Studies on selectin blockers. 7. Structure-activity relationships of sialyl Lewis X mimetics based on modified Ser-Glu dipeptides.
We have previously found that heterochiral fucodipeptides, L-Ser-D-Glu (3a) and D-Ser-L-Glu (3b), exhibited up to 20-100 times more potency than a sialyl Lewis X (sLeX, 1) and a 3'-sulfated Lewis X analogue (2) toward E-selectin binding and have also proposed, from molecular dynamics calculation, that their strong activities would depend on a possible formation of the type II and/or type II' beta-turn of compounds 3a,b (Tsukida, T.; Hiramatsu, Y.; Tsujishita, H.; Kiyoi, T.; Yoshida, M.; Kurokawa, K.; Moriyama, H.; Ohmoto, H.; Wada, Y.; Saito, T.; Kondo, H. J. Med. Chem. 1997, 40, 3534-3541). To clarify our hypothesis, we synthesized several analogues of compounds 3a,b and investigated their structure-activity relationships. As a result, it was indicated that the type II and/or type II' beta-turn conformation would be a comparatively tight form and would play important roles in favorable binding to E-selectin. These findings indicate that sLeX mimetics with type II and type II' beta-turn dipeptides could be a useful methodology for the design of an active selectin blocker.
Department of Medicinal Chemistry and Biology, Kanebo, New Drug Discovery Research Laboratories, 1-5-90 Tomobuchi-Cho, Miyakojima-Ku, Osaka 534, Japan.
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Tsukida
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Moriyama
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Kurokawa
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Achiha
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Inoue
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Kondo
D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019040:E-Selectin / Q000378:metabolism; D005643:Fucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019041:L-Selectin / Q000378:metabolism; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009844:Oligosaccharides / Q000737:chemistry*; D019007:P-Selectin / Q000378:metabolism; D019087:Selectins / Q000378:metabolism*; D000080506:Sialyl Lewis X Antigen; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C115424:(N-(2-tetradecylhexadecanoyl)-O-fucopyranosylseryl)glutamic acid 1-methylamide; D004151:Dipeptides; D019040:E-Selectin; D009844:Oligosaccharides; D019007:P-Selectin; D019087:Selectins; D000080506:Sialyl Lewis X Antigen; D019041:L-Selectin; D005643:Fucose