.04,2.02,2.01,2.00,1.97,1.96(s,OCH3)ppm;13C NMR(CDCl3,100MHz):δ=171.0,170.7,170.6,170.5,170.3(×2),170.2,169.9,169.7,169.6,133.9,128.0,97.5,95.8,95.6,78.0,77.2,75.5,75.3,73.3,72.2(×2),71.8(×2),71.0,70.9,70.7,70.5,70.1,69.8,69.1,63.0,62.7,62.2,61.1,55.8,52.1,20.8,20.7,20.6,20.5(×2),18.1ppm。
实施例14
乙酰化4-戊炔基阿卡波糖(15)
在0℃,将三氟化硼二乙基醚合物(5mL,42mmol)滴加到过乙酸酯阿卡波糖(1.0g,0.85mmol)和4-戊炔-1-醇(240μL,2.55mmol)在无水DCM(20mL)的混合物中。然后将混合物在室温下搅拌24小时。再将饱和NaHCO3(10mL)加入到反应混合物中,搅拌10分钟。提取有机层,干燥(MgSO4)并减压浓缩。获得的粗物质通过快速柱色谱法(3:1EtOAc/Pet.Sp.)纯化,得到乙酰化的4-戊炔基阿卡波糖15(146mg,14%),其为玻璃状固体。1H NMR(CDCl3,400MHz):δ=5.96(d,1H,J=5.2Hz),5.62-5.45(m,2H),5.36(dd,1H,J=7.9Hz,J=10.2Hz),5.31-5.19(m,2H),5.17-5.06(m,1H),4.93(dd,1H,J=4.0Hz,J=9.8Hz),4.86-4.69(m,3H),4.65,4.37(ABq,2H,J=13.1Hz),4.55-4.41(m,2H),4.32(m,1H),4.18(dd,1H,J=2.7Hz,J=12.2Hz),4.01-3.88(m,3H),3.78-3.67(m,2H),3.65-3.49(m,2H),2.40(t,1H,J=9.9Hz),2.23(dt,1H,J=2.6Hz,J=6.9Hz),2.16(s,3H),2.14(s,3H),2.10(s,3H),2,04(s,3H),2.02-2.00(s,15H),1.97(s,6H),1.21(d,3H,J=6.3Hz)ppm;13C NMR(CDCl3,100MHz):δ=170.9,170.7,170.6,170.5,170.4,170.3,170.2,170.1,169.9,169.7(×2),134.0,127.8,100.4,95.8,95.6,83.3,77.2,75.3,73.5,72.4,72.2,72.0,71.9,71.1,70.8,70.6,70.5,69.9,69.7,69.1,68.8,68.2,63.0,62.9,62.2,61.1,52.2,28.2,20.9,20.8,20.7,20.6(×2),20.5,18.1ppm。
实施例15
受保护的甘露糖二聚体(16)
将五水合硫酸铜(II)(72mg,0.288mmol)和抗坏血酸钠(171mg,0.846mmol)依次加入到甘露糖前体8(153mg,0.192mmol)和叠氮化物连接基团(19mg,0.096)的DMSO溶液中。将反应混合物在氮气下加热至60℃,持续3天。使反应冷却,置于氮气流下除去DMSO。将剩余物在乙酸乙酯(20ml)中稀释,并用NaCl溶液(3×20ml)洗涤。结合水层用乙酸乙酯(20ml)提取。将结合有机提取物用无水硫酸镁干燥并浓缩,得到二聚体16(170mg,98%)。
1H NMR(CDCl3,400MHz):δ=8.05(dd,4H,J=1.2,7.8Hz,H-Bz),7.91(dd,4H,J=1.2,7.8Hz,H-Bz),7.86(s,2H,H-三唑),7.77(dd,4H,J=1.2,7.8Hz,H-Bz),7.62-7.32(m,12H,H-Bz),7.23(bt,6H,J=7.6Hz,H-Bz),7.13(s,4H,H-TIPBS Ar),5.87(dd,2H,J=3.3,9.8Hz,H-3),5.79(t,2H,J=9.8Hz,H-4),5.65(dd,2H,J=1.1,2.7Hz,H-2),5.21(d,2H,J=1.1Hz,H-1),4.95(d,2H,J=12.5Hz,H-炔丙基CH2-a),4.79(d,2H,J=12.5Hz,H-炔丙基CH2-b),4.58(t,4H,J=4.9Hz,H-PEG连接基团CH2),4.53(m,2H,H-5),4.27(m,4H,H-6),4.09(m,4H,J=7.1Hz,H-TIPBS CH),3.90(t,4H,J=4.9Hz,H-PEG连接基团CH2),3.61(s,4H,H-PEG连接基团CH2),2.87(m,2H,J=7.1Hz,H-TIPBS CH),1.22(d,12H,J=7.1Hz,H-TIPBSCH3),1.19(d,12H,J=7.1Hz,H-TIPBS CH3),1.15(d,12H,J=7.1Hz,H-TIPBS CH3)。
实施例16
受保护的甘露糖二聚体双叠氮化物(17)
将二聚体16(172mg,0.0947mmol)和叠氮化钠(49mg,0.757mmol)的DMF(3ml)溶液搅拌并加热至50℃过夜。使反应冷却并用氮气流除去DMF。将剩余物在DCM(20ml)中稀释,并用1M HCl溶液(3×20ml)、NaHCO3溶液(3×20ml)、NaCl溶液(3×20ml)、CuSO4溶液(3×20ml)和水(20毫升)洗涤。用DCM(10ml)提取水层。有机提取液用无水硫酸镁干燥,减压浓缩,得到双叠氮化物二聚体17(96mg,76%)。
1H NMR(CDCl3,400MHz):δ=8.07(dd,4H,J=1.6,8.2Hz,H-Bz),7.94(dd,4H,J=1.6,8.2Hz,H-Bz),7.83(s,2H,H-三唑),7.78(dd,4H,J=1.6,8.2Hz,H-Bz),7.63-7.33(m,12H,H-Bz),7.24(bt,6H,J=7.6Hz,H-Bz),5.89(t,2H,J=9.8Hz,H-4),5.83(dd,2H,J=3.0,9.8Hz,H-3),5.67(dd,2H,J=1.6,3.3Hz,H-2),5.23(d,2H,J=161Hz,H-1),4.99(d,2H,J=12.5Hz,H-炔丙基CH2-a),4.81(d,2H,J=12.5Hz,H炔丙基CH2-b),4.58(t,4H,J=4.9Hz,H-PEG连接体CH2),4.36(m,2H,H-5),3.89(t,4H,J=4.9Hz,H-PEG连接基团CH2),3.61(s,4H,H-PEG连接基团CH2),2.87(m,2H,J=7.1Hz,H-TIPBS CH),3.50(bd,4H,J=4.3Hz,H-6)。
实施例17
受保护的六聚体(18)
将五水合硫酸铜(II)(23mg,0.0936mmol)和抗坏血酸钠(56mg,0.281mmol)依次加入到三氯蔗糖炔丙基醚26(44mg,0.0624mmol)和双叠氮化物二聚体17(41mg,0.0312mmol)的DMSO(3ml)溶液中。将反应混合物在氮气下加热至60℃,持续3天。使反应冷却,并用氮气流除去DMSO。将剩余物在DCM(10ml)中稀释,并用NaCl溶液(2×20ml)洗涤。将结合水层用DCM(15ml)反提取,结合有机提取物用无水硫酸镁干燥并浓缩,得到粗六聚体(83mg,97%)。将该油状物用甲醇沉淀,得到纯六聚体18(41mg,48%)。
1H NMR(CDCl3,400MHz):δ=8.01-7.96(m,8H,H-Bz),7.92(s,2H,H-三唑),7.77(s,2H,H-三唑),7.75(d,4H,J=1.2Hz,H-Bz),7.71(s,2H,H-三唑),7.64-7.34(m,12H,H-Bz),7.23(bt,6H,J=7.9Hz,H-Bz),5.85(dd,2H,J=3.4,10.1Hz,H-3),5.73-5.67(m,6H),5.62(dd,2H,J=1.7,3.4Hz,H-2),5.39(t,2H,J=7.3Hz),5.32(bs,4H),5.18(d,2H,J=1.7Hz,H-1),4.85-4.51(m,28H),4.41(m,2H),4.32-4.18(m,6H),3.87(t,4H,J=4.8Hz,H-PEG连接基团CH2),3.62(d,4H,J=12.1Hz),3.60(s,4H,H-PEG连接基团CH2),3.53(d,4H,J=12.1Hz),2.13(s,6H,H-AcO CH3),2.10(s,6H,H-AcO CH3),2.08(s,6H,H-AcO CH3),2.06(s,6H,H-AcO CH3),2.05(s,6H,H-AcO CH3)。
13C NMR(CDCl3,100MHz):δ=170.40,170.17,170.15,169.99,169.67,165.72,165.33,165.26,133.74,133.69,133.27,129.93,129.83,129.68,129.06,128.87,128.68,128.59,128.55,128.32,104.16,96.73,90.68,79.51,76.73,75.45,75.35,70.50,70.22,69.70,69.49,69.29,68.26,68.01,67.85,66.90,63.98,63.39,59.04,44.68,29.69,20.76,20.68,20.65,20.50。
实施例18
六聚体(19)的全水解
将六聚体18(41mg,0.015mmol)悬浮在甲醇(3ml)中,逐滴加入30%氨溶液(0.5ml)中。反应搅拌过夜。除去溶剂,将剩余物在水(10ml)中稀释。用氯仿(4×10ml)洗涤水层并减压浓缩。通过与乙醇共蒸发干燥样品,得到脱保护的六聚体19(25mg,99%)。
1H NMR(D2O,400MHz):δ=8.15(s,2H,H-三唑),7.97(s,2H,H-三唑),7.76(s,2H,H-三唑),5.44(d,2H,J=4.2Hz,H-1),4.87(bs,6H),4.70(bs,4H),4.59(bs,6H),4.54(d,2H,J=3.3Hz),4.48(t,4H,J=4.7Hz),4.45-4.38(m,4H),4.34-4.14(m,10H),3.98-3.87(m,6H),3.83-3.74(m,10H),3.71(s,4H),3.63(t,2H,J=9.9Hz),3.51(s,4H).
13C NMR(D2O,100MHz):δ=143.79(2C,三唑),142.93(2C,三唑),126.25(2CH,三唑),125.62(2CH,三唑),125.08(2CH,三唑),103.45(2C,C-2果糖),99.17(2CH,C-1甘露糖),92.45(2CH,C-1葡萄糖),79.57(2CH,C-5果糖),75.52(2CH,C-3果糖),74.85(2CH,C-4果糖),71.76,71.57,70.92,70.43,70.27,69.81,69.58,68.63,68.02,67.95,67.50,63.20,62.39,62.25,61.91,60.12,59.25,52.45,51.13,49.99,43.63(2CH2,C-1果糖).
实施例19
六聚体(20)的硫酸化
将六聚体19(24mg,0.014mmol)溶解在DMF(3ml)中,并用新制备的吡啶三氧化硫复合物(363mg,2.28mmol,10当量/六聚体上的OH基团)进行处理。将溶液在氮气下于75℃搅拌4天,用氮气流除去溶剂。将剩余物溶于水(10ml)中,并用NaOH(109mg,2.74mmol,1.2当量/PySO3)处理。将溶液在空气下搅拌20分钟,用乙酸乙酯(5×10ml)洗涤以除去过量的吡啶。除去溶剂,留下淡黄色粉末,其在高真空下干燥。用DMF(6×1ml)处理粉末。吸收可溶性组分,留下不需要的不溶性的简单盐。除去DMF,剩余物在高真空下干燥。用ACN(6×2ml)处理剩余物。除去可溶性组分。它仅包含DMF并被弃去。将不溶性组分在高真空下干燥,得到不含DMF的硫酸化六聚体20(4.7mg,10%)。
1H NMR(D2O,400MHz):δ=8.25(s,2H,H-三唑),8.10(s,2H,H-三唑),7.93(s,2H,H-三唑),5.82(d,2H,J=3.5Hz),5.38(d,2H,J=7.6Hz),5.24(d,2H,J=1.4Hz),5.16-5.06(m,5H),5.03-4.93(m,10H),4.89(m,6H),4.71(s,5H),4.60(t,4H,J=12.9Hz),4.55(d,2H,J=10.0Hz),4.43(s,4H),4.37-4.23(m,6H),3.99(d,2H,J=12.9Hz),3.92(m,6H),3.59(s,4H).
13C NMR(D2O,100MHz):δ=143.69(2C,三唑),142.85(2C,三唑),126.38(2CH,三唑),126.20(2CH,三唑),125.23(2CH,三唑),103.54(2C,C-2果糖),96.25(2CH,C-1甘露糖),90.91(2CH,C-1葡萄糖),79.53,79.46,78.33,75.15,73.52,72.72,72.37,71.33,70.39,69.67,68.78,68.46,67.92,62.27,60.27,59.96,52.76,50.97,50.07,43.90(2CH2,C-1果糖)。
实施例20
受保护的甘露糖四聚体(21)
将五水合硫酸铜(II)(31mg,0.124mmol)和抗坏血酸钠(74mg,0.373mmol)依次加入到甘露糖5(100mg,0.125mmol)和叠氮化物二聚体17(82mg,6.25x10-2 mmol)的DMSO(2ml)溶液中。将反应混合物在氮气下加热至60℃,持续3天。使反应冷却,并用氮气流除去DMSO。将剩余物在乙酸乙酯(10ml)中稀释,并用NaCl溶液(3×10ml)洗涤。结合水层用乙酸乙酯(10ml)提取。结合有机提取物用无水硫酸镁干燥并浓缩,得到粗的四聚体21(177mg,100%)。
1H NMR(CDCl3,400MHz):8.08(s,2H,H-三唑),8.04-7.96(m,12H),7.90-7.86(m,4H),7.80-7.72(m,10H),7.64-7.30(m,28H),7.25-7.19(m,4H),7.11(s,4H,H-TIPBS Ar),5.88(dd,2H,J=3.0,10.3Hz),5.79-5.72(m,6H),5.66(dd,2H,J=1.6,3.4Hz),5.56(t,2H,J=2.5Hz),5.23(d,2H,J=1.6Hz),5.18(d,2H,J=1.6Hz),4.93-4.57(m,14H),4.51(m,6H),4.29-4.17(m,4H),4.07(m,4H,J=6.7Hz,H-TIPBS CH),3.84(t,4H,J=5.0Hz,H-PEG连接基团CH2),3.57(s,4H,H-PEG连接基团CH2),2.85(m,2H,J=6.9Hz,H-TIPBS CH),1.20(d,12H,J=6.9Hz,H-TIPBS CH3),1.16(d,12H,J=6.9Hz,H-TIPBS CH3),1.13(d,12H,J=6.7Hz,H-TIPBS CH3)。
实施例21
受保护的甘露糖四聚体双叠氮化物(22)
将四聚体21(177mg,6.09×10-2mmol)和叠氮化钠(32mg,0.492mmol)的DMF(3ml)溶液搅拌并加热至50℃过夜。使反应冷却,并用氮气流除去DMF。将剩余物在乙酸乙酯(15ml)中稀释,并用5%的NaHCO3溶液(3×10ml)、CuSO4溶液(3×10ml)和NaCl溶液(3×10ml)洗涤。用乙酸乙酯(15ml)提取水层。有机提取物用无水硫酸镁干燥,减压浓缩,得到粗剩余物。将其通过柱色谱法纯化,使用乙酸乙酯/石油精(2:1)作为洗脱剂,得到四聚体22(69mg,46%)。
1H NMR(CDCl3,400MHz):δ=8.14-8.04(m,6H,),8.03-7.96(m,8H),7.92(d,4H,J=8.0Hz),7.74(m,8H),7.65-7.57(m,4H),7.56-7.31(m,26H),7.25-7.20(m,8H),5.97-5.73(m,8H),5.67(bs,2H),5.61(bs,2H),5.22(bs,4H),5.03-4.44(m,18H),4.33(m,12H),3.84(bs,4H),3.57(bs,4H),3.50(m,4H)。
实施例22
受保护的八聚体(23)
将五水合硫酸铜(II)(14mg,5.61×10-2mmol,1当量/N3基团)和抗坏血酸钠(34mg,0.172mmol,3当量/N3基团)依次加入到三氯蔗糖炔丙基醚26(41mg,5.78×10-2mmol)和双叠氮化物四聚体22(69mg,2.85×10-2mmol)的DMSO(3ml)溶液中。将反应混合物在氮气下加热至60℃,持续3天。使反应冷却,并用氮气流除去DMSO。将剩余物在乙酸乙酯(15ml)中稀释,并用NaCl溶液(3×10ml)和水(10ml)洗涤。将结合水层用乙酸乙酯(15ml)反提取。将结合有机提取物用无水硫酸镁干燥并浓缩,得到粗六聚体23(110mg,100%)。
1H NMR(CDCl3,400MHz):δ=8.25(bs,2H,H-三唑),8.16(bs,2H,H-三唑),8.03-7.90(m,20H),7.80-7.72(m,8H),7.64-6.56(m,4H),7.54-7.43(m,12H),7.43-7.32(m,12H),7.25-7.19(m,8H),5.88(dd,2H,J=2.6,8.6Hz),5.82-5.69(m,8H),5.67(bs,4H),5.53(bs,2H),5.42-5.32(m,6H),5.24(bs,2H),5.18(bs,2H),4.89-4.51(m,40H),4.44(bs,2H),4.32-4.19(m,4H),3.88(bs,4H),3.67-3.54(m,8H),2.14(s,6H,H-AcO CH3),2.10(s,6H,H-AcO CH3),2.07(s,6H,H-AcO CH3),2.06(s,6H,H-AcO CH3),2.05(s,6H,H-AcO CH3).
实施例23
八聚体(24)的全水解
将八聚体23(110mg,2.86×10-2mmol)溶解在氯仿(1ml)中。用甲醇(7ml)和30%氨溶液(1ml)处理所述溶液,将反应搅拌过夜。除去溶剂,将残余物用水(10ml)稀释,通过棉绒塞过滤,并用氯仿(3×10ml)洗涤。将溶液减压浓缩,样品在高真空下干燥,得到脱保护的八聚体24(51mg,82%)。
1H NMR(D2O,400MHz):δ=8.17(s,2H,H-三唑),7.97(s,2H,H-三唑),7.79(s,2H,H-三唑),7.81(s,2H,H-三唑),5.44(d,2H,J=3.3Hz),4.94-4.82(m,8H),4.70(bs,4H),4.63-4.59(m,16H),4.45-4.40(m,6H),4.36-4.15(m,16H),3.99-3.53(m,32H).
