SYNTHESIS AND EVALUATIONOF AGENTS FOR BRAIN NEOPLASMS

THE POOR PROGNOSIS ASSOCIATED WITH BRAIN NEOPLASMS IS A SIGNIFICANT HEALTH PROBLEM IN THE UNITED STATES. CURRENT CHEMOTHERAPEUTIC APPROACHES HAVE BEEN LIMITED BY THE INABILITY TO ACHIEVE THERAPEUTIC CONCENTRATIONS IN THE BRAIN. CYCLOPHOSPHAMIDE IS UNIQUE AMONG WIDELY USED CHEMOTHERAPEUTIC AGENTS IN THAT IT AND ITS CHEMOTHERAPEUTICALLY ACTIVE METABOLITES HAVE BEEN SHOWN TO HAVE AN EXTREMELY LOW NEUROTOXICITY PROFILE. IF THERAPEUTICLEVELS OF ACTIVATED CYCLOPHOSPHAMIDE COULD BE ACHIEVED IN THE BRAIN, CYCLOPHOSPHAMIDE COULD BECOME A CLINICALLY EFFECTIVE CHEMOTHERAPEUTIC AGENT FOR A VARIETY OF BRAIN NEOPLASMS. ORDINARILY, CYCLOPHOSPHAMIDE DOES NOT PENETRATE THE BLOOD-BRAIN BARRIER IN SIGNIFICANT AMOUNTS. IT IS PLANNED TO SYNTHESIZE A SERIES OF ACTIVATED CYCLOPHOSPHAMIDE DERIVATIVES BASED ON NOVEL IDEAS TO PROMOTE BOTH PENETRATION INTO THE BRAIN AS WELL AS STABILITY IN THE CIRCULATION. IN PHASE I, THESE ANALOGS WILL BE SYNTHESIZED,AND HYDROLYTIC STABILITY WILL BE DETERMINED BY HPLC AND NMR TECHNIQUES. IN VITRO MEASUREMENTS OF ALKYLATING ACTIVITY WILL BE PERFORMED, AS WELL AS IN VITRO AND IN VIVO EFFICACY STUDIES. IN PHASE II, THE MOST PROMISING COMPOUNDS WILL BE RADIOLABELED, AND PHARMACOKINETIC MEASUREMENTS AND BRAIN PENETRATION STUDIES WILL BE PERFORMED. NEW CHEMICAL MODIFICATIONS WILL BE INVESTIGATED TO IMPROVE EFFICACY OF THE MORE PROMISING COMPOUNDS, AND TOXICOLOGIC STUDIES WILL BE INITIATED.