CHEMICAL SYNTHESIS OF RADIOLABELED ANTITUMOR AGENTS

KNOWLEDGE OF BIOLOGIC MECHANISM OF ACTION OF THE DIFFERENT DRUGS AND ABOUT THE BIOCHEMICAL EVENTS IN THE PROGRESS OF CANCER DISEASE IS VERY VALUABLE FOR THE DESIGN OF NEW DRUGS AND THERAPIES. TRACER METHODOLOGY USING ISOTOPICALLY LABELED DRUGS CONTINUES TO BE A POWERFUL TOOL IN OBTAINING SUCH KNOWLEDGE WITH EXCEPTIONAL SENSITIVITY AND QUANTITATION ACCURACY. AVAILABILITY OF LABELED COMPOUNDS WITH ADEQUATELY HIGH SPECIFIC RADIOACTIVITY AND CHEMICAL AS WELL AS RADIOCHEMICAL PURITY IS ESSENTIAL AND REQUIRES SPECIALIZED EFFORT. THE DEVELOPMENT OF EFFICIENT PROCEDURES FOR PREPARATION, IDENTIFICATION, PURIFICATION, STORAGE, AND DISTRIBUTION OF SELECTED COMPOUNDS IMPORTANT FOR CANCER RESEARCH IS THE LONG-TERM OBJECTIVE OF THIS PROJECT. IN PHASE I THE SYNTHETIC APPROACHES TO LABELING A SMALL NUMBER OF COMPOUNDS OF INTEREST TO NCI WILL BE DEVELOPED TO SECURE EFFICIENT METHODS FOR THEIR PREPARATION. THE COMPOUNDS SELECTED ARE: ZEBULARINE-2-14C, WHICH CAN BE PREPARED FROM PROTECTED URIDINE-2-14C BY SELECTIVE CHLORINATION AND REDUCTIVE DEHALOGENATION; CYCLOPENTENONE-14C, WHICH WILL BE PREPARED IN A FOUR-STEP SYNTHESIS, STARTING WITH CONDENSATION OF 14C-LABELED METHYL PHOSPHONIC ESTER WITH CORRESPONDING LACTONE; MTX POLYGLUTAMATES WHICH WILL BE IN PHASE II, NEWLY EMERGING COMPOUNDS WITH PROMISING CANCEROSTATIC OR CYTOSTATIC PROPERTIES WILL BE INCLUDED IN THIS PROJECT.