13C NMR(D2O,100MHz):126.38(2CH,三唑),126.06(2CH,三唑),125.65(2CH,三唑),125.12(2CH,三唑),103.45(2C,C-2果糖),99.31,99.01,92.45(2CH,C-1葡萄糖),79.52,75.53,74.84,71.62,71.42,70.93,70.41,69.80,69.57,68.65,68.03,67.93,67.49,63.14,62.35,62.26,61.89,52.40,51.13,51.04,50.03,43.63(2CH2,C-1果糖).
实施例24
八聚体(25)的硫酸化
将八聚体24(51mg,2.35×10-2mmol)溶解在DMF(3ml)中,并用新制备的吡啶三氧化硫复合物(823mg,5.17mmol,10当量/八聚体上OH基团)处理。将溶液在氮气下于75℃搅拌4天,用氮气流除去溶剂。将剩余物溶于水(10ml)中,并用NaOH(496mg,1.24×10-2mmol,2.4当量/PySO3)处理。将溶液在空气下搅拌30分钟,用乙酸乙酯(10×10ml)洗涤以除去过量的吡啶。除去溶剂,留下淡黄色粉末,其在高真空下干燥。将干燥的粉末用DMF(15×2ml)处理,吸收可溶性组分,留下不需要的不溶性简单盐。将溶液通过棉绒塞过滤,除去DMF,剩余物在高真空下干燥。用ACN(20×2ml)处理剩余物,除去可溶性组分。它仅包含DMF并被弃去。将不溶性组分在高真空下干燥,得到硫酸化的八聚体25,其为米白色粉末(52mg,50%)。
1H NMR(D2O,400MHz):δ=8.25(s,2H,H-三唑),8.13(s,2H,H-三唑),8.08(s,2H,H-三唑),7.93(s,2H,H-三唑),5.82(d,2H,J=3.7Hz),5.40(d,2H,J=7.4Hz),5.25(m,4H),5.17-5.07(m,6H),5.05-5.95(m,10H),4.93-4.86(m,9H),4.74(bs,6H),4.70(m,3H),4.68-4.60(m,7H),4.60-4.50(m,5H),4.48-4.31(m,10H),4.30-4.19(m,6H),4.03-3.88(m,8H),3.62(bs,4H).
13C NMR(D2O,100MHz):δ=126.45(2CH,三唑),126.26(2CH,三唑),126.06(2CH,三唑),125.27(2CH,三唑),103.64(2C,C-2果糖),96.26,90.88,79.49,79.43,78.29,75.14,75.08,74.90,73.49,72.74,72.65,72.37,71.32,70.31,69.62,68.78,68.43,67.87,62.41,60.23,60.06,59.89,52.87,50.96,50.94,50.20,44.09(2CH2,C-1果糖).
点击反应的一般流程
将抗坏血酸钠(2当量)和五水合硫酸铜(1当量)加入到叠氮化物类似物(1当量)和炔烃类似物(1当量/N3)在1,4-二恶烷/H2O(3:1)的混合物中。然后将反应混合物在室温下搅拌18小时,用硅藻土垫过滤。减压浓缩滤液,将粗物质溶于EtOAc。用1M HCl、饱和NaHCO3水溶液洗涤有机层,干燥(MgSO4)并减压浓缩。得到的粗物质在硅胶上通过快速柱色谱法纯化,得到所需化合物。
1-(2,3,3’,4’,6-五-O-乙酰-6’-脱氧三氯蔗糖)-4-(甲基炔丙醚)三唑(26)
通过一般过程进行三氯蔗糖叠氮化物10(3.00g,4.89mmol)和炔丙醚(4.00mL,42.5mmol)的点击反应,得到化合物26(2.56g,74%),其为无色油状物;1H NMR(CDCl3,400MHz):δ=7.71(s,1H,H-7’),5.59(d,1H,J3,4=7.3Hz,H-3’),5.66-5.64(m,1H,H-1),5.38(t,1H,J3’,4’=J4’,5’=7.3Hz,H-4’),5.32-5.29(m,1H,H-2),4.81(dd,1H,J5’,6’a=3.5Hz,J6’a,6’b=14.3Hz,H-6’a),4.73(s,2H,H-9’),4.67(dd,1H,J5’,6’b=8.8Hz,J6’a,6’b=14.3Hz,H-6’b),4.60-4.54(m,2H,H-5,H-4),4.39(ddd,1H,J5,6’a=3.5Hz,J4’,5’=7.3Hz,J5’,6’b=8.8Hz,H-5’),4.30(dd,1H,J5,6a=4.5Hz,J6a,6b=11.7Hz,H-6a),4.26-4.18(m,3H,H-6b,H-10’),3.61,3.41(ABq,2H,J=12.0Hz,H-1a,H-1b),2.47(t,1H,J12’10’=2.3Hz,H-12’),2.13(s,3H,CH3),2.11(s,3H,CH3),2.08(s,3H,CH3),2.07(s,3H,CH3),2.06(s,3H,CH3);13C NMR(CDCl3,100MHz):δ=170.4,170.2,170.1,170.0,169.7(5×COCH3),104.0(C-7’),90.6(C-1),79.5(C-5’),79.2(C-12’),77.2(C-11’),75.3(C-3’),75.3(C-4’),75.1(C-12’),68.3(C-4),67.8(C-2),67.0(C-3),64.0(C-6),62.8(C-9’),58.9(C-5),57.6(C-10’),52.7(C-6’),44.7(C-1),20.7,20.6(×2),20.5(5×COCH3);HRMS(ESI);m/z[M+H]+针对C28H35Cl2N3O14计算;得到708.1575。
甘露糖乙烯连接二聚体(27)
通过一般过程进行的甘露吡喃糖苷5(1.00g,1.2mmol)和二叠氮化乙烯(70mg,0.6mmol)点击反应,得到化合物27(0.55g,68%),其为无色油状物;1H NMR(CDCl3,400MHz):δ=8.02(dd,4H,J=1.1Hz,J=8.5Hz,H-OBz),7.88(dd,4H,J=0.8Hz,J=8.5Hz,H-OBz),7.76(dd,4H,J=1.1Hz,J=8.3Hz,H-OBz),7.60(s,2H,H-9),7.59-7.53(m,1=2H,H-OBz),7.49-7.15(m,18H,H-OBz),7.10(s,4H,Ar-OTPS),5.87(dd,2H,J2,3=3.3Hz,J3,4=10.1Hz,H-3),5.74(dd,2H,J3,4=J4,5=10.1Hz,H-4),5.61(dd,2H,J1,2=1.8Hz,J2,3=3.3Hz,H-2),5.17(d,2H,,J1,2=1.8Hz,H-2),5.06-4.93(m,4H,H-10),4.86,4.79(ABq,4H,J=12.6Hz,H-7),4.53-4.44(m,2H,H-5),4.27-4.15(m,4H,H-6),4.05(h,1H,J=6.9Hz,J=13.3Hz,J=20.1Hz,CH-i-pr),2.84(h,1H,J=6.9Hz,J=13.3Hz,J=20.1Hz,CH-i-pr),1.20(s,3H,CH3),1.18(s,3H,CH3),1.17(s,3H,CH3),1.16(s,3H,CH3),1.13(s,3H,CH3),1.11(s,3H,CH3)ppm;13C NMR(CDCl3,100MHz):δ=165.5,165.4,165.3(6×C=O),153.8,150.9,133.5,133.4,133.5,133.4,133.1,129.9,129.8,129.7,129.1,129.0,128.9,128.7,128.6,128.4,128.3,128.2,124.5(C-9),123.8(Ar-OTPS),96.9(C-1),77.2(C-8),70.3(C-2),69.7(C-3),69.4(C-5),7.9(C-6),67.0(C-4),61.1(C-7),49.7(C-10),34.1(CH-i-pr),29.6(CH-i-pr),24.7,24.6,23.4(×2)(12×CH3)ppm。
甘露糖乙烯连接的二聚体双叠氮化物(28)
向27(300mg,0.23mmol)的无水DMF(10mL)溶液中加入叠氮化钠(0.1g,1.5mmol),将混合物在80℃、氮气氛下搅拌18小时。然后将反应混合物减压浓缩,将得到的粗物质悬浮在EtOAc(50mL)中。用HCl(2×50mL)、饱和NaHCO3洗涤有机层,干燥(MgSO4)并减压浓缩,得到二叠氮化物28(0.27g,99%),其为淡黄色油状物。然后在硅胶上通过快速柱色谱(EtOAc)纯化一小部分该物质,以获得分析数据。1H NMR(CDCl3,400MHz):δ=8.04(dd,4H,J=1.5Hz,J=8.1Hz,H-OBz),7.92(dd,4H,J=1.0Hz,J=8.0Hz,H-OBz),7.77(dd,4H,J=1.1Hz,J=8.3Hz,H-OBz),7.61-7.54(m,2H,H-OBz),7.49(s,2H,H-9),7.48-7.28(m,12H,H-OBz),7.23-7.18(m,4H,H-OBz),5.90-5.82(m,4H,H-2,H-3),5.62(dd,2H,J1,2=1.7Hz,J2,3=1.0Hz,H-2),5.18(d,2H,J1,2=1.7Hz,H-1),5.08-4.95(m,4H,H-10),4.93,4.78(ABq,4H,J=12.5Hz,H-7),4.37-4.30(m,2H,H-5),4.47(d,2H,J5,6=4.2Hz,H-6);13C NMR(CDCl3,100MHz):δ=171.1,165.5(×2),165.4(3×C=O),133.6,133.5,133.2,129.9,129.8,129.7,128.6,128.5,128.3,124.5(CH-三唑),96.7(C-1),70.5(C-5),70.2(C-2),69.7(C-3),67.6(C-4),60.72(CH2),51.2(C-6),49.7(H-10)。
甘露糖二乙烯连接二聚体(29)
通过一般程序进行甘露吡喃糖苷5(1.00g,1.30mmol)和双(2'-叠氮基乙基)醚(100mg,0.80mmol)的点击反应,得到29(1.0g,92%),其为玻璃状固体。化合物29无需进一步纯化即可用于后续步骤。1H NMR(CDCl3,400MHz):δ=8.03(dd,4H,J=1.0Hz,J=8.1Hz,H-OBz),7.90(dd,4H,J=1.5Hz,J=8.0Hz,H-OBz),7.84(s,2H,H-8),7.76(dd,4H,J=1.1Hz,J=8.3Hz,H-OBz),7.62-7.30(m,18H,H-OBz),7.26-7.18(m,2H,H-OBz),7.13(s,4H,Ar-OTPS),5.88(dd,2H,J2,3=3.2Hz,J3,4=10.0Hz,H-3),5.79(dd,2H,J3,4=J4,3=10.0Hz,H-4),5.65(dd,2H,J1,2=1.8Hz,J2,3=3.2Hz,H-2),5.23(d,2H,J1,2=1.8Hz,H-2),4.97,4.82(ABq,4H,J=12.6Hz,H-7),4.61(t,4H,J10,11=5.1Hz,H-10),4.55(ddd,2H,J5,6a=2.6Hz,J5,6b=6.0Hz,J4,5=10.0Hz,H-5),4.29(dd,2H,J5,6b=6.0Hz,J6a,6b=11.2Hz,H-6b),4.23(dd,2H,J5,6a=2.6Hz,J6a,6b=11.2Hz,H-6a),4.08(p,2H,J=6.3Hz,J=13.2Hz,CH-i-pr),3.92(t,4H,J10,11=5.1Hz,H-11),2.87(p,1H,J=6.9Hz,J=13.7Hz,CH-i-pr),1.22(s,3H,CH3),1.21(s,6H,CH3),1.19(s,6H,CH3),1.18(s,6H,CH3),1.16(s,6H,CH3),1.14(s,6H,CH3);13C NMR(CDCl3,100MHz):δ=165.5,165.4(6×C=O),153.8(Ar-OTPS),150.9,143.1,133.5,133.2,129.9,129.8,129.7,129.1(×2),129.0,128.7,128.6,128.4,128.3,128.9,124.9(C-9),123.8(Ar-OTPS),97.1(C-1),77.22(C-8),70.3(C-2),69.8(C-3),69.6(C-5),69.3(C-11),67.9(C-6),66.9(C-4),61.0(C-7),50.6(C-10),34.2(CH-i-pr),29.7(CH-i-pr),24.7(×2),23.5(12×CH3)。
甘露糖二乙烯连接二聚体(30)
通过一般程序进行甘露吡喃糖苷8(1.00g,1.70mmol)和双(2'-叠氮基乙基)醚(100mg,0.8mmol)的点击反应,得到30(0.7g,65%),其为玻璃状固体。1H NMR(CDCl3,400MHz):δ=7.45(s,2H,H-9),6.93(s,4H,Ar-OTPS),5.06(dd,2H,J2,3=3.4Hz,J3,4=10.0Hz,H-3),4.94(dd,2H,J1,2=1.7Hz,J2,3=3.4Hz,H-2),4.89(t,2H,J3,4=J4,5=10.0Hz,H-4),4.68(d,2H,J1,2=1.7Hz,H-1),4.56,4.44(ABq,4H,J=12.3Hz,H-7),4.29(t,4H,J10,11=5.0Hz,H-10),3.99-3.92(m,2H,H-5),3.90-3.80(m,4H,H-6a,CH-i-pr),3.60(t,4H,J10,11=5.0Hz,H-11),2.65(h,1H,J=6.9Hz,J=13.7Hz,CH-i-pr),1.83(s,6H,OCH3),1.71(s,6H,OCH3),1.69(s,6H,OCH3),1.01-0.99(m,18H,6×CH3);13C NMR(CDCl3,100MHz):δ=169.9,169.8,169.7(6×C=O),154.0,150.9(Ar-OTPS),143.2(C-8),129.0(Ar-OTPS),124.5(C-9),123.9(Ar-OTPS),96.9(C-1),77.2,69.4(C-2),69.3(C-11),69.1(C-5),68.8(C-3),67.7(C-6),66.5(C-4),60.8(C-7),50.4(C-10),34.2(CH-i-pr),29.7(CH-i-pr),24.7(×2),23.5(6×CH3),20.8,20.6(×2)(6×OCH3);HRMS(ESI);m/z[M+H]+针对C64H92N6O23S2计算;得到1377.5791。
甘露糖二乙烯连接的二聚体双叠氮化物(31)
向四聚体29(1.0g,0.6mmol)的无水DMF(15mL)溶液中加入叠氮化钠(150mg,2.3mmol),将混合物在60℃、氮气氛下搅拌18小时。然后将反应混合物减压浓缩,将得到的粗物质悬浮在EtOAc(100mL)中。用HCl(2×100mL)、饱和NaHCO3洗涤有机层,干燥(MgSO4)并浓缩。在硅胶上通过快速柱色谱(2:1EtOAc/Pet.Sp.)纯化粗物质,得到二叠氮化物31(0.6g,76%),其为玻璃状固体。1H NMR(CDCl3,400MHz):δ=8.06(dd,4H,J=1.0Hz,J=8.1Hz,H-OBz),7.94(dd,4H,J=1.5Hz,J=8.0Hz,H-OBz),7.80-7.75(m,5H,C-9,H-OBz),7.65-7.33(m,14H,H-OBz),7.26-7.19(m,5H,H-OBz),5.95-5.83(m,4H,H-3,H-4),5.69(dd,2H,J1,2=1.8Hz,J2,3=2.9Hz,H-2),5.27(d,2H,J1,2=1.8Hz,H-2),5.04,4.85(ABq,4H,J=12.3Hz,H-7),4.60(t,4H,J10,11=5.1Hz,H-10),4.44-4.37(m,2H,H-5),3.93(t,4H,J10,11=5.1Hz,H-11),3.54-3.50(m,4H,H-6);13C NMR(CDCl3,100MHz):δ=165.6,165.5(×2)(6×C=O),133.6,133.5,133.3,129.9,129.7,129.1,128.9,128.8,128.6,128.5,128.3,125.0(C-9),97.0(C-1),77.2(C-8),70.6(C-5),70.2(C-2),69.9(C-3),69.2(C-11),67.4(C-4),60.7(C-7),51.1(C-6),50.8(C-10)。
甘露糖二乙烯连接的二聚体双叠氮化物(32)
向四聚体30(0.7g,0.5mmol)的无水DMF(10mL)溶液中加入叠氮化钠(200mg,3.2mmol),将混合物在60℃、氮气氛下搅拌18小时。然后将反应混合物减压浓缩,将得到的粗物质悬浮在EtOAc(100mL)中。用HCl(2×100mL)、饱和NaHCO3洗涤有机层,干燥(MgSO4)并浓缩,得到双叠氮化物32。化合物32无需进一步纯化即可用于后续步骤。1H NMR(CDCl3,400MHz):δ=7.67(s,2H,H-9),5.33-4.24(m,4H,H-3,H-4),5.23-5.20(m,2H,H-2),4.98(d,2H,J1,2=1.6Hz,H-1),4.90,4.72(ABq,4H,J=12.3Hz,H-7),4.54(t,4H,J10,11=5.0Hz,H-10),4.09-4.03(m,2H,H-5),3.86(t,4H,J10,11=5.0Hz,H-11),3.38(d,4H,J=4.5Hz,H-6),2.15(s,6H,OCH3),2.05(s,6H,OCH3),2.00(s,6H,OCH3);13C NMR(CDCl3,100MHz):δ=170.1,170.0,169.6,124.3(C-9),96.6(C-1),77.2(C-8),70.2(C-5),69.4(C-2),69.3(C-11),68.8(C-3),67.0(C-4),60.8(C-7),51.0(C-6),50.3(C-10),20.8,20.7,20.6(6×OCH3);HRMS(ESI);m/z[M+H]+针对C34H46N12O17计算;得到895.3179。
三氯蔗糖甘露糖叠氮化物(34)
