Design, Synthesis, and Structure-Affinity Relationships of Novel Series of Sialosides as CD22-Specific Inhibitors
Design, Synthesis, and Structure-Affinity Relationships of Novel Series of Sialosides as CD22-Specific Inhibitors
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DOI：
10.1021/jm8000696
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发表时间：
2008-11-13
影响因子：
7.3
通讯作者：
Kiso, Makoto
中科院分区：
文献类型：
--
作者：
Abdui-Allah, Hajaj H. M.;Tainanaka, Taichi;Kiso, Makoto
在唾液酸部分的9-位引入取代的酰胺或胺的唾液酸苷已经被合成并被评价为CD 22抑制剂。几种衍生物在亚微摩尔至低微摩尔范围内表现出抑制效力（例如，例如，在一个实施例中，8 o、9d、9 g和9 k对hCD 22的IC 50值分别为0.40、0.47、0.24和0.23 μ M，而8 p. 8 q和9 f对mCD 22的IC 50值分别为1.70、2.90和4.10 μ M）。最显著的结果是含有9-（2'或4'-羟基-4-联苯）甲氨基取代基的9 g和9 k的亲和力强烈增强（对hCD 22的效力比相应的9-羟基衍生物; 7a强600倍）。进行分子模拟研究，以了解CD 22抑制的分子基础。据我们所知，这是第一个系统的结构-亲和力关系研究抑制CD 22。
Sialosides incorporating substituted amides or amines at 9-position of sialic acid moiety have been synthesized and evaluated as CD22 inhibitors. Several derivatives exhibited inhibitory potency in sub- to low micromolar range (e. g., 8o, 9d, 9g, and 9k showed IC50 values 0.40, 0.47, 0.24, and 0.23 mu M, respectively, for hCD22, while 8p. 8q, and 9f, showed IC50 values 1.70, 2.90, and 4.10 mu M, respectively, for mCD22). The most significant result was the strongly enhanced affinity of 9g and 9k containing 9-(2' or 4'-hydroxy-4-biphenyl) methylamino substituents (600-fold more potent for hCD22 than the corresponding 9-hydroxy derivative; 7a). Molecular modeling study was carried out to get some insights into the molecular basis of CD22 inhibition. To the best of our knowledge, this is the first systematic structure-affinity relationship study on inhibition of CD22.