NOVEL ANTICANCER DRUGS BASED ON GLYCOLIPID DEPLETION

THE GOAL OF THE RESEARCH IS TO DEVELOP A POTENT PHARMACOLOGICALLY USEFUL INHIBITOR OF GLYCOSPHINGOLIPID (GSL) BIOSYNTHESIS. GSLS PLAY IMPORTANT ROLES IN (1) CANCER CELL METASTASIS, PROLIFERATION, AND RESISTANCE AGAINST THE HOST'S IMMUNOSURVEILLANCE SYSTEM, (2) THE BINDING AND ACTIVATION OF PATHOGENIC ORGANISMS AND TOXINS TO TISSUES, AND (3) THE MODULATION OF GROWTH AND DIFFERENTIATION IN NORMAL CELLS. WE BELIEVE THAT SUCCESSFUL DRUGS WILL FIND IMPORTANT USE IN THE CHEMOTHERAPY OF CANCER, INFECTION, NERVE DAMAGE, AND PROBLEMS OF EXCESSIVE OR INSUFFICIENT GROWTH. OUR PROTOTYPE COMPOUND, 1-PHENYL-2-DECANOYLAMINO-3-MORPHOLINO-1-PROPANOL (PDMP) STRONGLY INHIBITS THE ENZYME THAT MAKES GLUCOSYLCERAMIDE AND THUS PRODUCES A RAPID DECREASE IN ALL TISSUE GSL LEVELS. THE INHIBITOR EXERTS A MARKED INHIBITORY ACTION AGAINST THE GROWTH AND METASTASIS OF TUMOR CELLS. UNFORTUNATELY, HIGH DOSES ARE NEEDED IN VIVO BEACUSE OF RAPID INACTIVATION BY CYTOCHROME P450. THE GOAL OF THIS PROJECT IS TO DEVELOP MORE POTENT ANALOGS OF PDMP WHICH ARE INERT TO CYTOCHROME P450. FLUORINATED ANALOGS OF PDMP WILL BE SYNTHESIZED WHICH SHOULD RESIST METABOLISM. ANOTHER SERIES OF ANALOGS WILL BE SYNTHESIZED TO STUDY THE STRUCTURE-ACTIVITY RELATIONSHIPS OF THE MORPHOLINO MOIETY WITH THE GOAL OF INCREASING POTENCY. ALL NEW COMPOUNDS WILL BE TESTED WITH THE GLUCOSYLACERAMIDE SYNTHASE AND RELATED ENZYMES, IN ENZYME PREPARATIONS AND WHOLE CELLS.