C-4 Modified Sialosides Enhance Binding to Siglec-2 (CD22): Towards Potent Siglec Inhibitors for Immunoglycotherapy
C-4 Modified Sialosides Enhance Binding to Siglec-2 (CD22): Towards Potent Siglec Inhibitors for Immunoglycotherapy
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DOI：
10.1002/anie.201207267
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发表时间：
2013-01-01
影响因子：
16.6
通讯作者：
Haselhorst, Thomas
中科院分区：
文献类型：
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作者：
Kelm, Sorge;Madge, Paul;Haselhorst, Thomas
Siglecs(唾液酸结合免疫球蛋白样凝集素)在免疫系统中的调节功能为多种免疫性疾病或癌症的创新治疗策略提供了机会(免疫糖疗法)。[1]Siglec-2(CD22)因其在B细胞激活中的关键作用，已成为治疗自身免疫性疾病和B细胞源非霍奇金S淋巴瘤的有吸引力的靶点。非霍奇金淋巴瘤是十种最常见的癌症之一，仅在美国就有超过20000人死亡。[2]Siglec-2与α(2，6)连接的唾液酸(SIA)、[3]如Neu5Acα(2，6)乳糖胺(方案1)高度结合。Neu5Acα2Me(1)主要通过1)其羧酸基上的负电荷，2)C-5 N-乙酰氨基取代基，3)甘油侧链与Siglec-2相互作用。此外，用氨基取代C-9羟基不会干扰与Siglecs的结合。[3]对Siglec-1(唾液粘附素，锡)[4]的结晶学研究表明，该氨基的酰化使Siglec-2配体对Siglec-2的整体亲和力提高了两到三个数量级。[5]开发有效的Siglec-2抑制剂的第一个突破是设计了9-联苯基甲酰胺Neu5Acα2Me(9-bpc-Neu5Acα2Me，2)，它对Siglec-2的亲和力比1，[5d]和2高两个数量级以上，并证明了它有可能调节B细胞的信号转导。此外，还开发了基于2的化合物，可杀死B细胞淋巴瘤细胞。[6]结构研究[4a，b]以及对N-乙酰神经氨酸的C-5 N-酰基取代基和C-2苷元部分的修饰(Neu5Ac)进一步提高了亲和力。[5a-c，e，f]在此我们首次报道了设计、合成、我们的基于结构的设计方法得到了一种新的先导化合物9-biphenylcarboxamido-4-m-nitrophenylcarboxamido-4，9-二脱氧Neu5Acα2Me(9-bpc-4-mNPC-Neu5Acα2Me，6b)，它与Siglec-2具有亚微摩尔亲和力，可能为免疫治疗策略提供一条途径。
The regulatory functions of Siglecs (sialic acid binding immunoglobulin-like lectins) in the immune system provide opportunities for innovative therapeutic strategies for a wide range of immunological disorders or cancer (immunoglycotherapy).[1] Siglec-2 (CD22), as a consequence of its pivotal role in B cell activation, has become an attractive target for therapies of autoimmune diseases and B cell-derived non-Hodgkin s lymphoma (NHL). NHL is among the ten most common cancers with over 20000 deaths in 2010 for the US alone.[2] Siglec-2 binds with high preference to α (2, 6)-linked sialic acids (Sia),[3] such as Neu5Acα (2, 6) lactosamine (Scheme 1). Neu5Acα2Me (1) interacts with Siglec-2 mainly through 1) the negative charge on its carboxylate group, 2) the C-5 N-acetamido substituent, and 3) the glycerol side chain. Furthermore, replacement of the C-9 hydroxy group by an amino group did not interfere with binding to Siglecs.[3] Crystallographic studies on Siglec-1 (sialoadhesin, Sn)[4] demonstrated that acylation of this amino group enhances the overall affinity of the ligand for Siglecs by two to three orders of magnitude.[5] The first breakthrough in the development of potent Siglec-2 inhibitors was the design of 9-biphenylcarboxamido Neu5Acα2Me (9-BPC-Neu5Acα2Me, 2) which has a more than two orders of magnitude higher affinity to Siglec-2 than 1,[5d] and 2 has demonstrated potential to modulate signal transduction in Bcells. Furthermore, based on 2, compounds were developed, which kill B cell lymphoma cells.[6] Structural studies [4a, b] and modifications of the C-5 N-acyl substituent and the C-2 aglycon moiety of N-acetylneuraminic acid (Neu5Ac) have led to further improvement in affinity.[5a–c, e, f]Herein we report, for the first time the design, synthesis, and evaluation of a novel class of disubstituted Neu5Ac derivatives that is modified at the C-4 and C-9 positions of 1. Our structure-based design approach resulted in a promising novel lead compound 9-biphenylcarboxamido-4-m-nitrophenylcarboxamido-4, 9-dideoxy Neu5Acα2Me(9-BPC-4-mNPC-Neu5Acα2Me, 6b) that has sub-micromolar affinity for Siglec-2 and may provide a pathway for immunoglycotherapy strategies.