Synthesis and biological evaluation of a unique heparin mimetic hexasaccharide for structure-activity relationship studies.
To date, the structure-activity relationship studies of heparin/heparan sulfate with their diverse binding partners such as growth factors, cytokines, chemokines, and extracellular matrix proteins have been limited yet provide early insight that specific sequences contribute to this manifold biological role. This has led to an impetus for the chemical synthesis of oligosaccharide fragments of these complex polysaccharides, which can provide an effective tool for this goal. The synthesis of three heparin mimetic hexasaccharides with distinct structural patterns is described herein, and the influence of the targeted substitution on their bioactivity profiles is studied using in vitro affinity and/or inhibition toward different growth factors and proteins. Additionally, the particularly challenging synthesis of an irregular hexasaccharide is reported, which, interestingly, in spite of being considerably structurally similar with its two counterparts, displayed a unique and remarkably distinct profile in the test assays.
Momenta Pharmaceuticals Inc. , 675 West Kendall Street, Cambridge, Massachusetts 02142, United States.
Sucharita
S
Roy
Ahmed
A
El Hadri
Sebastien
S
Richard
Fanny
F
Denis
Kimberly
K
Holte
Jay
J
Duffner
Fei
F
Yu
Zoya
Z
Galcheva-Gargova
Ishan
I
Capila
Birgit
B
Schultes
Maurice
M
Petitou
Ganesh V
GV
Kaundinya
D016207:Cytokines / Q000737:chemistry; D005966:Glucuronidase / Q000037:antagonists & inhibitors; D006493:Heparin / Q000737:chemistry*; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry; D018716:Molecular Mimicry; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000737:chemistry; D000099175:Heparanase
D016207:Cytokines; D005966:Glucuronidase; D006493:Heparin; D036341:Intercellular Signaling Peptides and Proteins; D009844:Oligosaccharides; D013451:Sulfonic Acids; D000099175:Heparanase