通过一般程序进行炔丙基甘露糖5(2.4g,3.00mmol)和三氯蔗糖叠氮化物10(1.8g,2.9mmol)的点击反应,得到三糖33(3.7g,93%)。向三糖(1.0g,0.6mmol)的无水DMF(50mL)溶液中加入叠氮化钠(400mg,6.30mmol),将混合物在60℃、氮气氛下搅拌18小时。然后将反应混合物减压浓缩,将得到的粗物质悬浮在EtOAc(100mL)中。用HCl(2×100mL)、饱和NaHCO3水溶液洗涤有机层,干燥(MgSO4)并浓缩。在硅胶上通过快速柱色谱(1:1的EtOAc/Pet.Sp.)纯化粗物质,得到叠氮化物34(1.7g,56%),其为玻璃状固体。1H NMR(CDCl3,400MHz):δ=8.11–8.07(m,2H,H-Bz),7.98–7.93(m,2H,H-Bz),7.87(s,1H,三唑),7.83–7.78(m,2H,H-Bz),7.64–7.59(m,1H,H-Bz),7.55–7.34(m,6H,H-Bz),7.28–7.21(m,2H,H-Bz),5.93–5.83(m,2H,H-3”,H-4”),5.77–5.71(m,2H,H-3,H-1),5.68(dd,1H,J=2.9Hz,1.8Hz,H-3’),5.42(t,1H,J=7.2Hz,H-4),5.38–5.32(m,2H,H-2,H-2”),5.25(d,1H,J=1.8Hz,H-1”),5.04(d,1H,J=12.5Hz,H-7”a),4.90(m,2H,H-7”b,H-6a),4.77(dd,1H,J=14.3Hz,9.0Hz,H-6b),4.66–4.59(m,2H,H-4’,H-5’),4.49(m,1H,H-5),4.41–4.32(m,2H,H-5”,H-6’b),4.28(dd,1H,J=11.8,7.0Hz,H-6’a),3.65(d,1H,J=12.0Hz,H-1’a),3.59–3.48(m,3H,H-1’b,H-6”a,H-6”b),2.16-2.01(5x s,15H,5x OAc)ppm;13C NMR(CDCl3,100MHz):δ=170.63–169.70(5x C=O),165.79–165.38(3x C=O),143.76(C,三唑)133.70(CH,Bz),133.70(CH,Bz),133.28(CH,Bz),130.33–129.58(CH,Bz),129.38(C,Ar),129.23(C,Ar),128.95(C,Ar),128.86–128.25(6CH,Bz),124.82(CH,三唑),104.33(C,C-2’),97.06(CH,C-1”),90.79(CH,C-1),79.71(CH,C-5),75.63(CH),75.57(CH),70.73(CH,C-5”),70.46(CH,C-3’),69.83(CH),68.51(CH),67.95(CH),67.79(CH),67.15(CH,C-2),64.17(CH2,C-6’),61.28(CH2,C-7”),59.09(CH),53.01(CH2,C-6),51.37(CH2,C-6”),44.88(CH2,C-1’),20.92–20.61(CH3)ppm。
三氯蔗糖甘露糖甘露糖叠氮化物(36)
通过一般程序进行炔丙基甘露糖5(600mg,0.80mmol)和叠氮化物34(900mg,0.80mmol)的点击反应,得到四糖35(1.5g,定量)。粗产物无需进一步纯化即可使用。向四糖(1.5g,0.76mmol)的无水DMF(50mL)溶液中加入叠氮化钠(150mg,2.3mmol),将混合物在60℃、氮气氛下搅拌18小时。然后将反应混合物减压浓缩,将得到的粗物质悬浮在EtOAc(100mL)中。用HCl(2×100mL)、饱和NaHCO3洗涤有机层,干燥(MgSO4)并浓缩。在硅胶上通过快速柱色谱法(1:1的EtOAc/Pet.Sp.)纯化粗物质,得到叠氮化物36(1.2g,91%),其为玻璃状固体。1H NMR(CDCl3,400MHz):δ=8.09–7.98(m,6H),7.96–7.90(d,2H),7.79(m,5H),7.66–7.58(m,2H),7.50(m,7H),7.45–7.33(m,7H),7.23(m,3H),5.94–5.73(m,6H,H-1),5.66(dd,1H,J=3.3,1.5Hz),5.59(dd,1H,J=3.3,1.6Hz),5.46–5.30(m,3H),5.22(s,2H),5.00(d,1H,J=12.1Hz),4.91–4.59(m,11H),4.48(t,1H,J=7.2Hz),4.34(m,2H),4.30–4.21(m,1H),3.63(s,2H),3.57–3.43(m,2H),2.16(s,3H),2.09(s,6H),2.07(s,3H),1.97(s,3H)ppm;13C NMR(CDCl3,100MHz):δ=170.6,170.3,170.3,167.0,169.8,166.0,165.7,165.5(×3),165.4,134.0–133.60,133.30,130.3–129.7,129.3,129.2,129.0–128.5,128.4,125.4,125.0,104.3,97.1,96.8,90.9,79.6(×3),70.6,70.4,69.89,69.9,69.7,68.4(×2),68.1,67.7,67.0,64.2,61.4,60.8,59.2,53.0,51.4(×2),44.9,21.2–20.2ppm。
三氯蔗糖甘露糖(36)
通过一般程序进行三糖34(540mg,0.46mmol)和4-戊炔-1-醇(110mg,0.46mmol)的点击反应,得到三糖36(370mg,58%)。1H NMR(CDCl3,400MHz):δ=7.98(dd,4H,J=7.1Hz,J=16.4Hz),7.78(s,1H,H-三唑),7.77(d,2H,J=8.5Hz),7.63(s,1H,H-三唑),7.62-7.56(m,1H),7.54-7.42(m,3H),7.42-7.33(m,3H),7.21(m,2H),5.86(dd,1H,J=3.2Hz,J=9.9Hz),5.80(d,1H,J=2.8Hz),5.77-5.70(m,2H),5.62-5.58(m,1H),5.38(t,1H,J=7.1Hz),5.36-5.32(m,2H),5.14-5.11(m,1H),4.87(dd,1H,J=3.6Hz,J=14.3Hz),4.79-4.67(m,2H),4.66-4.41(m,8H),4.32(dd,1H,J=4.5Hz,J=11.9Hz),4.25(dd,1H,J=7.3Hz,J=11.9Hz),3.74-3.52(m,4H),2.79(br-t,2H,J=7.1Hz),2.13(s,3H),2.08(s,3H),2.07(s,3H),2.05(s,3H),1.92(s,3H),1.87(br-t,2H,J=6.5Hz);13C NMR(CDCl3,100MHz):δ=171.03,170.3,170.1(×2),169.7,169.6,165.7,165.3,165.1,143.3,133.6,133.5,133.1,129.8,129.7,129.6,129.0,128.8,128.5,128.4,128.1,124.5,122.8,104.1,96.1,90.6,79.4,74.4,75.3,70.3,69.7,69.4,68.2,68.0,67.8,66.7,64.0,61.1,58.9,52.7,50.8,44.5,31.6,21.7,20.9,20.6,20.5(×2),20.4(×2)。
三氯蔗糖甘露糖(37)
向醇36(370mg,0.30mmol)的无水DCM(20mL)溶液中加入三乙胺(140mg,1.40mmol)和甲磺酰氯(40mg,0.35mmol),并在室温下搅拌18小时。将反应混合物用1M HCl(2×30mL)、饱和NaHCO3(30mL)洗涤,干燥(MgSO4)并减压浓缩。向粗物质的无水DMF(20mL)溶液中加入NaN3(60mg,1.00mmol)并在60℃下搅拌18小时。减压浓缩反应混合物,将粗物质溶于EtOAc(100mL)中,用1M HCl(50mL)、饱和NaHCO3(50mL)洗涤,干燥(MgSO4)并减压浓缩。通过快速柱色谱法(1.5:1的EtOAc/Pet.Sp至EtOAc)纯化粗物质,得到叠氮化物37(250mg,60%)。1HNMR(CDCl3,400MHz):δ=8.02-7.93(m,4H),7.79-7.74(m,3H),7.64(s,1H),7.63-7.57(m,1H),7.52-7.43(m,4H),7.42-7.34(m,3H),7.21(t,2H,J=8.1Hz),5.85(dd,1H,J=3.3Hz,J=10.0Hz),5.82(d,1H,J=3.4Hz),5.77-5.68(m,2H),5.60(dd,1H,J=1.7Hz,J=3.4Hz),5.41(t,1H,J=7.3Hz),5.34(dd,1H,J=3.3Hz,J=9.6Hz),5.16(d,1H,J=1.6Hz),4.88(dd,1H,J=3.5Hz,J=14.3Hz),4.76(d,1H,J=9.2Hz),4.70(d,1H,J=11.8Hz),4.65-4.52(m,6H),4.50-4.42(m,1H),4.32(dd,1H,J=4.2Hz,J=11.8Hz),4.24(dd,1H,J=7.0Hz,J=11.9Hz),3.63(d,2H,J=3.7Hz),3.27(t,2H,J=6.8Hz),2.76(ddd,2H,J=3.1Hz,J=7.4Hz,J=10.4Hz),2.14(s,3H),2.10(s,3H),2.08(s,3H),2.06(s,3H),1.95(s,3H),1.91(t,2H,J=7.0Hz);13C NMR(CDCl3,100MHz):δ=170.3,170.1,170.0,169.7,169.6,165.6,165.2,165.1,146.6,143.2,133.6,133.5,133.1,129.8,129.7,129.6,129.0,128.8,128.5(×2),128.4,128.1,125.6,122.7,104.0,96.3,90.6,79.4,77.2,75.4,75.2,70.3,69.5,68.2,67.9,67.8,66.8,64.0,60.4,58.9,52.7,50.8,50.5,44.6,42.7,28.3,22.5,22.6(×2),20.5(×2),20.4.。
甘露糖乙烯连接的四聚体(38)
通过一般程序进行二叠氮化物28(400mg,0.40mmol)和吡喃甘露糖苷5(600mg,0.80mmol)的点击反应,得到38(600mg,65%),其为玻璃状固体;1H NMR(CDCl3,400MHz):δ=8.06(s,2H,H-9,H-9’),8.02-7.93(m,12H,OBz),7.87(dd,4H,J=1.3Hz,J=8.3Hz,OBz),7.77(dd,8H,J=0.9Hz,J=8.3Hz,OBz),7.73(dd,4H,J=1.3Hz,J=8.1Hz,OBz),7.62-7.51(m,4H,OBz),7.51-7.14(m,34H,OBz),7.10(s,4H,Ar-OTPS),5.94(dd,2H,J2,3=3.5Hz,J3,4=10.1Hz,H-3’),5.81-5.70(m,6H,H-3,H-4’,H-4),5.64(dd,2H,J1’,2’=1.6Hz,J2’,3’=3.4Hz,H-2’),5.57-5.53(m,2H,H-2),5.22,5.16(m,4H,H-1’,H-1),4.94-4.63(m,12H,H-6’,H-10’,H-5,H-7),4.60,4.54(Abq,4H,J=12.6Hz,H-7’),4.51-4.44(m,2H,H-5’),4.29-4.16(m,4H,H-6),),4.06(p,2H,J=6.9Hz,J=13.8Hz,CH-i-pr),2.84(p,1H,J=6.9Hz,J=13.7Hz,CH-i-pr),1.20(s,3H,CH3),1.18(s,3H,CH3),1.16(s,3H,CH3),1.14(s,3H,CH3),1.13(s,3H,CH3),1.11(s,3H,CH3);13C NMR(CDCl3,100MHz):δ=165.8,165.4,165.3(×2),165.2(×2)(12×C=O),153.7,150.9(Ar-OTPS),143.5,143.2(C-8,C-8’),133.6,133.5,133.1,129.9(×2),129.8,129.7,129.6,129.1(×2),129.0,128.9,128.7,128.6(×2),128.5(×2),128.4,128.3,125.2,128.6(C-9,C-9’),123.8(Ar-OTPS),96.9,96.4(C-1,C-1’),70.3(C-2),70.1(C-2’),69.8(C-3),69.7(C-3’),69.4(×2)(C-5,C-5’),68.2(C-4’),67.8(C-6),66.9(C-4),61.1(C-7),60.3(C-7’),51.2(C-6’),49.5(C-10’),34.2(CH-i-pr),29.6(CH-i-pr),24.7,24.6,23.5(12×CH3)。
甘露糖乙烯连接的四聚体双叠氮化物(39)
向四聚体38(600mg,0.20mmol)的无水DMF(10mL)溶液中加入叠氮化钠(60mg,0.9mmol),将混合物在60℃、氮气氛下搅拌18小时。然后将反应混合物减压浓缩,将得到的粗物质悬浮在EtOAc(50mL)中。用HCl(2×50mL)、饱和NaHCO3洗涤有机层,干燥(MgSO4)并减压浓缩,得到二叠氮化物39,其为黄色油状物。粗产物无需进一步纯化即可使用。1H NMR(CDCl3,400MHz):δ=8.13(s,2H,H-9),8.09-7.88(m,16H,H-OBz),7.84-7.72(m,8H,H-OBz),7.65-7.16(m,44H,H-OBz,H-9’),5.98(dd,2H,J2’,3’=3.4Hz,J3’,4’=10.0Hz,H-3’),5.86(dd,2H,,J3,4=J4,5=10.1Hz,H-4),5.82-5.74(m,4H,H-3,H-4’),5.64(dd,2H,J1’,2’=1.6Hz,J2’,3’=3.4Hz,H-2’),5.60(dd,2H,J1,2=1.6Hz,J2,3=3.2Hz,H-2),5.23(d,2H,J1’,2’=1.6Hz,H-1’),5.19(d,2H,J1,2=1.6Hz,H-1),4.98,4.82(ABq,4H,J=12.6Hz,H-7’),4.87-4.64(m,10H,H-6’,H-7,H-5’),4.60,4.34(ABq,4H,J=12.7Hz,H-10’),4.35(ddd,2H,J5,6a=2.7Hz,J5,6b=5.4Hz,J4,5=10.0Hz,H-5),3.52(dd,2H,J5,6a=2.7Hz,J6a,6b=13.4Hz,H-6a),3.46(dd,2H,J5,6b=5.4Hz,J6a,6b=13.4Hz,H-6b);13C NMR(CDCl3,100MHz):δ=165.9,165.5,165.4(×3),165.3,148.6,148.4,143.4,143.2,133.7,133.6,133.5,133.2,130.0,129.9(×3),129.7(×2),129.2,129.1,129.0,128.9,128.8,128.6(×2),128.5(×2),128.3,125.5(C-9),124.9(C-9’),97.1(C-1’),96.3(C-1),77.2(C-8,C-8’),70.4(×2)(C-5,C-2’),70.1(C-2),69.8(C-3),69.7(C-3’),69.4(C-5’),68.2(C-4’),67.5(C-4),61.0(C-7’),60.1(C-10’),51.5(C-6’),51.1(C-6),49.7(C-7)。
甘露糖二乙烯连接的四聚体(40)
通过一般程序进行二叠氮化物32(500mg,0.40mmol)和甘露吡喃糖苷5(600mg,0.80mmol)的点击反应,得到40(900mg,99%),其为玻璃状固体;1H NMR(CDCl3,400MHz):δ=8.11(s,2H,H-9),8.09-7.84(m,16H,H-OBz),7.84-7.66(m,8H,H-OBz),7.66-7.16(m,36H,H-OBz),7.11(s,4H,Ar-OTPS),5.90(dd,2H,J2’,3’=3.5Hz,J3’,4’=10.0Hz,H-3’),5.82-5.72(m,6H,H-3,H-4,H-4’),5.68(dd,2H,J1’,2’=1.7Hz,J2’,3’=3.5Hz,H-2’),5.58-5.54(m,2H,H-2),5.24(d,2H,J1’,2’=1.7Hz,H-1’),5.19(d,2H,J1,2=1.7Hz,H-1),4.91,4.79(ABq,4H,J=12.3Hz,H-7’),4.85-4.57(m,10H,H-5’,H-6,H-7),4.57-4.45(m,6H,H-10’,H-5),4.26(dd,2H,J5,6a=6.0,J6a,6b=11.1Hz,H-6a),4.20(dd,2H,J5,6b=2.7Hz,J6a,6b=11.1Hz,H-6b),4.07(p,2H,J=6.3Hz,J=13.2Hz,CH-i-pr),3.83(t,4H,J10’,11’=5.2Hz,H-11’),2.85(p,1H,J=6.9Hz,J=13.7Hz,CH-i-pr),1.22(s,6H,CH3),1.20(s,6H,CH3),1.17(s,6H,CH3),1.15(s,6H,CH3),1.14(s,6H,CH3),1.12(s,6H,CH3);13C NMR(CDCl3,100MHz):δ=165.8,165.4,165.3,153.8,150.9,143.4,133.6,133.5,133.2,129.9,129.8(×3),129.7(×2),129.1,128.9(×2),128.7,128.6,128.5,128.4,128.3,123.8,96.9,96.8,77.2,70.2,70.1,69.9,69.7,69.5,69.4,68.1,67.8,66.8,61.0,60.4,51.3,34.2,29.6,24.7,24.6,23.5。
甘露糖二乙烯连接的四聚体双叠氮化物(41)
向四聚体40(0.9g,0.4mmol)的无水DMF(10mL)溶液中加入叠氮化钠(100mg,1.6mmol),将混合物在60℃、氮气氛下搅拌18小时。然后将反应混合物减压浓缩,将得到的粗物质悬浮在EtOAc(75mL)中。用HCl(2×75mL)、饱和NaHCO3洗涤有机层,干燥(MgSO4)并浓缩,得到二叠氮化物41。该物质无需进一步纯化即可用于后续步骤。1H NMR(CDCl3,400MHz):δ=8.21(s,2H,H-三唑),8.11-7.69(m,28H,H-OBz,H-三唑),7.65-7.15(m,38H,H-OBz),5.94-5.83(m,4H),5.82-5.72(m,4H),5.70-5.66(m,2H),5.60-5.54(m,2H),5.27-5.19(m,4H),5.04-5.96(m,2H),4.82-4.36(m,16H),4.30-4.32(m,2H),3.94-3.76(m,4H),3.61-3.41(m,4H);13C NMR(CDCl3,100MHz):δ=165.6,165.5(×2),133.6(×2),133.3,129.9,129.8,129.7,129.1,128.9,128.8,128.6,128.5,128.3,125.0,97.0,77.2,70.6,70.2,69.9,67.4,60.7,51.2,50.8。
乙烯连接的六聚体(42)
