Glycosidase Inhibition with Fullerene Iminosugar Balls: A Dramatic Multivalent Effect
Glycosidase Inhibition with Fullerene Iminosugar Balls: A Dramatic Multivalent Effect
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DOI：
10.1002/anie.201002802
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发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Nierengarten, Jean-Francois
中科院分区：
文献类型：
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作者：
Compain, Philippe;Decroocq, Camille;Nierengarten, Jean-Francois
富勒烯衍生物的电子和结构性质使它们成为构建纳米结构的非常有吸引力的候选者，这些纳米结构在材料科学和生物化学中具有潜在的应用价值。[1]特别是，最初由Hirsch及其同事[2]开发的具有Th-对称八面体加成模式的C60六加合物是独特的有机分子，具有用于构建多功能纳米材料的吸引人的紧凑球形支架。[3]然而，由丙二酸酯和C60合成功能化富勒烯六加合物是困难的。[3，4]这一主要问题限制了此类系统的应用，并且最近已经通过基于富勒烯六加合物的易于获得的结构单元的后官能化的合成方法的开发而得到解决。[5，6]已经表明，通过将未保护的糖衍生物接枝到富勒烯核上，可以以优异的产率制备带有12个外围碳水化合物部分的富勒烯六加合物。[7]虽然这些富勒烯糖球显然非常适合在碳水化合物-凝集素相互作用领域的应用[8]，但用这种多价衍生物对碳水化合物加工酶抑制的评价不太明显。事实上，在获得特异性有效糖苷酶抑制的可能策略中，多价设计的概念显然被忽视了。[9]事实上，大多数酶都有一个单一的深层活性位点，通常比凝集素表面的浅结合口袋或凹槽更难接近。[10]因此，可能存在有限数量的结合机制，包括统计学再结合，而多价配体可能通过其他机制选择（例如螯合作用、受体聚集）与多种受体相互作用。[9，11]这些因素可能阻碍了对设计多价糖苷酶抑制剂的项目的兴趣。此外，迄今取得的实验结果并不特别令人鼓舞。[12]1-脱氧野尻霉素的二价至四价类似物是一种众所周知的糖苷酶抑制剂[13]，与其单体对应物相比，通常显示出相当的抑制作用（如果不是降低的话）。迄今为止报道的最好结果是发现三价亚氨基糖对刀豆α-甘露糖苷酶的亲和力增强了六倍。[14]本文报道了一种由12个亚氨基糖残基修饰的富勒烯六加成物的合成。这种富勒烯亚胺糖球的抑制特性已经被系统地评估了对各种糖苷酶的抑制作用，[15]并且首次观察到了戏剧性的多价效应。为了探索在富勒烯支架周围构建的球状多位配体对糖苷酶抑制的多价性的潜力，选择1-脱氧野尻霉素的N-烷基类似物作为外周配体。这类化合物确实选择性差，并显示出适度至良好的糖苷酶抑制。[13]因此，预期这些化合物可以是用于检查多价性对大范围的糖苷酶的抑制选择性的影响的优良模型。此外，亚氨基糖的内环氮原子上的烷基链是理想的间隔基，其可以允许通过环加成反应容易地接枝到中心C60核上。[16]叠氮化物结构单元的合成基于Overkleeft等人独立报道的策略的优化。[17]还有瓦塞拉和同事[18]如方案1中所示，δ-羟基酰胺2直接从市售的四-O.
The electronic and structural properties of fullerene derivatives make them very attractive candidates for the construction of nanostructures that are potentially useful for applications in materials science and biological chemistry.[1] In particular, the C60 hexakis adducts with a Th-symmetrical octahedral addition pattern initially developed by Hirsch and co-workers [2] are unique organic molecules with an appealing compact spherical scaffold for the construction of multifunctional nanomaterials.[3] However, the synthesis of functionalized fullerene hexakis adducts from malonates and C60 is difficult.[3, 4] This major problem limits the applications of such systems and has been recently solved by the development of synthetic methodologies based on the postfunctionalization of easily accessible building blocks of fullerene hexakis adducts.[5, 6] It has been shown that fullerene hexakis adducts that bear 12 peripheral carbohydrate moieties can be prepared in excellent yields by grafting unprotected sugar derivatives onto the fullerene core.[7] Although these fullerene sugar balls are obviously perfectly suited for applications in the field of carbohydrate–lectin interactions,[8] the evaluation of carbohydrate-processing enzyme inhibition with such multivalent derivatives is less obvious. Indeed, among the possible strategies to attain specific potent glycosidase inhibition, the concept of multivalent design has been clearly overlooked.[9] Most enzymes actually have a single, deep active site that is usually less accessible than the shallow binding pockets or grooves on the lectin surfaces.[10] Consequently, a limited number of binding mechanisms, including statistical rebinding, are possible, whereas multivalent ligands may interact with multiple receptors by additional mechanistic options (eg, the chelate effect, receptor clustering).[9, 11] It is likely that these factors may have hampered interest in projects directed towards the design of multivalent glycosidase inhibitors. In addition, the experimental results obtained to date were not particularly encouraging.[12] Di-to tetravalent analogues of 1-deoxynojirimycin, which is a well-known glycosidase inhibitor,[13] generally displayed comparable if not decreased inhibition compared with their monomeric counterparts. The best result reported to date was found for a trivalent iminosugar that showed a sixfold affinity enhancement towards Jack bean α-mannosidase.[14] Herein we report the synthesis of a fullerene hexakis adduct decorated with 12 iminosugar residues. The inhibition profile of this fullerene iminosugar ball has been systematically evaluated against various glycosidases,[15] and dramatic multivalent effects have been observed for the first time. In order to explore the potential of multivalency on glycosidase inhibition with a globular polytopic ligand constructed around the fullerene scaffold, an N-alkyl analogue of 1-deoxynojirimycin was selected as the peripheral ligand. This class of compounds is indeed poorly selective and displays modest to good glycosidase inhibition.[13] It was thus anticipated that these compounds could be excellent models for the examination of the influence of multivalency on inhibition selectivity over a large range of glycosidases. In addition, the alkyl chain on the endocyclic nitrogen atom of the iminosugar is an ideal spacer that may allow for easy grafting onto the central C60 core by means of a cycloaddition reaction.[16] The synthesis of the azide building block is based on the optimization of a strategy reported independently by Overkleeft et al.[17] and Vasella and co-workers.[18] As shown in Scheme 1, the δ-hydroxy amide 2 was obtained directly from commercially available tetra-O …