Design, synthesis, and structure-affinity relationships of novel series of sialosides as CD22-specific inhibitors.
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 IC 50 values 0.40, 0.47, 0.24, and 0.23 microM, respectively, for hCD22, while 8p, 8q, and 9f, showed IC 50 values 1.70, 2.90, and 4.10 microM, 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.
Department of Applied Bio-organic Chemistry, The United Graduate School of Agricultural Sciences, Gifu University, Gifu 501-1193, Japan.
Hajjaj H M
HH
Abdu-Allah
Taichi
T
Tamanaka
Jie
J
Yu
Lu
L
Zhuoyuan
Magesh
M
Sadagopan
Takahiro
T
Adachi
Takeshi
T
Tsubata
Soerge
S
Kelm
Hideharu
H
Ishida
Makoto
M
Kiso
D000478:Alkylation; D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011485:Protein Binding; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism*; D012794:Sialic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000577:Amides; D000588:Amines; D051918:Sialic Acid Binding Ig-like Lectin 2; D012794:Sialic Acids