title: Design and syntheses of hyaluronan oligosaccharide conjugates as inhibitors of CD44-Hyaluronan binding.
abstract: Hyaluronan (HA) is an integral component of the extracellular matrix. Its interactions with a cell surface receptor CD44 has been shown to play important roles in a variety of biological events including cell proliferation and metastasis. As multivalent CD44-HA binding is critical for downstream signaling, compounds that can selectively disrupt the complex formation of HA polysaccharide with CD44 can serve as useful probes of CD44 mediated cellular events as well as potential leads for novel therapeutics. Herein, we report the synthesis of several series of HA conjugates to target the HA binding pocket of CD44. As a small library of HA disaccharide derivatives failed to exhibit any inhibitory activities, we focused on HA tetrasaccharide based analogs. Traditional synthetic strategies towards HA oligosaccharides involve the construction of backbone from the corresponding monosaccharide building blocks, which can be quite tedious. In order to expedite the synthesis, we designed a new synthetic route taking advantage of the ability of hyaluronidase to generate large quantities of HA tetrasaccharide through digestion of HA polysaccharides. The HA tetrasaccharide obtained was utilized to prepare multiple S-linked HA analogs bearing aromatic groups at the reducing end glycan. One such compound containing an m-benzyl phenyl moiety exhibited significant inhibition of CD44-HA binding. Our approach provides a new direction towards the design of HA based CD44 antagonists.
authors.affiliation: Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI, 48824, USA.|NIDDK, National Institutes of Health, Building 8, Room 1A21, 9000 Rockville Pike, Bethesda, MD, 20892-0815, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI, 48824, USA. xuefei@chemistry.msu.edu.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Huang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000737:chemistry / Q000378:metabolism; D009362:Neoplasm Metastasis; D009844:Oligosaccharides / Q000737:chemistry / Q000235:genetics; D015398:Signal Transduction
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D009844:Oligosaccharides; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase
keywords: CD44; Hyaluronan; Inhibitor design; Synthesis