通过一般程序进行二叠氮化物28(270mg,0.20mmol)和三唑26(300mg,0.40mmol)的点击反应,得到26(222mg,38%),其为玻璃状固体;1H NMR(CDCl3,400MHz):δ=7.91(dd,8H,J=1.3Hz,J=8.3Hz,OBz),7.86(s,2H,H-三唑),7.74-7.64(m,6H,OBz,H-三唑),7.57-7.22(m,14H,OBz),7.16(t,4H,OBz),5.85(dd,2H,J2,3=3.4Hz,J3,4=10.1Hz,H-c),5.70-5.61(m,6H,H-1,H-3’,H-d),5.45(dd,2H,J1,2=1.7Hz,J2,3=3.4Hz,H-b),5.33(t,2H,J=7.2Hz,H-4’),5.28-5.24(m,4H,H-2,H-3),5.05(d,2H,J=1.2Hz,H-a),4.98-4.81(m,4H,H-16’),4.81-4.50(m,20H,H-4,H-5,H-6’,H-9’,H-10’,H-e,H-f),4.47,4.40(ABq,4H,J=12.1Hz,H-13’),4.22(dd,2H,J5,6a=4.6Hz,J6a,6b=11.8Hz,H-6a),4.16(dd,2H,J5,6b=6.9Hz,J6a,6b=11.8Hz,H-6b),3.57,3.49(ABq,4H,J=12.1Hz,H-1’),2.07(s,6H,OCH3),2.04(s,6H,OCH3),2.01(s,6H,OCH3),2.00(s,6H,OCH3),1.99(s,6H,OCH3);13C NMR(CDCl3,100MHz):δ=206.9,171.1,170.4,170.1(×2),169.9,169.6,165.8,165.3,165.2,133.6,133.2,129.9,129.6,129.1,128.9,128.6,128.5(×2),128.3,104.7,96.3,90.6,75.3,70.3,69.6,68.2,67.8,66.8,63.9,60.3,59.0,44.7,21.0,20.7,20.6,20.4。
二乙烯连接的六聚体(43)
通过一般程序进行二叠氮化物32(500mg,0.50mmol)和三唑26(700mg,1.00mmol)的点击反应,得到43(200mg,20%),其为玻璃状固体;1H NMR(CDCl3,400MHz):δ=7.86,7.70,7.57(3×(s,2H,H-三唑)),5.69-5.64(s,4H,H-3",H-3’),5.33(t,2H,J=7.3Hz,H-4"),5.29-5.26(m,4H,H-1’,H-4’),5.24(dd,2H,J=3.3Hz,J=10.0Hz,H-3),5.13(dd,2H,J=1.7Hz,J=3.3Hz,H-2),5.07(t,2H,J=10.0Hz,H-4),4.86-4.81(m,2H,H-1),4.77(dd,2H,J=3.5Hz,J=14.3Hz),4.71-4.29(m,28H,H-5’,H-5,H-6",H-6’,H-7,H-10,H-14,H-15),4.20-4.12(m,6H,H-6,H-5"),3.82-3.73(m,4H,H-11),3.58,3.51(ABq,4H,J=12.1Hz,H-1"),2.15-1.97(m,48H,16×OCH3);13C NMR(CDCl3,100MHz):δ=170.4,170.2,170.1,170.0,169.9,169.8,169.7,169.6,144.1,142.4,125.3,124.9,124.8,104.1,96.6,90.7,79.4,77.2,75.4,75.3,69.3,69.2,68.7,68.3,67.8,67.4,66.9,64.0,63.1,63.0,60.4,60.1,59.0,53.0,51.2,50.4,44.7,20.8,20.7,20.6(×3),20.5。
乙烯连接的八聚体(44)
通过一般程序进行二叠氮化物39(500mg,0.20mmol)和三唑26(300mg,0.40mmol)的点击反应,得到44(500mg,74%),其为玻璃状固体;1H NMR(CDCl3,400MHz):δ=8.06-7.89(m,20H,H-OBz),7.82-7.69(m,12H,H-OBz,H-三唑),7.66-7.16(m,52H,H-OBz,H-三唑),5.97(dd,2H,J=3.3Hz,J=9.9Hz,H-3’),5.82-5.75(m,4H,H-3,H-1”),5.74-5.66(m,6H,H-4,H-4’,H-3”’),5.64(dd,2H,J=1.7Hz,J=3.3Hz,H-2’),5.55(dd,2H,J=1.6Hz,J=3.3Hz,H-2),5.39(t,2H,J=7.1Hz,H-4"’),5.35-5.31(m,4H,H-3”,H-4”),5.21-5.16(m,4H,H-1’,H-1),4.90-4.47(m,40H,H-5,H-5’,H-5",H-6"’.H-6’,H-6,H-7,H-7’,H-9,H-9"’,H-10’),4.45-4.37(m,2H,H-5"’),4.29(dd,2H,J=4.6Hz,J=11.8Hz,H-6”a),4.21(dd,2H,J=6.8Hz,J=11.8Hz,H-6”b),3.62,3.53(ABq,4H,J=12.1Hz,H-1”’),2.13(s,6H,OCH3),2.10(s,6H,OCH3),2.06(s,6H,OCH3),2.05(s,6H,OCH3),2.05(s,6H,OCH3);13C NMR(CDCl3,100MHz):δ=170.4,170.2,170.0,169.4,169.7,165.4,165.3(×2),165.2(×2),143.2,143.1,133.7,133.2,129.9(×2),129.8,129.7,128.9,128.6,128.5,128.3,104.2,96.8,90.7,79.5,75.3,70.2,69.6,69.4,68.3,68.0,67.8,66.9,64.0,63.3,63.2,59.0,44.8,20.7,20.6,20.5。
二乙烯连接的八聚体(45)
通过一般程序进行二叠氮化物41(900mg,0.40mmol)和三唑26(500mg,0.80mmol)的点击反应,得到45(800mg,57%),其为玻璃状固体;1H NMR(CDCl3,400MHz):δ=8.14-7.86(m,18H,H-OBz,H-三唑),7.83-7.68(m,10H,H-OBz),7.65-7.12(m,64H,H-OBz,H-三唑),5.90(dd,2H,J=3.1Hz,J=10.0Hz),5.83-5.63(m,10H),5.58-5.54(m,2H),5.39(t,2H,J=7.1Hz),5.34-5.32(m,4H),5.23(br-s,2H),5.18(br-s,2H),4.88-4.35(m,40H),4.29(dd,2H,J=4.6Hz,J=11.6Hz),4.22(dd,2H,J=6.8Hz,J=11.6Hz),3.91-3.74(m,4H),3.63,3.53(ABq,J=12.0Hz),2.14,2.11,2.07,2.06,2.05(10×(s,3H))。
六糖(46)
通过一般程序进行三氯蔗糖甘露糖叠氮化物34(410mg,0.35mmol)和双炔丙基乙二醇连接基团(24mg,0.18mmol)的点击反应,得到六糖46(90mg,20%),其为油状物。1H NMR(CDCl3,400MHz):δ=8.09-7.92(m,8H),7.89(s,2H),7.82-7.72(m,6H),7.66-7.56(m,2H),7.56-7.44(m,6H),7.44-7.34(m,6H),7.26-7.18(m,4H),5.91-5.68(m,8H),5.62(br-s,2H),5.46-5.30(m,6H),5.17(s,2H),4.97-4.41(m,24H),4.38-4.20(m,4H),3.87-3.40(m,10H),2.15(s,6H),2.10(s,6H),2,09(s,6H),2.07,2.06(s,6H)ppm;13C NMR(CDCl3,100MHz):δ=170.4,170.2,170.1,169.8,169.7,165.7,165.3,165.2,143.2,133.7(×2),133.1,129.9,129.8,129.7,129.1,128.9,128.6,128.5,128.2,124.7,104.2,96.6,90.7,79.4,77.2,75.4,75.3,70.3,69.5,68.3,67.9,66.8,64.1,60.7,60.3,59.0,52.8,51.2,44.6,20.7(×2),20.6(×3)ppm。
八糖(47)
通过一般程序进行叠氮化物36(800mg,0.46mmol)和炔丙醚(22mg,0.23mmol)的点击反应,得到油状的八糖47(350mg,43%);1H NMR(CDCl3,400MHz):δ=8.09-7.84(m,18H),7.83-7.68(m,8H),7.66-7.29(m,24H),7.25-7.16(m,6H),5.95-5.82(m,4H),5.81-70(m,4H),5.69-5.61(m,4H),5.58-5.52(m,2H),5.46-5.29(m,6H),5.21(s,2H),5.16(s,2H),4.93-4.39(m,30H),4.40-4.19(m,4H),3.73-3.57(m,4H),2.15(s,6H),2.10(s,12H),2.05(s,6H),1.95(s,6H)ppm;13C NMR(CDCl3,100MHz):δ=171.1,170.4,170.1,169.8,169.7,165.7,165.6,165.3,165.2,165.1(×2),144.3,143.1,133.6,133.1,129.9,129.8(×2),129.7(×2),129.6,129.1,129.0,128.9(×2),128.6,128.5(×2),128.2,125.3,125.0,124.7,104.1,96.7,96.6,90.6,79.3,77.2,75.3,70.3,70.1,69.5,69.3,68.2,68.1,68.0,67.9,66.7,64.0,60.3,59.0,52.7,51.1,44.7,20.7,20.6(×2),20.5ppm。
八糖(48)
通过一般程序进行叠氮化物36(400mg,0.23mmol)和双炔丙基乙烯连接基团(16mg,0.11mmol)的点击反应,得到八糖48(150mg,38%),其为油状物;1H NMR(CDCl3,400MHz):δ=8.09-7.83(m,20H),7.83-70(m,10H),7.66-7.55(m,4H),7.55-7.43(m,12H),7.42-7.31(m,12H),7.26-7.17(m,8H),5.89(dd,2H,J=3.3Hz,J=10.0Hz),5.85(d,2H,J=3.5Hz),5.81-5.69(m,6H),5.69-5.61(m,4H),5.54(dd,2H,J=1.7Hz,J=3.2Hz),5.42(t,2H,J=7.3Hz),5.39(dd,2H,J=3.6Hz,J=10.8Hz),5.32(dd,2H,J=3.3Hz,J=10.8Hz),5.21(d,2H,J=1.5Hz),5.16(d,2H,J=1.5Hz),4.84(dd,2H,J=3.6Hz,J=14.4Hz),4.78-4.39(m,32H),4.33(dd,2H,J=4.4Hz,J=11.7Hz),4.25(dd,2H,J=7.1Hz,J=11.9Hz),3.72-3.52(m,8H),2.15(s,6H),2.07(s×2,12H),5.56(s,6H);13C NMR(CDCl3,100MHz):δ=170.4,170.1,169.8,169.7,165.8,165.6,165.3,165.2,165.1,144.6,143.1(×2),133.7,133.6,133.1,129.9(×2),129.8(×2),129.7,129.6,129.1,129.0(×2),128.9,128.6,128.5(×2),128.2,125.3,124.8,124.7,104.1,96.7,96.6,90.6,79.3,77.2,75.4,75.3,70.3,70.2,69.6,69.3,68.3,68.1,68.0,67.9,67.0,66.7,64.0,59.0,52.7,51.1,44.7,21.0,20.7,20.6(×2),20.5ppm。
乙烯连接的双麦芽三糖(49)
通过一般程序进行叠氮化物28(160mg,0.13mmol)和炔丙基麦芽三糖13(250mg,0.25mmol)的点击反应,得到低聚糖49(235mg,57%),其为玻璃状固体;1H NMR(CDCl3,400MHz):δ=8.07-7.89(m,5H),7.83-7.73(m,1H),7.66-7.56(m,1H),7.54-7.29(m,6H),7.25-7.16(m,2H),6.09(dd,1H,J=3.2Hz,J=9.9Hz),5.76(t,1H,J=9.9Hz),5.66-5.56(m,1H),5.43-5.30(m,3H),5.20(d,1H,J=4.1Hz),5.14(s,1H),5.05(t,2H,J=10.0Hz),4.98-4.68(m,9H),4.67-4.31(m,6H),4.31-4.11(m,3H),4.09-3.83(m,5H),3.77-3.59(m,1H),2.16–1.78(10x s,30H,10x OAc)ppm;13C NMR(CDCl3,100MHz):δ=170.5,170.3,169.9,169.8,169.7,169.6,169.4,165.8,165.4,165.2,143.8,143.2,133.7,133.5,133.2,129.8(×2),129.6,129.0,128.8,128.6(×2),128.4,128.3,125.4,124.9,98.8,95.8,95.6,95.4,77.2,74.9,73.9,72.5,71.9,71.6,70.4,70.0,69.8,69.3(×2),68.9,68.5,68.1,67.9,62.8,62.3,62.2,61.3,59.2,51.1,50.3,20.8,20.7,20.6,20.5。
二乙烯连接的双麦芽三糖(50)
通过一般程序进行叠氮化物32(260mg,0.21mmol)和乙酰化的炔丙基麦芽三糖13(400mg,0.42mmol)的点击反应,得到低聚糖50(205mg,31%),其为玻璃状固体;1H NMR(CDCl3,400MHz):δ=8.02-7.89(m,9H),7.87(s,2H),7.77-7.69(m,6H),7.63-7.56(m,2H),7.53-7.42(m,6H),7.41-7.30(m,6H),7.24-7.16(m,4H),5.91-5.82(m,2H),5.76-5.67(m,3H),5.65-5.58(m,2H),5.41-5.29(m,6H),5.25-5.20(m,2H),5.19-5.16(m,2H),5.13(t,2H,J=9.2Hz),5.04(t,2H,J=10.0Hz),4.92-4.38(m,34H),4.29-4.12(m,6H),4.06-3.99(m,2H),3.98-3.83(m,14H),3.70-3.62(m,2H),2.16–1.88(10x s,30H,10x OAc)ppm;13CNMR(CDCl3,100MHz):δ=171.02,170.5(×2),170.4(×2),170.3,169.9,169.7,169.6(×2),169.3,165.6,165.2(×2),144.0,142.9,133.6(×2),133.2,129.8,129.7,129.6,129.0,128.8,128.6,128.5,128.4,128.2,124.7,124.5,99.1,96.3,95.6(×2),77.2,75.1,73.7,72.5,72.0,71.9,71.6,70.4,70.2,70.0,69.6,69.3(×2),68.8,68.4,67.9(×2),62.5,62.2,61.3,60.5,60.3,50.9,50.2,20.9(×2),20.8,20.7(×2),20.6,20.4。
三氯蔗糖-阿卡波糖(51)
通过一般程序进行三氯蔗糖叠氮化物10(105mg,0.17mmol)和乙酰化的炔丙基阿卡波糖14(400mg,0.42mmol)的点击反应,得到低聚糖51(100mg,33%),其为玻璃状固体;1HNMR(CDCl3,400MHz):δ=7.65(s,1H),5.93(d,1H,J=5.4Hz),5.73-5.64(m,2H),5.59-5.48(m,2H),5.40-5.28(m,3H),5.26-5.16(m,3H),5.07(t,2H,J=10.1Hz),4.93-4.86(m,2H),4.85-4.54(m,9H),4.54-4.11(m,8H),3.96(t,1H,J=9.2Hz),3.92-3.85(m,2H),3.77-3.65(m,2H),3.62,3.49(ABq,2H,J=12.1Hz),3.54-3.45(m,1H),2.36(t,1H,J=9.9Hz),2.14(s,3H),2.12(2,3H),2.11(s,3H),2.10(s,3H),2.07(s,6H),2.06(s,3H),2.05(s,3H),2.02(s,3H),2.00(s,3H),1.97(×2)(s,9H),1.95(×2)(s,6H),1.93(s,3H),1.17(d,3H,J=6.1Hz)ppm;13C NMR(CDCl3,100MHz):δ=171.0,170.9,170.7,170.6,170.5,170.3(×2),170.2,170.1(×2),170.0,169.8,169.6(×2),169.5,133.8,127.9,124.2,104.1,99.2,95.8,95.6,90.5,79.5,77.2,75.3,75.2,75.1,73.4,72.1(×2),71.9,71.8,71.0,70.8,70.6,70.4,70.0,69.7,69.0,68.2,67.7,66.8,63.9,63.0,62.7,62.6,62.2,61.1,58.9,52.5,52.1,20.9,20.8(×2),20.6(×2),20.5(×2),20.4,18.1ppm。
三氯蔗糖-阿卡波糖(52)
通过一般程序进行三氯蔗糖叠氮化物10(75mg,0.12mmol)和炔丙基阿卡波糖15(146mg,0.12mmol)的点击反应,得到寡糖36(90mg,41%),其为玻璃状固体;1H NMR(CDCl3,400MHz):δ=7.51-7.40(m,1H),5.94(d,1H,J=5.4Hz),5.71-5.66(m,1H),5.60-5.49(m,2H),5.42-5.18(m,6H),5.08(t,1H,J=10.2Hz),4.90(dd,1H,J=4.2Hz,J=10.1Hz),4.83-4.13(m,16H),3.99-3.84(m,3H),3.74-3.66(m,2H),3.62,3.49(ABq,2H,J=12.2Hz),3.58-3.46(m,1H);13C NMR(CDCl3,100MHz):δ=171.1,170.9,170.7(×2),170.6,170.5,170.3(×2),170.2,170.1(×3),170.0(×2),169.8,169.7,169.6(×2),147.0,133.9,127.9,122.7,122.4,104.0,100.2,95.8,95.6,90.5,79.5,77.2,75.3(×2),75.2,73.5,72.2,72.1(×2),71.8,71.0,70.8,70.6,70.4,70.0,69.7,69.1,68.2,67.7,66.9,63.9,63.0,62.8,62.2,61.1,60.3,60.0,52.1,44.8,20.96-20.57,18.1。
