The surface of animal cells is coated with carbohydrate structures whose functions remain very poorly understood. k has been widely observed, however, that these oligosaccharide structures change in a systematic way during cellular development including embryogenisis and tumor-progression. The new carbohydrate structures that appear during these processes are referred to as differentiation antigens or tumor-associated antigens. It has been postulated that these new structures mediate cell-cell recognition or adhesion. The biosynthesis of these cell-surface carbohydrate structures is mediated by enzymes termed glycosyltransferases. If these enzymes could be inhibited in a specific manner, then the expression of cell-surface carbohydrates could be precisely controlled Should certain oligosaccharides provide growth advantages to tumor-cells, as has been proposed, then inhibition of their biosynthesis would negate these advantages and possibly lead to a new mode of cancer therapy. In this proposal, 4 glycosyltransferases implicated in the production of aberrant cell-surface carbohydrates have been selected as targets for inhibition. For each of these enzymes, a specific substrate will be defined and analogs of this substrate, which cannot be acted on by the enzyme, will be chemically synthesized. These analogs are predicted to be specific inhibitors and they will be prepared in a form that should allow their entry into cells in order to access the target enzymes. If successful, the ability to change the cell surface carbohydrate structures would be in hand, as would the ability to control their function.
