Swainsonine is a potent inhibitor of Golgi a-mannosidase II, a late-stage glycoprotein processing enzyme necessary for the incorporation of cancer-associated antigenic carbohydrates. Inhibition of this enzyme prevents the expression of these tumor-associated glycoproteins, resulting in good antitumor and antimetastatic activity without the usual cytotoxic effects of traditional chemotherapy agents. A limitation of swainsonine as an anticancer agent is its inhibition of lysosomal mannosidase, and enzyme necessary in normal glycoprotein catabolism. Thus, high-mannose oligosaccharides may accumulate in lysosomes, resulting in a condition similar to mannosidosis.
Researchers at the University of Michigan have synthesized the novel mannosidase inhibitors (3R)- and (3S)-3-(hydroxymethyl)swainsonine, analogs of swainsonine that bear a hydroxymethyl group at C3, the site most like the anomeric position of mannose in N-linked glycoproteins. These analogs have been found to selectively inhibit Golgi a-mannosidase and not lysosomal mannosidase, and retain the crucial ability to inhibit the expression of tumor-associated glycoproteins on the surface of cells. Further, the analogs of swainsonine wherein another sugar (or sugar-like) residue have been synthesized by linking various groups onto the 3-hydroxymethyl group. These disaccharide mimics more closely resemble the Man(a-1,3) or Man(a-1,6) linkage recognized and cleaved by the human glycoprotein processing enzyme mannosidase II, and may result in more potent and selective inhibitors.
Applications and Advantages
- Cancer chemotherapy
- Therapeutics based on swainsonine
- Favorable cell-entry properties
- Able to alter the cell surface glycoproteins
- Effective inhibitors of a-mannosidase from jack bean, as well as Golgi a-mannosidase II