三氯蔗糖-甘露糖-阿卡波糖(53)
通过一般程序进行乙酰化的炔丙基阿卡波糖14(280mg,0.24mmol)和叠氮化物37(310mg,0.24mmol)的点击反应,得到化合物53(340mg,58%),其为玻璃状固体;1H NMR(CDCl3,400MHz):δ=7.97-7.85(m,4H),7.74(s,1H),7.72-7.66(m,2H),7.62(s,1H),7.59-7.50(m,2H),7.48-7.36(m,3H),7.36-7.27(m,3H),7.15(t,2H,J=7.7Hz),5.89(d,1H,J=5.1Hz),5.78(dd,1H,J=3.3Hz,J=10.0Hz),5.75(d,1H,J=2.9Hz),5.68(d,1H,J=7.8Hz),5.64(t,1H,J=9.7Hz),5.56-5.43(m,4H),5.34(t,1H,J=7.1Hz),5.32-5.23(m,3H),5.21-5.11(m,4H),5.10(s,1H),5.03(t,1H,J=10.1Hz),4.90-4.07(m,34H),3.91(t,1H,J=9.2Hz),3.88-3.80(m,2H),3.73-3.52(m,5H),3.50-3.40(m,1H),2.62(br-t,2H,J=6.5Hz),2.32(t,1H,J=9.8Hz),2.17(t,2H,J=6.7Hz),2.08-1.85(15×s,51H),1.17(d,3H,J=6.1Hz)ppm;13C NMR(CDCl3,100MHz):δ=170.7,170.5,170.4,170.3,170.2(×2),170.1(×2),170.0,169.9,169.8,169.7,169.6,169.4(×2),165.5,165.1,165.0,145.8,143.6,143.1,133.6,133.5,133.0,129.6,129.5,129.4,128.9,128.7,128.4(×2),128.3,128.0,127.8,124.5,123.1,123.0,103.9,99.1,96.2,95.6,95.4,90.4,79.3,75.3,75.1,75.0,73.2,72.0,71.9,71.8,71.6,70.9,70.7,70.5,70.3,70.1,69.8,69.6,69.3,68.9,68.1,67.8,67.7,66.5,63.9,62.8,62.5(×2),62.0,60.9,60.3,58.9,52.5,51.9,50.6,49.0,44.5,29.4,21.9,20.7-20.2,17.9ppm。
乙烯连接的双阿卡波糖(54)
通过一般程序进行乙酰化的炔丙基阿卡波糖14(40mg,0.20mmol)和二叠氮化乙烯(6.70mg,60μmol)的点击反应,得到固体的双阿卡波糖54(93mg,81%);1H NMR(CDCl3,400MHz):δ=7.39(s,1H),5.94(d,J=5.2Hz),5.60-5.50(m,2H),5.37-5.30(m,1H),5.27-5.17(m,4H),5.09(t,1H,J=10.3Hz),4.95-4.87(m,3H),4.86-4.67(m,6H),4.66-4.58(m,2H),4.51(dd,1H,J=2.6Hz,J=12.3Hz),4.43(d,1H,J=12.2Hz),4.34(d,1H,J=13.2Hz),4.23(dd,1H,J=3.9Hz,J=12.1Hz),3.95(t,1H,J=9.2Hz),3.91-3.86(m,2H),3.71-3.62(m,2H),3.48(ddd,1H,J=6.0Hz,J=12.2Hz,J=16.0Hz);13C NMR(CDCl3,100MHz):δ=171.0,170.7,170.6,170.5,170.3,170.2(×2),170.0,169.9,169.6(×2),133.9,127.9,124.1,99.7,95.8,95.6,77.2,75.1,73.2,72.3,72.1,72.0,71.8,71.0,70.8,70.6,70.5,70.0,69.1,63.0(×2),62.6,62.4,62.2,61.1,60.3,52.1,49.3。
丁烯连接的双阿卡波糖(55)
通过一般程序进行乙酰化的炔丙基阿卡波糖14(1.00g,0.90mmol)和1,4-二叠氮丁烷(60mg,0.42mmol)的点击反应,得到固体的双阿卡波糖55(0.7g,70%);1H NMR(CDCl3,400MHz):δ=7.47(s,2H),5.87(d,2H,J=5.3Hz),5.53-5.43(m,4H),5.32-5.24(m,2H),5.21-5.12(m,6H),5.02(t,1H,J=10.3Hz),4.88-4.53(m,18H),4.51-4.16(m,12H),4.14-4.06(m,2H),3.91(t,2H,J=9.3Hz),3.87-3.82(m,4H),3.69-3.59(m,4H),3.44-3.39(m,2H),2.31(t,2H,J=9.9Hz),2.10(s,6H),2.06(s,6H),2.02(s,6H),1.97-1.86(m,54H)1.12(d,6H,J=6.2Hz);13C NMR(CDCl3,100MHz):δ=170.8,170.6,170.5,170.3,170.2(×2),170.1,170.0,169.9,169.7,169.5(×2),144.1,133.8,127.8,122.9,99.4,95.7,95.5,77.2,75.1,73.1,72.1,72.0,71.9,71.7,70.9,70.7,70.5,70.3,69.9,69.6,69.0,63.0,62.9,62.5,62.1,61.0,52.0,49.2,26.9,20,8,20.7,20.5(×2),20.4,18.0。
二乙烯醚连接的双阿卡波糖(56)
通过一般程序进行炔丙基阿卡波糖14(100mg,0.09mmol)和双(2-叠氮基乙基)醚(6.60mg,0.04mmol)的点击反应,得到固体的双阿卡波糖56(80mg,74%);1H NMR(CDCl3,400MHz):δ=7.55(s,2H),5.94(d,2H,J=4.7Hz),5.59-5.49(m,4H),5.39-5.29(m,1H),5.27-5.19(m,6H),5.09(t,1H,J=10.2Hz),4.96-4.85(m,4H),4.84-4.12(m,32H),3.98(t,2H,J=9.4Hz),3.94-3.66(m,12H),3.57-3.47(m,2H),2.45-2.33(m,2H),2.15(s,6H),2.12(s,6H),2.09(s,6H),2.04-1.93(m,54H),1.19(d,6H,J=6.0Hz)。
三乙烯醚连接的双阿卡波糖(57)
通过一般程序进行炔丙基阿卡波糖14(350mg,0.30mmol)和1,2-双(2-叠氮基乙氧基)乙烷(30mg,0.13mmol)的点击反应,得到固体的双阿卡波糖57(235mg,71%);1H NMR(CDCl3,400MHz):δ=7.62(s,2H),5.93(d,2H,J=5.2Hz),5.59-5.49(m,4H),5.37-5.29(m,2H),5.26-5.17(m,6H),5.07(t,2H,J=10.2Hz),4.93-4.86(m,4H),4.83-4.58(,12H),4.56-4.40(m,8H),4.38-4.22(m,4H),4.19-4.11(m,2H),4.00-3.79(m,10H),3.74-3.65(m,4H),3.54-3.44(m,4H),2.36(t,2H,J=10.0Hz),2.14(s,6H),2.12(s,6H),2.10(s,6H),2.04-1.91(m,54H),1.18(d,6H,J=6.2Hz);13C NMR(CDCl3,100MHz):δ=171.0,170.7,170.6,170.4,170.3(×2),170.2,170.0,169.9,169.7,169.6,143.8,133.9,128.0,124.0,99.44,95.8,95.6,77.2,75.3,73.4,72.2(×2),72.0,71.9,71.0,70.9,70.7,70.5,70.4,70.1,69.8,69.4,69.1,63.0,62.9,62.7,62.2,61.1,52.1,50.2,20.9,20.8,20.7,20.6(×2),20.5,18.1。
四乙烯醚连接的双阿卡波糖(58)
通过一般程序进行炔丙基阿卡波糖14(1.00g,0.85mmol)和双(2'-叠氮基乙氧基乙烷)醚(0.09mL,0.43mmol)的点击反应,得到固体的双阿卡波糖58(980mg,88%);1H NMR(CDCl3,400MHz):δ=7.63(s,2H),5.89(s,2H,J=5.4Hz),5.54-5.45(m,4H),5.32-5.25(m,2H),5.21-5.13(m,6H),5.04(t,2H,J=10.2Hz),4.90-4.53(m,16H),4.50-4.36(m,8H),4.34-4.18(m,4H),4.16-4.08(m,2H),3.92(t,2H,J=9.3Hz),3.88-3.77(m,8H),3.71-3.61(m,4H),3.56-3.40(m,12H),2.31(t,2H,J=9.9Hz),2.11(s,6H),2.08(s,6H),2.04(s,6H),1.99-1.86(m,54H),1.14(d,3H,J=6.2Hz);13C NMR(CDCl3,100MHz):δ=170.9,170.7,170.6(×2),170.4,170.3(×2),170.2,170.1,170.0,169.9,169.6(×2),143.6,133.8,128.0,124.0,99.2,95.7,95.5,77.2,75.2,73.3,72.1,72.0,71.8,71.0,70.8,70.6,70.4,70.3,70.0,69.7,69.2,69.0,62.9,62.7(×2),62.1,61.0,60.3,52.0,50.1,20.8,20.7,20.6(×2),20.5(×2),20.4,18.0。
五乙烯醚连接双阿卡波糖(59)
通过一般程序进行炔丙基阿卡波糖14(1.00g,0.85mmol)和1,2-双(2”-叠氮基-2'-乙氧基乙氧基)乙烷(0.12g,0.43mmol)的点击反应,得到固体的双阿卡波糖59(980mg,88%);1H NMR(CDCl3,400MHz):δ=7.61(s,2H),5.85(d,2H,J=5.1Hz),5.49-5.40(m,4H),5.28-5.20(m,2H),5.17-5.08(m,6H),4.99(t,2H,J=10.3Hz),4.83-4.75(m,4H),4.73-4.50(m,12H),4.46-4.30(m,8H),4.29-4.23(m,2H),4.18(dd,2H,J=3.9Hz,J=12.1Hz),4.10-4.03(m,2H),3.87(t,2H,J=9.2Hz),3.83-3.72(m,8H),3.66-3.57(m,4H),3.57-3.36(m,16H),2.27(t,2H,J=10.0Hz),2.06(s,6H),2.03(s,6H),1.99(s,6H),1.95-1.80(m,54H),1.09(d,3H,J=6.2Hz);13C NMR(CDCl3,100MHz):δ=170.8(×2),170.5,170.4,170.3(×2),170.2,170.1(×2),170.0,169.8,169.7,169.4(×2),143.4,133.6,127.8,123.9,99.0,95.6,95.4,77.2,75.1,73.2,72.0,71.8,71.6,70.9,70.7,70.5,70.2,70.1,69.8,69.6,69.1,68.9,62.8,62.6,62.5,62.0,60.9,60.1,51.9,50.0,20.7,20.6(×2),20.4(×3),20.3(×2),17.9。
乙酸酯和苯甲酰酯水解的一般程序
将30%的NH3水溶液(3-5mL)和低聚糖的甲醇溶液室温搅拌48小时。减压浓缩反应混合物,将粗物质溶于超纯水(5-10mL)中,用EtOAc(5×10mL)洗涤。浓缩水层,得到纯化合物。
乙烯连接的六聚体(60)
根据一般程序,化合物42(150mg,0.06mmol)的乙酸酯和苯甲酰酯水解得到寡糖60(96mg,98%);1H NMR(D2O,400MHz):δ=8.07(s,2H),7.92(s,2H),7.48(s,2H),5.26(d,2H,J=3.9Hz),4.90-4.60(m,16H),4.59-4.44(m,8H),4.41-4.31(m,4H),4.23-4.07(m,10H),3.94-3.60(m,18H),3.59-3.50(m,2H);13C NMR(D2O,400MHz);δ=103.5,99.0,92.4,79.5,75.5,74.8,71.6,70.9,70.4,69.8,68.0,67.5,63.1,62.4,61.9,51.2,43.6。
二乙烯连接的六聚体(61)
根据一般程序,化合物43(240mg,0.09mmol)的乙酸酯和苯甲酰酯水解得到低聚糖61(150mg,81%);1H NMR(D2O,400MHz):δ=8.09(s,2H,H-三唑),7.91(s,2H,H-三唑),7.51(s,2H,H-三唑),5.37(d,2H,J=4.3Hz),4.87-4.74(m,10H),4.68-4.63(m,12H),4.58-4,45(m,10H),4.43-4.32(m,10H),4.30-4.98(m,14H),4.00-3.51(m,26H);13C NMR(D2O,100MHz):δ=143.8,142.8,126.3,125.6,124.9,103.5,99.2,92.4,79.5,75.5,74.8,71.6,70.9,70.4,69.8,68.5,68.0,67.9,67.5,63.1,62.4,62.3,61.9,59.3,52.4,51.1,49.9,43.6。
乙烯连接的八聚体(62)
根据一般程序,化合物44(344mg,0.09mmol)的乙酸酯和苯甲酰酯水解得到低聚糖62(150mg,81%);1H NMR(D2O,400MHz):δ=8.10(s,2H,H-三唑),7.90(s,2H,H-三唑),7.59(s,2H,H-三唑),5.37(d,2H,J=4.0Hz),4.92-4.61(m,22H),4.57-4.43(m,10H),4.40-4.32(m,4H),4.28-4.07(m,14H),3.92-3.47(m,28H);13C NMR(D2O,100MHz):δ=143.8,143.4,142.9,126.3,126.0,125.6,125.0,103.5,99.1,99.0,79.5,75.5,74.9,71.6,71.4,70.9,70.4,69.8,68.0,67.9,67.5,63.2,62.4,62.3,61.9,59.1,52.4,51.1,51.0,49.9,43.6。
二乙烯连接的八聚体(63)
根据一般程序,化合物45(800mg,0.20mmol)的乙酸酯和苯甲酰酯水解得到寡糖63(400mg,94%);1H NMR(D2O,400MHz):δ=8.18,7.99,7.92,7.67(8×H-三唑),5.46(d,2H,J=4.1Hz),4.99-4.81(m,12H),4.77-4.68(m,6H),4.67-4.9(m,16H),4.48-4.40(m,4H),4.39-4.16(m,14H),4.02-3.55(m,32H);13C NMR(D2O,100MHz):δ=143.8,143.0(×2),126.3,126.0,125.6,124.9,103.5,99.4,99.0,92.5,79.5,75.5,74.9,71.6,71.4,70.9,70.4,69.8(×2),68.6,68.0,67.9(×2),67.5,63.2,62.4,62.3,61.9,59.1,52.4,51.1,50.0,43.6。
三乙烯连接的六聚体(64)
根据一般程序,化合物46(90mg,0.04mmol)的乙酸酯和苯甲酰酯水解得到寡糖64(44mg,85%);1H NMR(D2O,400MHz):δ=8.02(s,2H),7.87(s,2H),5.39(d,2H,J=3.8Hz),4.88-4.73(m,8H),4.60-4.45(m,10H),4.43-4.32(m,6H),4.20-4.08(m,8H),3.97-3.79(m,8H),3.78-3.68(m,8H),3.66-3.60(m,4H),3.57-3.49(m,4H);13C NMR(CDCl3,100MHz):δ=143.9,143.2,126.1,125.6,103.5,99.4,92.4,79.6,75.5,74.9,71.5,71.0,70.4,69.8,68.6,68.0,67.9,67.5,63.1,63.0,61.9,60.3,59.5,52.5,51.0,43.6。
化合物(65)
根据一般程序,化合物47(350mg,0.10mmol)的乙酸酯和苯甲酰酯水解得到寡糖65(120mg,65%);1H NMR(D2O,400MHz):δ=8.00(s,2H),7.85(×2),(s,4H),5.40(d,2H,J=4.02Hz),4.91-4.74(m,10H),4.59-4.44(m,10H),4.41-4.09(m,20H),3.96-3.67(m,20H),3.67-3.58(m,6H),3.56-3.46(m,4H);13C NMR(CDCl3,100MHz):δ=143.7,143.3,143.0,126.0(×2),125.6,103.5,99.5,98.9,92.4,79.6,75.4,74.9,71.5,71.4,71.0,70.4,69.8,68.0,67.9,67.8,67.5,63.2,62.2,61.9,59.5,59.1,52.6,51.1,51.0,43.6。
化合物(66)
根据一般程序,化合物48(150mg,0.04mmol)的乙酸酯和苯甲酰酯水解得到低聚糖66(47mg,59%);1H NMR(D2O,400MHz):δ=8.03(s,2H),7.90(s,2H),7.89(s,2H),5.40(d,2H,J=3.9Hz),4.91-4.08(m,12H),4.58-4.44(m,30H),3.97-3.40(m,32H);13C NMR(CDCl3,100MHz):δ=126.0,125.7,103.5,99.5,98.9,92.5,79.6,75.4,71.5,71.4,71.0,70.4,69.8,68.7,68.0,67.9,67.8,67.5,63.2,63.0,61.9,59.5,59.1,52.6,51.1,51.0,43.6。
乙烯连接的二麦芽三糖(67)
