The proposed investigation is designed to evaluate the potential for development of hexokinase inhibitors as antineoplastic agents. A series of 15 N-acyl-2-amino-2-dexoy-D-glucose analogs will be synthesized and tested as inhibitors of hexokinase type II isoenzyme isolated from Ehrlich ascites tumor cells. The N- acylglucosamine derivatives will also be examined for their ability to inhibit the Crabtree effect in Ehrlich ascites tumor cell suspensions as an indication of membrane transport and intracellular inhibition of hexokinase. A comparison of isolated hexokinase and whole cell inhibition data will be developed by establishing quantitive structure-activity relationships describing the action of the N-acylglucosamines in each biological test system. The results should provide an indication of inhibitor physicochemcial properties which facilitate cell membrane transport as well as those specific structural features which enhance binding and inhibition of the tumor cell hexokinase type II enzyme.
| Coats, E A; Skau, K A; Caperelli, C A et al. (1992) Exploring the hexokinase glucose binding site through correlation analysis and molecular modeling of glucosamine inhibitors. J Enzyme Inhib 6:271-82 |
