(Principal Investigator's) The major aims of this proposal are to investigate the antimetastatic effect that has been observed for certain oligosaccharides derived by the action of hyaluronate lyase (EC 4.2.2.1) on hyaluronic acid (HA). Using information to be gleaned from these studies, a synthetic effort toward designing and synthesizing metabolically stable mimics of these oligosaccharides will be undertaken. The proposal has three Specific Aims: (l) To isolate, purify, and characterize the antimetastatic oligosaccharides derived by hyaluronate lyase (EC 4.2.2.1) degradation of HA. Determination of molecular weight, dp, and structure are important for developing any structure-activity relationships (SAR). (2) To investigate other HA-degrading enzymes, among them hyaluronidases from testicular tissue (EC 3.2.1.35) and from leeches (EC 3.2.1.36) that give products that are different in structure from those of the lyase digests. These will be subjected to screening for antimetastatic activity and will be fully characterized. (3) Using SAR developed from the studies in (1) and (2), oligosaccharides having their -O-linkages strategically replaced by -CH2- and -S- will be designed, synthesized, and evaluated. Our strategy is to make use of C- and S-disaccharides that can be glycosidically O-linked to provide oligosaccharides of appropriate size to maximize antimetastatic activity.
| Ren, Zhong-Xu; Yang, Qiang; Price, Kenneth N et al. (2007) Synthesis of a C-linked hyaluronic acid disaccharide mimetic. Carbohydr Res 342:1668-79 |