根据一般程序,化合物49(235mg,0.07mmol)的乙酸酯和苯甲酰酯水解得到低聚糖67(129mg,98%);1H NMR(D2O,400MHz):δ=8.20(s,2H),7.72(s,2H),5.46-5.36(m,6H),5.09-4.84(m,16H),4.70-4.61(m,4H),4.56(d,J=7.9Hz,4H),4.41(s,4H),4.05-3.54(m,66H),3.47(t,2H,J=9.3Hz),3.33(t,2H,J=8.3Hz);13C NMR(CDCl3,100MHz):δ=143.6,143.5,126.6,125.1,101.2,99.8,99.6,99.1,77.2,76.8,76.1,75.9,74.6,73.3,72.9,72.8,72.7,71.8,71.5,71.4,71.2,70.4,69.8,69.3,67.9,62.0,61.7,60.7,60.5,60.2,59.3,51.1,50.0。
二乙烯连接的二麦芽三糖(68)
根据一般程序,化合物50(150mg,0.05mmol)的乙酸酯和苯甲酰酯水解得到低聚糖68(70mg,86%);1H NMR(D2O,400MHz):δ=8.20(s,2H),7.71(s,2H),5.44(d,2H,J=3.9Hz),5.40(d,2H,J=4.0Hz),5.03,4.91(ABq,4H,J=12.8Hz),4.96-4.85(m,4H),4.66(dd,2H,J=8.4Hz,J=14.6Hz),4.62-4.54(m,6H),4.43(ABq,4H,J=12.7Hz),4.03-3.55(m,50H),3.47(t,2H,J=9.5Hz),3.33(dd,2H,J=8.0Hz,J=9.3Hz);13C NMR(CDCl3,100MHz):δ=143.5,143.2,126.5,124.9,101.2,99.8,99.6,99.5,77.2,76.8,76.1,74.6,73.3,72.9,72.8,72.7,71.8,71.5,71.4,71.2,70.4,69.8,69.3,68.5,67.9,61.7,60.7,60.5,59.7,51.1,50.0。
化合物(69)
根据一般程序,化合物51(150mg,0.08mmol)的乙酸酯水解得到低聚糖69(86mg,96%);1H NMR(D2O,400MHz):δ=8.05(s,1H),5.88-5.81(m,1H),5.42(d,1H,J=4.1Hz),5.31(d,1H,J=3.9Hz),5.26(d,1H,J=3.9Hz),4.93,4.85(ABq,2H,J=12.7Hz),4.49(dd,1H,J=0.9Hz,J=3.9Hz),4.48-4.35(m,3H),4.23-4.07(m,5H),4.05-4.00(m,1H),3.94-3.82(m,4H),3.82-3.63(m,12H),3.63-3.45(m,5H),3.28(dd,1H,J=8.1Hz,J=9.4Hz),2.70(t,1H,J=10.1Hz),1.31(d,3H,J=6.3Hz););13C NMR(D2O,100MHz):δ=143.4,141.8,126.4,120.5,103.5,100.9,99.9,99.6,92.5,79.5,77.4,77.1,76.2,75.6,74.9,74.6,73.3,72.8,72.6,72.5,71.5,71.3,71.2,71.0,70.9,69.3,69.0,67.8,67.5,64.2,63.1,61.9,61.7,61.4,60.7,60.5,56.1,52.5,43.6,17.3。
化合物(70)
根据一般程序,化合物52(150mg,0.08mmol)的乙酸酯水解得到寡糖70(86mg,96%);1H NMR(D2O,400MHz):δ=7.79(s,1H),5.88-5.81(m,1H),5.38(d,1H,J=4.1Hz),5.33(d,1H,J=4.0Hz),5.29(d,1H,J=3.8Hz),4.52-4.46(m,1H),4.42-4.33(m,3H),4.24-4.00(m,6H),3.99-3.42(m,25H),3.33-3.20(m,1H),2.88-2.71(m,2H),1.33(d,3H,J=6.2Hz)。
化合物(71)
根据一般程序,化合物53(340mg,0.14mmol)的乙酸酯水解得到低聚糖71(季铵化合物);1H NMR(D2O,400MHz):δ=7.89(s,1H),7.87(s,1H),7.79(s,1H),5.85-5.80(m,1H),5.33(d,1H,J=3.9Hz),5.30(d,1H,J=3.9Hz),5.25(d,1H,J=3.8Hz),4.93-4.76(m,3H),4.53-4.43(m,3H),4.40-4.23(m,6H),4.21-4.04(m,5H),4.04-3.95(m,1H),3.94-3.40(m,26H),3.28(dd,1H,J=8.2Hz,J=9.2Hz),2.70-2.58(m,3H),2.15(t,1H,J=7.0Hz),1.29(d,3H,J=6.2Hz);13C NMR(D2O,100MHz):δ=146.6,143.5,143.3,141.4,125.5,125.1,124.3,120.8,103.5,101.4,99.9,99.6,99.4,92.4,79.6,77.3,77.2,76.1,75.5,74.9,74.6,73.3,72.9,72.6,72.5,71.5,71.2,70.9,70.5,69.8,69.5,68.0,67.9,67.5,64.3,63.2,61.9,61.5,60.7,60.5,59.5,56.2,52.5,50.9,49.4,43.7,17.4。
乙烯连接的双阿卡波糖(72)
根据一般程序1,化合物54(93mg,37.9μmol)的乙酸酯水解得到双阿卡波糖化合物72(42mg,73%)。1H NMR(D2O,400MHz):δ=7.93(s,2H),5.93(s,2H),5.44-5.36(m,4H),5.07-4.84(m,8H),4.51(d,2H,J=8.0Hz)4.35-3.50(m,42H),3.35(t,2H,J=8.6Hz),3.23(t,2H,J=10.2Hz),2.21,2.14(m,2H),1.45(d,6H,6.1Hz);13C NMR(D2O,100MHz):δ=146.0,145.0,143.8,129.5,125.6,125.5,115.4,101.1,99.6(×2),77.4,77.1,76.1,74.5,73.2,72.9,72.3,71.7,71.5,71.1,70.5,68.7,67.0,65.0,63.0,61.7,61.2,60.6,60.5,56.4,50.0,17.4。
化合物(73)
根据一般程序2,化合物55(0.56g,0.22mmol)的乙酸酯水解得到双阿卡波糖化合物73(0.33mg,99%)。1H NMR(D2O,400MHz):δ=8.05(s,1H),5.94-5.88(m,1H),5.39(d,1H,J=3.9Hz),5.33(d,1H,J=3.7Hz),4.99,4.87(ABquat.2H,J=12.6Hz),4.57(d,1H,J=8.1Hz),4.50-4.40(m,1H),4.25,4.17(ABquat.2H,J=14.1Hz),4.08(d,1H,J=6.3Hz),4.00-3.55(m,17H),3.35(t,1H,J=8.5Hz),2.66(t,1H,J=9.9Hz),1.38(d,1H,J=6.4Hz);13C NMR(D2O,100MHz):δ=143.6,140.8,125.2,121.5,101.4,100.0,99.6,77.4,77.2,76.1,74.6,73.3,72.9,72.6,71.9,71.5,71.2,71.0,69.9,68.4,64.5,62.0,61.5,60.7,60.6,56.2,49.7,17.4。
化合物(74)
根据一般程序1,化合物56(60mg,24μmol)的乙酸酯水解得到双阿卡波糖化合物74(22mg,61%)。1H NMR(D2O,400MHz):δ=7.12(s,1H),5.16-5.12(m,1H),4.62(d,1H,J=4.0Hz),4.56(d,1H,J=3.6Hz),4.21,4.08(ABquat.2H,J=12.7Hz),3.83-3.76(m,3H),3.48,3.38(ABquat.2H,J=14.2Hz),3.30(d,1H,J=6.6Hz),3.22-2.79(m,22H),2.58(dd,1H,J=8.0Hz,J=9.4Hz),1.85(t,1H,J=9.7Hz),1.37(d,3H,J=6.4Hz);13C NMR(D2O,100MHz):δ=143.4,140.4,125.5,122.1,101.4,99.9,99.5,77.2,77.1,76.1,74.6,73.3,72.9,72.7,72.6,72.1,71.55,71.2,71.0,70.0,68.7,68.5,64.6,61.9,61.5,60.7,60.5,56.1,50.0,30.3,17.3。
化合物(75)
根据一般程序1,化合物57(0.24g,94μmol)的乙酸酯水解得到双阿卡波糖化合物75(0.15mg,99%)。1H NMR(D2O,400MHz):δ=8.00(s,1H),5.86-5.82(m,1H),5.32(d,1H,J=3.8Hz),5.25(d,1H,J=3.4Hz),4.92,4.80(ABquat.2H),4.56-4.47(m,2H),4.17,4.06(ABquat.,2H,J=13.7Hz),3.98(d,1H,J=6.9Hz),3.91-3.43(m,22H),3.26(dd,1H,J=8.0Hz,J=9.4Hz),2.41(t,1H,J=9.5Hz),1.28(d,3H,J=6.3Hz);13C NMR(D2O,100MHz):δ=143.5,138.9,125.7,123.8,101.3,100.0,99.5,77.1,77.0,74.6,73.3,73.0,72.9(×2),72.7,71.4,71.2(×2),70.8,69.6,68.7,64.9,61.9,61.6,60.7,60.5,56.0,50.1,17.3。
化合物(76)
根据一般程序2,化合物58(0.44g,170μmol)的乙酸酯水解得到双阿卡波糖化合物76(0.26g,99%)。1H NMR(D2O,400MHz):δ=8.13(s,1H),5.96-5.92(m,1H),5.42(d,1H,J=3.9Hz),5.36(d,1H,J=3.8Hz),5.01,4.88(ABquat.2H,J=12.7Hz),4.69-4.63(m,2H),4.60(d,1H,J=7.9Hz),4.28,4.19(ABquat.2H,J=14.2Hz),4.11(d,1H,J=6.1Hz),4.05-3.56(m,24H),3.36(dd,1H,J=8.0Hz,J=9.4Hz),2.67(t,1H,J=9.7Hz),1.40(d,3H,J=6.2Hz);13C NMR(D2O,100MHz):δ=143.5,140.7,125.7,121.7,101.3,99.9,99.6,77.2,77.1,74.6,73.3,72.9,72.6,72.0,71.5,71.2,71.0,69.9,69.7,69.6,69.4,68.7,68.5,64.5,61.9,61.5,60.7,60.5,56.1,50.1,17.4。
化合物(77)
根据一般程序2,化合物59(0.84g,319μmol)的乙酸酯水解得到双阿卡波糖化合物77(0.26g,99%)。1H NMR(D2O,400MHz):δ=8.15(s,1H),5.96-5.92(m,1H),5.42(d,1H,J=4.0Hz),5.36(d,1H,J=3.7Hz),5.03,5.90(ABquat.2H,J=12.5Hz),4.70-4.65(m,2H),4.60(d,1H,J=8.0Hz),4.28,4.18(ABquat.2H,J=14.3Hz),4.10(d,1H,J=6.2Hz),4.06-3.56(m,25H),3.37(dd,1H,J=8.0Hz,J=9.4Hz),2.66(t,1H,J=9.7Hz),1.40(d,3H,J=6.3Hz);13C NMR(D2O,100MHz):δ=143.5,140.5,125.7,121.9,101.3,99.9,99.6,66.2,77.1,76.1,74.6,73.3,72.9,72.7,72.1,71.5,71.2,71.0,70.0,69.7,69.6,69.5,69.2,68.7,68.6,64.6,61.9,61.5,60.7,60.5,56.1,50.0,17.4。
合成SO3.Py的过程
在0℃,向吡啶(4mL)的DCM(20mL)溶液中逐滴加入氯磺酸(1.6mL)并将混合物搅拌30分钟。然后过滤反应混合物,用冰冷的水(3×20mL)、冰冷饱和NaHCO3(2×10mL)、冰冷水(2×10mL)(直至滤液的pH为7)、冷EtOH(2×20mL)、冷甲苯(10mL)和冷DCM(10mL)洗涤沉淀。然后将沉淀的SO3.Py在高真空下彻底干燥并在24小时内使用。
硫酸化的一般程序1
将新制备的SO3.Py(10当量/OH)络合物加入到原料的无水DMF(10mL)的溶液中,该溶液保持在氮气氛下。将反应混合物在室温下搅拌2天,用5M NaOH(2当量/SO3.Py)使其呈碱性。然后将混合物减压浓缩,将粗物质溶于超纯水(10-20mL)中,并按照一般程序透析。
硫酸化的一般程序2
将新制备的SO3.Py(10当量/OH)络合物加入到原料的无水DMF(10mL)的溶液中,该溶液保持在氮气氛下。将反应混合物在室温下搅拌2天。然后从反应混合物中倾析出DMF,将沉淀的物质溶于超纯水(10mL)中,用5M NaOH(PH=9-11)使其呈碱性,然后根据一般程序透析溶液。
透析的一般程序
商购的MWCO为0.5KD、1KD和2KD的纤维素膜透析管用于透析。在使用前用miliQ水洗涤透析管(约洗涤5-10分钟)。透析管的一端是打结的,将样品装入管中。然后用夹子封闭管子,留下很小的气泡空间。在室温下,将装有搅拌子的3L烧瓶装入miliQ水并置于磁力搅拌板上。设置搅拌,使透析袋在烧瓶中围绕溶液的顶部缓慢地漂浮。2小时后,所述水用新鲜的miliQ水代替,继续透析2天,每18小时更换透析水。然后从烧瓶中取出透析袋,收集袋中的内容物并冷冻干燥。
硫酸化乙烯连接的六聚体(78)
按照一般程序1,硫酸化脱保护六聚体60(60mg,0.04mmol),之后透析,得到六聚体78(46mg,51%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.17(s,1H),8.06(s,2H),7.66(s,2H),5.75(d,2H,J=3.6Hz),5.33(d,2H,J=7.6Hz),5.16-5.11(m,2H),5.09-5.01(m,4H),5.00-5.78(m,20H),4.77-4.56(m),4.53-4.44(m,4H),4.39-4.10(m,12H),3.94,3.85(ABq,4H,J=12.5Hz);13C NMR(D2O,100MHz):δ=143.8,143.2,126.2,125.6,125.2,103.6,96.3,90.9,79.5(×2),78.3,75.1,73.5,72.7,72.4,71.4,70.6,70.3,68.5,67.9,62.4,60.3,60.0,52.8,51.0,49.8,43.9。
硫酸化二乙烯连接的六聚体(79)
按照一般程序1,硫酸化去保护的六聚体61(80mg,0.05mmol),之后透析,得到了六聚体79(90mg,60%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.22(s,2H),8.08(s,2H),7.86(s,2H),5.74(d,2H,J=3.6Hz),5.74(d,2H,J=3.6Hz),5.29(d,2H,J=7.6Hz),5.18-5.14(m,2H),5.10-5.96(m,4H),4.96-4.84(m,8H),4.83-4.54(m),4.54-4.41(m,8H),4.37(s,4H),4.29-4.09(m,6H),3.91,3.82(ABq,4H,J=12.8Hz),3.83-3.72(m,4H)。
硫酸化乙烯连接的八聚体(80)
按照一般程序1,硫酸化脱保护的八聚体62(50mg,0.02mmol),之后透析,得到八聚体80(56mg,59%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.26(s,2H),8.13(s,2H),8.08(s,2H),7.92(s,2H),5.82(d,2H,J=3.5Hz),5.39(d,2H,J=7.6Hz),5.29-5.16(m,8H),5.15-5.04(m,10H),5.04-4.93(m,18H),4.93-4.59(m),4.59-4.13(m,30H),3.99,3.91(ABq,4H,J=12.6Hz)。
硫酸化二乙烯连接的八聚体(81)
按照一般程序1,硫酸化脱保护的八聚体63(20mg,0.01mmol),之后透析,得到了六聚体81(36mg,91%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.22(s,2H),8.07(2×s,4H),7.92(s,2H),5.79(s,2H),5.34(d,2H,J=7.4Hz),5.21(s,4H),5.13-4.12(m,72H),3.91,3.82(ABq,4H,J=12.6Hz),3.87-3.82(m,4H)。
化合物(82)
按照一般程序1,硫酸化脱保护的六聚体64(30mg,0.02mmol),之后透析,得到六聚体82(37mg,64%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.28(s,2H),8.05(s,2H),5.85(d,2H,J=3.5Hz),5.38(d,2H,J=7.8Hz),5.31-5.27(m,2H),5.16-4.84(m,20H),4.84-4.74(m),4.74-4.60(m,10H),4.54(t,2H,J=9.5Hz),4.45(s,4H),4.38-4.30(m,4H),4.26(dd,2H,J=4.5Hz,J=10.6Hz),3.99,3.91(ABq,4H,J=12.4Hz),3.71(s,4H);13C NMR(D2O,100MHz):δ=125.9,103.4,96.6,90.8,79.4,79.3,78.1,75.1,73.5,72.7,72.4,71.3,70.0,68.8,68.3,67.7,63.0,60.2,60.0,52.9,50.8,43.8。
化合物(83)
按照一般程序1,硫酸化脱保护的六聚体65(68mg,0.04mmol),之后透析,得到六聚体83(21mg,16%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.23(s,2H),8.17(s,2H),8.06(s,2H),5.87(s,2H,J=3.6Hz),5.38(d,2H,J=7.8Hz),5.30(d,2H,J=1.5Hz),5.26(d,2H,J=1.8Hz),5.16-4.86(m,22H),5.86-4.62(m),4.61-4.49(m,8H),4.46(s,4H),4.42-4.22(m,8H),4.00,3.92(ABq,4H,J=12.4Hz);13C NMR(D2O,100MHz):δ=143.6,143.1,143.0,126.5,126.3,125.8,103.4,96.5,96.4,90.8,79.4,79.3,78.1,75.1,73.5,72.7,72.6,72.5,71.3,69.9,68.3,67.6,62.4,60.4,60.2,60.0,52.9,50.8,50.6,43.8。
