Glycoconj J (2015) 32:549–556
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0. Bourguignon, L.Y.: Hyaluronan-mediated CD44 activation of Rho
GTPase signaling and cytoskeleton function promotes tumor pro-
gression. Semin. Cancer Biol. 18, 251–259 (2008)
of CD44 with HA. The HA library did not exhibit any appre-
2
ciable activities. As assembly of higher HA oligosaccharides
could be very tedious, a new synthetic approach towards HA
oligosaccharides was developed by taking advantage of the
ability of hyaluronidase to produce HA tetrasaccharides by
digesting HA polysaccharides. The HA tetrasaccharides gen-
erated by hyaluronidase were utilized to synthesize multiple
HA conjugates. Compared to the traditional chemical synthe-
sis [26–29], this strategy was more efficient as it utilized read-
ily available sources of materials (HA polysaccharide and hy-
aluronidase) and obviated the need to assemble the
tetrasaccharide through glycosylation reactions. Furthermore,
with the simplified protective group patterns utilized,
deprotection of the final product was much simpler than the
lengthy and at times unpredictable deprotection procedures
encountered in traditional synthesis [38, 28]. Among all con-
jugates synthesized, analog 36 bearing the m-benzyl phenyl
carbamate moiety gave the strongest inhibition of CD44-HA
polysaccharide binding. While its inhibitory activity is still
modest, the structure of 36 provides a lead in designing HA
based CD44 inhibitors, which demonstrates strategically
placed aromatic rings can improve the potency. Further opti-
mization of HA conjugates is underway to enhance the
affinity.
2. Toole, B.P., Ghatak, S., Misra, S.: Hyaluronan oligosaccharides as a
potential anticancer therapeutic. Curr. Pharm. Biotech. 9, 249–252
(2008)
3. Harada, H., Nakata, T., Hirota-takahata, Y., Tanaka, I., Nakajima,
M., Takahashi, M.: F-16438s, novel binding inhibitors of CD44 and
hyaluronic acid. J. Antibiot. 59, 770–776 (2006)
4. Hirota-takahata, Y., Harada, H., Tanaka, I., Nakata, T., Nakajima,
M., Takahashi, M.: F-16438s, novel binding inhibitors of CD44 and
hyaluronic acid. J. Antibiot. 59, 777–784 (2006)
15. Hirota-Takahata, Y., Harada, H., Tanaka, I., Nakata, T., Nakajima,
M., Takahashi, M.: F-19848 A, a novel inhibitor of hyaluronic acid
binding to cellular receptor CD44. J. Antibiot. 60, 633–639 (2007)
1
6. Liu, L.-K., Finzel, B.C.: Fragment-based identification of an induc-
ible binding site on cell surface receptor CD44 for the design of
protein − carbohydrate interaction inhibitors. J. Med. Chem. 57,
2714–2725 (2014)
1
7. Banerji, S., Wright, A.J., Noble, M., Mahoney, D.J., Campbell,
I.D., Day, A.J., Jackson, D.G.: Structures of the CD44-hyaluronan
complex provide insight into a fundamental carbohydrate-protein
interaction. Nat. Struct. Mol. Biol. 14, 234–239 (2007)
18. Cumpstey, I., Salomonsson, E., Sundin, A., Leffler, H., Nilsson,
U.J.: Double affinity amplification of galectin–ligand interactions
through arginine–arene interactions: synthetic, thermodynamic, and
computational studies with aromatic diamido thiodigalactosides.
Chem. Eur. J. 14, 4233–4245 (2008)
Acknowledgments We are grateful for financial support from the De-
partment of Chemistry, Michigan State University as well as the National
Institute of General Medical Sciences, NIH (R01GM072667) and the
National Science Foundation (CHE-1507226).
1
9. Sörme, P., Arnoux, P., Kahl-Knutsson, B., Leffler, H., Rini, J.M.,
Nilsson, U.J.: Structural and thermodynamic studies on cation − π
interactions in lectin − ligand complexes: High-affinity galectin-3
inhibitors through fine-tuning of an arginine − arene interaction. J.
Am. Chem. Soc. 127, 1737–1743 (2005)
0. Zeng, Y., Rademacher, C., Nycholat, C.M., Futakawa, S., Lemme,
K., Ernst, B., Paulson, J.C.: High affinity sialoside ligands of my-
elin associated glycoprotein. Bioorg. Med. Chem. Lett. 21, 5045–
Compliance with ethical standards The authors declare that there are
no potential conflicts of interests. All authors agree with the submission.
2
5
049 and references cited therein (2011)
2
2
1. Huang, L., Wang, Z., Li, X., Ye, X., Huang, X.: Iterative one-pot
syntheses of chitotetroses. Carbohydr. Res. 341, 1669–1679 (2006)
2. Huang, L., Teumelsan, N., Huang, X.: A facile method for oxida-
tion of primary alcohols to carboxylic acids and its application in
glycosaminoglycan syntheses. Chem. Eur. J. 12, 5246–5252 (2006)
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