化合物(84)
按照一般程序1,硫酸化脱保护的六聚体66(30mg,0.02mmol),然后透析,得到六聚体84(25mg,41%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.24(br s,2H),8.15(s,2H),8.05(s,2H),5.86(d,2H,J=3.6Hz),5.38(d,2H,J=7.8Hz),5.31-5.28(m,2H),5.26-5.22(m,1H),5.17-4.83(m,30H),4.83-4.74(m),4.75-4.61(m,12H),4.60-4.48(m,8H),4.47-4.40(4H),4.39-4.22(m,10H),4.00,3.92(ABq,4H,J=12.4Hz),3.75(s,4H)。
硫酸化乙烯连接二麦芽三糖(85)
按照一般程序1,硫酸化脱保护的六聚体67(100mg,0.06mmol),之后透析,得到了六聚体85(70mg,27%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.30(s,2H),7.94(s,2H),5.74-5.67(m,2H),5.64-5.56(m,2H),5.32-4.88(m,25H),4.67-4.10(m,40H);13C NMR(CDCl3,100MHz):δ=126.9,125.3,99.4,96.4,94.4,93.8,76.2,75.1,74.8,73.5,73.0,72.8,72.6,71.8,71.7,70.3,69.9,67.8,66.5,66.0,61.9,61.2,51.0,49.8。
硫酸化二乙烯连接的二麦芽三糖(86)
按照一般程序1,硫酸化脱保护的六聚体68(70mg,0.04mmol),之后透析,得到六聚体86(40mg,23%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.32(s,2H),8.02(s,2H),5.70(d,2H,J=3.2Hz),5.61(d,2H,J=3.6Hz),5.26(s,2H),5.21-5.04(m,6H),5.03-4.67(20H),4.67-4.08(m,40H);13C NMR(CDCl3,100MHz):δ=127.0,125.6,99.4,96.3,94.3,93.5,76.3,75.1,74.6,73.5,72.9,72.7,72.5,71.5,71.4,70.3,69.7,68.9,67.8,66.5,65.9,61.8,60.0,57.4,51.2,50.3。
硫酸化的五聚体(87)
按照一般程序1,硫酸化脱保护的五聚体69(41mg,0.04mmol),之后透析,得到五聚体87(63mg,59%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.17(s,1H),6.15(s,1H),5.89(d,1H,J=3.6Hz),5.72-5.52(m,3H),5.40(d,1H,J=7.8Hz),5.26-4.86(m,16H),4.74-4.58(m,5H),4.57-4.06(m,16H),4.00,3.93(ABq,2H,J=12.2Hz),1.55(d,3H,J=6.2Hz)。
化合物(88)
按照一般程序1,硫酸化脱保护的五聚体71(210mg,0.15mmol),之后透析,得到五聚体88(70mg,20%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.13(s,1H),8.04(s,1H),8.03(s,1H),6.19(s,1H),5.86(d,1H,J=3.6Hz),5.70(d,1H,J=2.7Hz),5.64-5.57(m,2H),5.39(d,1H,J=7.8Hz),5.35-5.27(m,2H),5.17-4.85(m,16H),4.86-4.60(m),4.62-4.08(m,20H),4.01,3.93(ABq,2H),3.93-3.83(m,1H),2.84-2.74(m,2H),2.32(t,2H,J=7.1Hz),1.64(d,3H,J=6.2Hz);13C NMR(CDCl3,100MHz):δ=146.8,143.6,142.9,134.2,125.8,125.5,124.5,120.9,103.4,99.3,96.6,94.3,93.7,90.9,79.4,78.1,76.2,75.8,75.2,73.6,73.4,72.7,72.4,72.3,71.5,71.3,70.1,70.0,69.8,68.4,67.8,67.6,67.4,66.3,62.0,60.3,60.0,52.9,52.7,50.7,49.6,43.9,29.0,21.6,18.1。
硫酸化乙烯连接的双阿卡波糖(89)
按照一般程序2,硫酸化脱保护的八聚体72(110mg,0.07mmol),之后透析,得到六聚体89(69mg,25%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.15(s,2H),6.18(s,2H),5.68(s,2H),5.59(s,4H),5.32(s,2H),5.20-4.57(m),4.59-4.07(m,20H),4.03-3.92(m,2H),1.63(d,6H,J=6.2Hz)。
硫酸化的双阿卡波糖(90)
按照一般程序1,硫酸化脱保护的八聚体73(10mg,0.007mmol),之后透析,得到六聚体90(20mg,74%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.18(s,2H),6.16(s,2H),5.69(d,2H,J=3.7Hz),5.62(d,2H,J=3.7Hz),5.58(dd,2H,J=1.6Hz,J=4.2Hz),5.22-5.15(m,2H),5.12-4.94(m,10H),4.93-4.66(m),4.66-4.59(m,2H),4.59-4.42(m,12H),4.40-4.22(m,8H),4.22-4.10(m,4H),4.07-3.95(m,2H),3.20(t,2H,J=8.7Hz),1.53(d,6H,J=6.2Hz);13C NMR(CDCl3,100MHz):δ=143.8,129.5,125.6,99.3,94.3,94.1,78.6,76.7,76.3,75.5,74.8,73.1,72.6,72.5,71.9,71.6,70.9,70.1,69.9,69.4,68.3,67.7,66.5,62.2,59.3,50.1,49.8,18.6。
硫酸化二乙烯连接的双阿卡波糖(91)
按照一般程序1,硫酸化脱保护的八聚体74(55mg,0.04mmol),之后透析,得到六聚体91(47mg,30%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.13(s,2H),6.15(s,2H),5.67(d,2H,J=3.7Hz),5.61(d,2H,J=3.3Hz),5.57(d,2H,J=3.7Hz),5.2-5.12(m,2H),5.11-4.94(m,12H),4.92-4.55(m),4.54-4.40(m,8H),4.38-4.18(m,8H),4.17-4.06(m,4H),4.03-3.90(m,6H),3.11(t,2H,J=9.0Hz),1.51(d,6H,J=6.0Hz);13C NMR(CDCl3,100MHz):δ=143.8,130.6,129.0,125.8,99.4,94.4,94.1,78.7,76.7,75.4,74.9,72.9,72.6,72.4,71.9,71.6,71.0,70.1,69.7,68.8,68.4,67.7,66.6,62.2,59.4,18.6。
硫酸化的双阿卡波糖(92)
按照一般程序1,硫酸化脱保护的八聚体75(50mg,0.03mmol),之后透析,得到六聚体92(60mg,53%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.18(s,2H),6.14(s,2H),5.67(d,2H,J=3.1Hz),5.59(d,2H,J=2.7Hz),5.57-5.52(m,2H),5.22-5.14(m,2H),5.14-5.55(m),4.55-4.38(m,6H),4.37-4.18(m,8H),4.18-4.04(m,4H),4.02-3.90(m,4H),3.74-3.57(m,4H),3.45-3.27(m,2H),1.54(d,6H,J=6.0Hz)。
硫酸化的双阿卡波糖(93)
按照一般程序2,硫酸化脱保护的八聚体76(170mg,0.11mmol),之后透析,得到六聚体93(142mg,32%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.22(s,2H),6.22(s,2H),5.72-5.57(s,4H),5.41-5.31(m,2H),5.22-4.95(10H),4.63-4.49(m,6H),4.49-4.14(m,12H),4.11-3.93(m,4H),3.74-3.58(m,6H),1.67(d,3H,J=6.3Hz);13C NMR(CDCl3,100MHz):δ=143.8,134.8,127.5,125.9,120.0,99.00,94.3,94.1,99.01,94.3,94.1,77.7,76.2,75.9,73.8,73.5,73.3,72.8,72.3,71.5,71.4,70.1,69.7,69.4,68.8,67.6,67.3,66.3,66.0,61.8,53.1,50.2,18.1。
硫酸化的双阿卡波糖(94)
按照一般程序2,硫酸化脱保护的八聚体77(250mg,0.16mmol),之后透析,得到六聚体94(390mg,60%),其为白色粉末;1H NMR(D2O,400MHz):δ=8.20(s,2H),6.15(s,2H),5.66(d,2H,J=3.3Hz),5.59(d,2H,J=3.4Hz),5.58-5.54(m,2H),5.23-5.13(m,2H),5.13-4.92(m,12H),4.55-4.38(m,9H),4.38-3.93(m,20H),3.78-3.57(m,12H),3.47-3.26(m,2H),1.55(d,6H,J=6.1Hz););13C NMR(CDCl3,100MHz):δ=143.9,130.8,125.8,99.3,94.1,76.5,75.6,74.4,73.1,72.4,72.3,71.6,70.6,70.0,69.6,69.5,69.4,69.2,68.8,68.5,68.0,67.7,66.4,62.1,59.1,50.8,50.0,18.4。
实施例25
BIAcore筛选试验
表面等离子体激元共振的光学现象用于监测分子之间的物理相互作用。将潜在蛋白质配体(例如IL-4、IL-5、IL-6、IL-13、嗜酸性粒细胞趋化因子-1、嗜酸性粒细胞趋化因子-2、IL-8或MCP-1)的溶液通过与靶标(例如肝素)连接的传感器表面,监测蛋白质配体与固定化靶标的实时结合。通过测量非常靠近传感器表面的折射率变化来实现检测。当折射率改变时,等离子体激元共振发生的角度改变,并且这种改变直接关联与表面相互作用的蛋白质的量。BIAcore T200使用方便。它非常灵敏,其微流体确保只需要少量的材料。
生物素化的肝素固定在生物传感器芯片上。使用磺基-NHS-生物素,生物素化通过氨基发生,或通过由还原胺化用氨改性的还原末端发生。将含有目标潜在蛋白质配体的溶液注射到传感器芯片表面上,并实时测量结合(Fernig,In:Proteoglycan protocols,Ed.R.V.Iozzo,Humana Press,Totowa,NJ,USA,2001)。杆状病毒表达的重组人IL-5(rhIL-5)易于与通过该方法固定的肝素结合(参见PCT/AU2005/000551)。类似地,结合是特异性的,因为IL-5与缺乏肝素的传感器芯片几乎没有相互作用。
实施例26
对哮喘靶蛋白IL-13的简化硫酸化糖缀合物的功能分析
各种简化的硫酸化糖缀合物以不同程度抑制IL-13应答细胞系的增殖。这在非常低的剂量下发生,并且据信不是由于糖缀合物的毒性作用,因为在相同浓度的IL-13和多糖下,其他类似的硫酸化多糖(例如蔗糖八硫酸盐)没有效果。这些实验利用在2ng/ml重组人(rh)GM-CSF中生长的TF-1细胞,TF-1细胞最初是从患有严重全血细胞减少症的男性骨髓样品确定的。这些细胞依赖于IL-3或GM-CSF进行长期生长,并且对包括IL-13在内的多种人细胞因子有反应。
简言之,在适合于此类测定的96孔微孔板中进行增殖测定。常规地,在测定前将细胞在低剂量rhGM-CSF(0.1ng/ml)中培养24小时。洗涤细胞以除去生长培养基中的任何细胞因子,然后重悬浮于RPMI/5%w/v FCS中,并且常规地将2.5×104个细胞加入到不含rhIL-13(阴性对照)或各种rhIL-13稀释液的微孔板的孔中。常规地从25ng/ml的起始浓度滴定rhIL-13。当测量不同简化的硫酸化糖缀合物的效果时,所述孔还含有各种浓度的这些分子(10μg/ml和2.5μg/ml),并且rhIL-13浓度恒定保持在4ng/ml。细胞增殖48小时,之后通过用CellTiter 96Aqueous One中每孔20μL染色来定量存在的细胞数。将试剂与TF1细胞一起培养最后3.5至4小时,然后在Enspire多模板读取器(PerkinElmer)上读取490nm处的吸光度。这些数据显示在图1中。从这些数据中可以清楚地看出,不同的糖缀合物结构在不同程度上抑制IL-13刺激的细胞增殖。
用TF-1.8细胞也可以做这些实验。TF-1.8细胞是已被选择用于在IL-4或IL-5中生长的TF-1细胞的亚克隆。用表达载体pPGK-嘌呤霉素-荧光素酶中含有的萤火虫荧光素酶基因转染TF-1.8细胞(Coombe等(1998)Journal of Immunological Methods 215:145-150)。克隆阳性转染子以产生具有良好荧光素酶表达的品系。增殖测定在适合于此类测定的96孔微孔板(Falcon)中进行。这些孔是平底的,有白色的边和清晰的底部。该测定如前针对TF1细胞和IL-13所述,不同之处在于使用10ng/ml的rhIL-13,并且通过测量荧光素酶活性来定量增殖48小时后的细胞数。通过添加50μl荧光素酶底物缓冲液(50mM Tris-HCl,pH7.8,15mM MgSO4,33.3mM DTT,0.1mM EDTA,0.5mM荧光素钠,0.5mM ATP,0.25mM Li Co A和0.5%v/v Triton X-100)测量荧光素酶活性。在加入荧光素酶缓冲液后立即测定所述板的荧光素酶活性。在Enspire多模板读取器(PerkinElmer)上检测光发射。该测定的数据显示在图8中,并且从该图中可以清楚地看出,选择的糖缀合物是IL-13刺激的细胞增殖的非常有效的抑制剂,而不同结构的糖缀合物不那么有效。
实施例27
简化硫酸化糖缀合物对哮喘和过敏性鼻炎靶蛋白IL-5的功能分析
各种简化的硫酸化糖缀合物以不同程度抑制IL-5应答细胞系的增殖。这发生在非常低的剂量下并且不是由于糖缀合物的毒性作用,因为其他类似的硫酸化多糖在该测定中没有效果。用IL-5应答细胞Ba/F-IL-5进行这些实验。Ba/F-IL-5细胞来源于Ba/F3细胞系。通过用pGL3对照载体(Promega,USA)和pEE6hcmv-IL-5Rα共转染细胞,将Ba/F3细胞系转化为IL-5依赖性的,并表达荧光素酶。对照载体pGL3在SV40启动子和增强子的直接控制下表达修饰的荧光素酶,但不含可选择的标记物。为了制备pEE6hcmv-hIL-5Rα,通过RT PCR从HL60细胞克隆全长人IL-5受体α链(hIL-5R-α)。Coombe等人(1998,同上)描述了Ba/F-IL-5细胞的制备。Ba/F-IL-5细胞可以通过与pPGK-嘌呤霉素-荧光素酶共转染进一步修饰,pPGK-嘌呤霉素-荧光素酶是含有荧光素酶的载体,其受具有可选择标记物嘌呤霉素的SV40启动子控制。
转染后,在3μg/mL嘌呤霉素中选择阳性转染子。然后克隆阳性转染子以产生具有可检测的荧光素酶表达的品系。增殖测定在适合于此类测定的96孔微孔板中进行。这些孔是平底的,有白色的边和清晰的底部。洗涤细胞以除去生长培养基中的任何细胞因子,然后重悬浮于RPMI/5%w/v FCS中。用Coulter Z2粒子计数器和尺寸分析仪(CoulterElectronics,England)计数细胞,并常规地将1.6×104个细胞加入不含rhIL-5(阴性对照)或各种rhIL-5稀释液的微孔板的孔中。当要测量硫酸化糖缀合物或其他硫酸化多糖的效果时,所述孔还含有各种浓度的这些分子。
细胞在37℃下在潮湿的气氛中增殖24小时,之后通过加入50μl荧光素酶底物缓冲液(50mM Tris-HCl,pH 7.8,15mM MgSO4,33.3mM DTT,0.1mM EDTA,0.5mM荧光素钠,0.5mMATP,0.25mM Li Co A和0.5%v/v Triton X-100)来测量荧光素酶活性。在加入荧光素酶缓冲液后立即测定所述板的荧光素酶活性。在Enspire多模板读取器(PerkinElmer)上检测光发射。使用该测定法已经证明,一些简化的硫酸化糖缀合物是rhIL-5依赖性的Ba/F-IL-5细胞增殖的非常有效的抑制剂,而其他的则不那么有效。这些数据显示在图2和图9中,肝素和蔗糖八硫酸盐分别用作阳性和阴性对照。
实施例28
简化的硫酸化糖缀合物对哮喘和COPD靶蛋白IL-4的功能分析
各种简化的硫酸化糖缀合物以不同程度抑制IL-4应答细胞系的增殖。这在非常低的剂量下发生且不是由于糖缀合物的毒性效果,因为在相同浓度的IL-4和多糖下其他类似的硫酸化多糖(蔗糖八硫酸盐)没有效果。这些实验利用在2ng/ml重组人(rh)GM-CSF中生长的TF-1细胞。TF-1细胞最初是从患有严重全血细胞减少症的男性骨髓样品确定的。这些细胞依赖于IL-3或GM-CSF进行长期生长,并且对包括人IL-4在内的多种人细胞因子有反应。
简言之,在适合于此类测定的96孔微孔板中进行增殖测定。常规地,在测定前将细胞在低剂量rhGM-CSF(0.1ng/ml)中培养24小时。洗涤细胞以除去生长培养基中的任何细胞因子,然后重悬浮于RPMI/5%w/v FCS中,并且常规地将2.5×104个细胞加入到不含rhIL-4(阴性对照)或各种rhIL-4稀释液的微孔板的孔中。常规地,从25ng/ml的起始浓度滴定rhIL-4。当测量不同简化的硫酸化糖缀合物的效果时,所述孔还含有各种浓度的这些分子(10μg/ml和2.5μg/ml),并且rhIL-4浓度恒定保持在4ng/ml。细胞增殖48小时,之后通过用CellTiter 96Aqueous One每孔20μL染色来定量存在的细胞数。将试剂与TF1细胞一起培养最后3.5至4小时,然后在Enspire多模板读取器(PerkinElmer)上读取490nm处的吸光度。
在图3所示实施例的两种糖缀合物中,一种是比另一种更有效的抑制剂,活性较低的糖缀合物需要较高浓度才能获得良好的活性。
用TF-1.8细胞也可以进行这些实验。TF-1.8细胞是已被选择用于在IL-4或IL-5中生长的TF-1细胞的亚克隆。用表达载体pPGK-嘌呤霉素-荧光素酶中含有的萤火虫荧光素酶基因转染TF-1.8细胞(Coombe等(1998)同上)。克隆阳性转染子以产生具有良好荧光素酶表达的品系。增殖测定在适合于此类测定的96孔微孔板(Falcon)中进行。这些孔是平底的,有白色的边和清晰的底部。该测定如前面针对TF1细胞和IL-4所述,不同的是使用1ng/ml的rhIL-4,并且通过测量荧光素酶活性来定量增殖48小时后的细胞数。通过添加50μl荧光素酶底物缓冲液(50mM Tris-HCl,pH 7.8,15mM MgSO4,33.3mM DTT,0.1mM EDTA,0.5mM荧光素钠,0.5mM ATP,0.25mM Li Co A和0.5%v/v Triton X-100)测量荧光素酶活性。在加入荧光素酶缓冲液后立即测定所述板的荧光素酶活性,在Enspire多模板读取器(PerkinElmer)上检测光发射。该测定的数据显示在图10中,从该图中可以清楚地看出,一些糖缀合物是IL-4刺激的细胞增殖非常有效的抑制剂,然而不同结构的糖缀合物不那么有效。
实施例29
简化的硫酸化糖缀合物对骨关节炎和COPD以及ARDS靶蛋白(IL-1β和IL-6)的功能分析
各种简化的硫酸化糖缀合物以不同程度抑制IL-1β应答细胞系的增殖,然而,几乎没有检测到IL-6活性的抑制。IL-1β活性的抑制在非常低的剂量下发生,并且据信不是由于糖缀合物的毒性作用,因为在相同浓度的IL-1β和多糖下,其他类似的硫酸化多糖没有效果。这些实验利用在2ng/ml rhGM-CSF中生长的TF-1细胞,TF-1细胞最初是从患有严重全血细胞减少症的男性骨髓样品确定的。这些细胞长期生长依赖于IL-3或GM-CSF,并且对包括人IL-1β和人IL-6的多种细胞因子有反应。
简言之,在适合于此类测定的96孔微孔板中进行增殖测定。常规地,在测定前将细胞在低剂量rhGM-CSF(0.1ng/ml)中培养24小时。洗涤细胞以除去生长培养基中的任何细胞因子,然后重悬浮于RPMI/5%w/v FCS中,常规地将2.5×104个细胞加入到不含细胞因子(IL-1β或IL-6(阴性对照))或这些细胞因子的各种稀释液的微孔板的孔中。常规地,这些细胞因子从25ng/ml的起始浓度滴定。当测量不同简化的硫酸化糖缀合物的效果时,所述孔也含有各种浓度的这些分子,且细胞因子浓度保持恒定。rhIL-1β浓度恒定保持在2ng/ml。细胞增殖48小时,之后通过用CellTiter 96Aqueous One中每孔20μL染色来定量存在的细胞数量。将试剂与TF1细胞一起培养最后3.5至4小时,然后在Enspire多模板读取器(PerkinElmer)上读取490nm处的吸光度。
在实施例中的两种糖缀合物中,一种是比另一种更有效的rhIL-1β抑制剂,并且两种糖缀合物都不能令人信服地抑制rhIL-6诱导的细胞增殖。这些数据显示在图4和图5中。这些实验表明,具有不同结构的硫酸化糖缀合物与不同的细胞因子不同地结合,或具有不同的活性水平。rhIL-6未被抑制的事实(图4)也表明测试的硫酸化糖缀合物对这些细胞无毒。
实施例30
简化的硫酸化糖缀合物对促炎细胞因子(TNF-α)的功能分析
TNF-α是促炎细胞因子,参与COPD、ARDS以及骨关节炎和其他炎症性疾病。各种简化的硫酸化糖缀合物抑制hTNFα诱导的髓单核细胞白血病细胞系U937的细胞凋亡。通过Apo-ONE Homogenous Caspase-3/7测定试剂盒(Promega)监测细胞凋亡。该试剂盒测量胱天蛋白酶-3和胱天蛋白酶-7的活性。它们是半胱氨酸天冬氨酸特异性蛋白酶(胱天蛋白酶)家族的成员,并且在哺乳动物细胞的凋亡中起关键效应子作用。该试剂盒由缓冲液和底物组成,缓冲液和底物在使用当天组合。缓冲液快速有效地溶解培养的细胞,并支撑最佳的胱天蛋白酶-3/7酶活性。非荧光底物Z-DEVD-R110(罗丹明110)被胱天蛋白酶-3/7裂解,除去DEVD肽以产生荧光罗丹明110。
U937细胞在含有10%热灭活的胎牛血清(FBS)的无酚红的RPMI1640中培养。它们在使用前至少7小时进行传代培养,以使细胞同步并降低可变性。将重组人TNFα在室温下与96孔板的孔中稀释的抑制剂(总体积25μl)一起预孵育3小时。然后向孔中加入25μl的U937细胞[细胞数2×104],并且将25μl培养基加入仅限培养基的孔中,得到在所有孔中50μl的总体积50μl,并在37℃下孵育16小时。在Apo-ONE试剂盒提供的缓冲液中,制备Apo-ONE底物(稀释1/250)。向所有孔中加入50μl的Apo-ONE底物的缓冲液溶液,混合并在室温下孵育30分钟。读取EnSpire多模板读取器上485/535nm处的荧光信号。在进行任何进一步的计算之前,减去仅培养基的信号。数据表示为细胞凋亡抑制%。
两种测试的简化硫酸化糖缀合物始终优于肝素及蔗糖八硫酸盐的特异性控制(图6)。在该测定中,硫酸化糖缀合物在抑制U937细胞的TNF-α凋亡方面同样有效。
实施例31
简化的硫酸化糖缀合物对与COPD相关的炎症有关的趋化因子的功能分析
已知的在与COPD相关的炎症的介导中起重要作用的趋化因子包括IL-8、MCP-1和MIP-1α(Barnes(2004)同上)。各种简化的硫酸化糖缀合物显示出可阻断由IL-8引发的细胞迁移。使用DMSO处理的人早幼粒细胞HL-60进行这些实验。这些细胞来自患有急性早幼粒细胞白血病的患者。在用于实验之前,将细胞用DMSO(1.2%w/v)处理4天。在96孔Costar趋化性板中进行趋化性测定,所述板包含一个底室,其中加入人IL-8(+/-抑制剂),然后将RPMI和1%v/v FCS中的细胞加入顶室中。将板在37℃下孵育1小时,使细胞从顶室移动到底部。通过用CellTiter96Aqueous One试剂标记1.75小时来定量迁移到底室中的细胞数量,然后在Enspire多模板读取器(PerkinElmer)上读取490nm处的吸光度。
为了检查各种糖缀合物是否是趋化因子MCP-1的有效抑制剂,使用了人单核细胞系THP-1。这些细胞最初来源于患有急性单核细胞白血病患者的外周血。该测定与上面描述的那些非常相似,除了在测定开始前将细胞置于1%胎牛血清中20小时。在96孔Costar趋化性板中进行趋化性测定,并将人MCP-1(+/-抑制剂)加入到底室中,将RPMI/1%FCS中的THP-1细胞加入顶室中,将板在37℃下孵育2.5小时,使细胞从顶室移动到底部。通过用CellTiter 96Aqueous One试剂标记1.75小时来定量迁移到底室中的细胞数量,然后在Enspire多模板读取器(PerkinElmer)上读取490nm处的吸光度。
实施例32
简化硫酸化糖缀合物对细胞增殖靶标IL-2的功能分析
小鼠细胞毒性T淋巴细胞系(CTLL)是衍生自C57bl/6小鼠的T细胞的亚克隆,这些细胞需要白介素-2(IL-2)进行生长,并用于测定其在条件培养基中的存在。这些细胞对小鼠和人IL-2都有反应。用表达载体pPGK-嘌呤霉素-荧光素酶中含有的萤火虫荧光素酶基因转染CTLL细胞(Coombe等(1998)同上),克隆阳性转染子以产生具有良好荧光素酶表达的品系,这些细胞被称为CTL-Luc。增殖测定在适合于此类测定的96孔微孔板(Falcon)中进行。这些孔是平底的,有白色的边和清晰的底部。洗涤细胞以除去生长培养基中的任何细胞因子,然后重悬浮于RPMI/5%w/v FCS中。用Coulter Z2粒子计数器和尺寸分析仪(CoulterElectronics,England)计数细胞,并且常规地将1.6×104个细胞加入到不含重组人IL-2(rhIL-2)(阴性对照)或各种rhIL-2的稀释液的微孔板的孔中。当要测量糖缀合物或其他硫酸化多糖的效果时,孔还含有各种浓度的这些分子。
CTL-Luc细胞在37℃、潮湿空气中增殖24小时,然后加入50μL荧光素酶底物缓冲液(50mM Tris-HCl,pH 7.8,15mM MgSO4,33.3mM DTT,0.1mM EDTA,0.5mM荧光素钠,0.5mMATP,0.25mM Li Co A和0.5%v/v Triton X-100)来测量荧光素酶活性。在加入荧光素酶缓冲液后立即测定板的荧光素酶活性。在Enspire多模板读取器(PerkinElmer)上检测光发射。
使用IL-2应答细胞系的这些实验的结果表明,所测试的硫酸化糖缀合物不影响IL-2的增殖活性(图7)。这些实验的结果还表明,测试的硫酸化糖缀合物对细胞因子依赖性淋巴细胞系无毒。该实施例表明,尽管本发明测试的糖缀合物可以与细胞因子结合,但并非所有细胞因子的活性都受到抑制。因此,硫酸化的糖缀合物对某些细胞因子具有特异性。
实施例33
如在BIAcore测定中所测量的简化硫酸化糖缀合物与IL-4结合的功能分析
表面等离子体激元共振的光学现象用于监测分子之间的物理相互作用。将潜在蛋白质配体(例如IL-4、IL-5或MCP-1)的溶液通过与靶标(例如肝素)结合的传感器表面,来监测蛋白质配体与固定靶标的实时结合。通过测量非常靠近传感器表面的折射率变化来实现检测。当折射率改变时,等离子体激元共振发生的角度改变,并且这种改变直接与和表面相互作用的蛋白质的量相关。BIAcore T200使用方便,它非常敏感,其微流体确保只需要少量的材料。
表面等离子体激元共振的光学现象用于监测分子之间的物理相互作用。将潜在蛋白质配体(例如IL-4、IL-5或MCP-1)的溶液通过与靶标(例如肝素)结合的传感器表面,来监测蛋白质配体与固定靶标的实时结合。通过测量非常靠近传感器表面的折射率变化来实现检测。当折射率改变时,等离子体激元共振发生的角度改变,并且这种改变直接与和表面相互作用的蛋白质的量相关。BIAcore T200使用方便,它非常敏感,其微流体确保只需要少量的材料。
将生物素化的肝素固定在生物传感器芯片上。生物素化通过氨基发生,或通过使用磺基-NHS-生物素利用还原胺化用氨改性的还原末端发生。将含有目标潜在蛋白质配体的溶液注射到传感器芯片表面上,并实时测量结合(Fernig(2001)同上)。杆状病毒表达的重组人IL-4(rhIL-4)容易地与通过该方法固定的肝素结合(参见PCT/AU2005/000551)。结合是特异性的,因为IL-4与缺乏肝素的传感器芯片几乎没有相互作用。
硫酸化寡糖的各种阴离子寡糖缀合物的制剂抑制IL-4与固定在BIAcore芯片表面上的肝素的结合。从50%抑制100nM IL-4结合所需的不同糖缀合物的浓度(IC50)的图11中所示的数据可以清楚地看出,一些糖缀合物在这方面比其他糖缀合物更有效。
本领域技术人员将理解,除了具体描述的那些之外,本文描述的公开内容易于进行变化和修改。应理解的是,本发明考虑了所有这些变化和修改。本发明还实现了本说明书中提及或指出的所有步骤、特征、组合物和化合物(单独地或共同地),以及任何两个或更多个步骤、特征、组合物或化合物的任何和所有组合。
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Claims (19)
1.式(I)的化合物:
其中,
L是连接键或任选取代的二价连接基团;
L1和L2独立地选自键和任选取代的二价连接基团;
L3和L4独立地选自键和任选取代的二价连接基团;
X1和X2各自为封端糖,其中X1和X2独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;
Y1和Y2各自为连接糖,其中Y1和Y2独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;并且
n是0到3的整数。
2.根据权利要求1所述的化合物,其中,X1、X2、Y1和Y2包括一种或多种硫酸基、磷酸基、草酸基或其组合。
3.根据权利要求1或2所述的化合物,其中该化合物具有净负电荷。
4.根据前述任一权利要求所述的化合物,其中,
X1和X2是相同的,选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;且
L1和L2是相同的,且选自键和任选取代的二价连接基团。
5.根据权利要求1或2所述的化合物,其中,
Y1和Y2是相同的,且选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;并且
L3和L4相同的,且选自键和任选取代的连接基团。
6.根据前述任一权利要求所述的化合物,其中,X1、X2、Y1和Y2选自任选取代的葡萄糖、果糖、半乳糖、甘露糖、三氯蔗糖、蔗糖、乳糖、乳果糖、海藻糖、麦芽糖、新霉胺、卡那霉素A、异麦芽三糖、黑曲霉三糖、麦芽三糖、阿卡波糖、麦芽四糖、水苏糖、松三糖、麦芽丙酮糖、棉子糖、蔗果三糖、葡糖醛酸、艾杜糖醛酸、葡糖胺、庚酮糖、戊糖、半乳糖胺、葡糖胺和由其衍生的化合物。
7.根据前述任一权利要求所述的化合物,其中,L是键或二价连接基团,所述二价连接基团选自以下的基团:C1-C18亚烷基、C2-C18亚烯基、C2-C18亚炔基、C6-C18亚芳基、、C3-C18亚杂芳基、C3-C18亚碳环基、C2-C18亚杂环基、C6-C18烷基亚芳基、C4-C18烷基亚杂芳基、C4-C18烷基亚碳环基、C3-C18烷基亚杂环基、C6-C18芳基酰基、C1-C18烷氧基、C2-C18烯氧基、C2-C18炔氧基、C5-C18芳氧基、酰基、酰氧基、C1-C18烷硫基、C2-C18烯硫基、C2-C18炔硫基、C5-C18芳硫基、酰硫基、磺酰基、亚砜基、C1-C18烷基氨基、C2-C18烯基氨基、C2-C18炔基氨基、C5-C18芳基氨基和酰胺基。
8.根据前述任一权利要求所述的化合物,其中,L1、L2、L3和L4各自独立地为键或二价连接基团,所述二价连接基团选自C1-C18亚烷基、C2-C18亚烯基,C2-C18亚炔基,C6-C18亚芳基,C3-C18亚杂芳基,C3-C18亚碳环基,C2-C18亚杂环基,C6-C18烷基亚芳基,C4-C18烷基亚杂芳基,C4-C18烷基亚碳环基,C3-C18烷基亚杂环基,C6-C18芳基酰基,C1-C18烷氧基,C2-C18烯氧基,C2-C18炔氧基,C5-C18芳氧基,酰基,酰氧基,C1-C18烷硫基,C2-C18烯硫基,C2-C18炔硫基,C5-C18芳硫基,酰硫基,磺酰基,亚砜基,C1-C18烷基氨基,C2-C18烯基氨基,C2-C18炔基氨基,C5-C18芳基氨基和酰氨基。
9.制备根据权利要求1-8任一项所述式(I)化合物的方法,包括:
i)提供二价连接基团;
ii)通过二价连接基团缀合至少两个当量的封端糖,
以形成式(I)化合物。
10.制备根据权利要求1-8任一项所述式(I)化合物的方法,包括:
(i)提供二价连接基团;
(ii)通过二价连接基团缀合至少两个当量的连接糖以形成缀合中间体;并且
(iii)通过缀合中间体与至少两个当量的封端糖缀合,
以形成式(I)化合物。
11.根据权利要求10所述的制备式(I)化合物的方法,其中,在步骤(iii)之前,将至少2个或更多个额外当量的连接糖与步骤(ii)的缀合中间体缀合。
12.制备根据权利要求1-8中任一项所述式(I)化合物的方法,包括:
(i)提供封端糖,
(ii)将封端糖与连接糖缀合以形成缀合中间体;并且
(iii)通过二价连接基团与至少两当量的缀合物中间体缀合,
以形成式(I)化合物。
13.根据权利要求10所述的制备式(I)化合物的方法,其中,在步骤(iii)之前,将至少2个或更多个额外当量的连接糖与步骤(ii)的缀合中间体缀合,以形成式(I)化合物。
14.治疗选自炎性疾病和病原体感染的疾病或病症的方法,包括给予有此需要的人治疗有效量的式(I)化合物:
其中,
L是连接键或任选取代的二价连接基团;
L1和L2独立地选自键和任选取代的二价连接基团;
L3和L4独立地选自键和任选取代的二价连接基团;
X1和X2各自为封端糖,其中X1和X2独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;
Y1和Y2各自为连接糖,其中Y1和Y2各自独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;并且
n是0到3的整数。
15.根据权利要求14的方法,其中炎性疾病选自由哮喘、过敏性呼吸道疾病、过敏性鼻炎、气道高反应性的上皮下纤维化、慢性鼻窦炎、常年性过敏性鼻炎、囊性纤维化患者的过敏性支气管肺曲霉病、慢性阻塞性肺病、嗜酸细胞性支气管炎、支气管扩张、支气管痉挛、支气管收缩、支气管高反应性和支气管肥大组成的组。
16.式(1)化合物在制备用于治疗选自炎性疾病和病原体感染的疾病或病症的药物中的用途:
其中,
L是键或任选取代的二价连接基团;
L1和L2独立地选自键和任选取代的二价连接基团;
L3和L4独立地选自键和任选取代的二价连接基团;
X1和X2各自为封端糖,其中X1和X2独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;
Y1和Y2各自为连接糖,其中Y1和Y2独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;并且
n是0到3的整数。
17.根据权利要求16的用途,其中炎性疾病选自由哮喘、过敏性呼吸道疾病、过敏性鼻炎、气道高反应性的上皮下纤维化、慢性鼻窦炎、常年性过敏性鼻炎、囊性纤维化患者的过敏性支气管肺曲霉病;慢性阻塞性肺病、嗜酸细胞性支气管炎、支气管扩张、支气管痉挛、支气管收缩、支气管高反应性和支气管肥大组成的组。
18.用于治疗选自炎性疾病和病原体感染的疾病或病症的式(1)的化合物:
其中,
L是键或任选取代的二价连接基团;
L1和L2独立地选自键和任选取代的二价连接基团;
L3和L4独立地选自键和任选取代的二价连接基团;
X1和X2各自为封端糖,其中X1和X2各自独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;
Y1和Y2各自为连接糖,其中Y1和Y2各自独立地选自任选取代的单糖、二糖、三糖、四糖和五糖,或衍生自任选取代的单糖、二糖、三糖、四糖或五糖的化合物;并且
n是0到3的整数。
19.根据权利要求18的所述用途的式(I)化合物,其中,炎性疾病选自由哮喘、过敏性呼吸道疾病、过敏性鼻炎、气道高反应性的上皮下纤维化、慢性鼻窦炎、常年性过敏性鼻炎、囊性纤维化患者的过敏性支气管肺曲霉病、慢性阻塞性肺病、嗜酸细胞性支气管炎、支气管扩张、支气管痉挛、支气管收缩、支气管高反应性和支气管肥大构成的组。
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US20210386770A1 (en) | 2021-12-16 |
CN110573520B (zh) | 2024-02-09 |
EP3526230A1 (en) | 2019-08-21 |
AU2021286254A1 (en) | 2022-01-06 |
IL265971A (en) | 2019-06-30 |
US11903958B2 (en) | 2024-02-20 |
WO2018068090A1 (en) | 2018-04-19 |
AU2021286254B2 (en) | 2023-12-07 |
IL265971B (en) | 2022-05-01 |
EP3526230A4 (en) | 2020-11-25 |
AU2017341671A1 (en) | 2019-05-23 |
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