THE ANALYTICAL CHEMISTRY OF NEW ANTICANCER DRUGS

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The goal of this project is the development and application of bioanalytical methods to: (1) establish the structure and purity of new antitumor agents and their metabolites, (2) determine physical, chemical and biochemical properties of new anticancer drugs and (3) measure drugs, their metabolites, and potential biomodulators and biomarkers in biological samples to elucidate in vitro and in vivo pharmacology and to determine in vivo pharmacokinetics. High-performance liquid chromatography (HPLC) is the primary analytical approach. Cyclopentenyl cytosine (CPE-C), a carbocyclic nucleoside whose Phase I clinical trial was suspended because of severe and unpredictable hypotension, continues under collaborative study. CPE-C infusion studies in dogs with hemodynamic and pharmacologic monitoring have produced some similarities to patient hypotensive episodes, and the biochemical and pharmacological basis of this is being investigated. A tetrahydropyridoindole of novel structure has been identified and confirmed as an inhibitor of dihydroorotate dehydrogenase (DHOD), an enzyme required for de novo pyrimidine biosynthesis. This new compound possesses a potency equal to or greater than that of brequinar, a DHOD inhibitor that is an investigational antitumor agent. A study to compare hydrophobicity indices determined by liquid-liquid partitioning (log P) and reversed-phase HPLC (log k') for cytosine and adenine nucleosides of low lipophilicity showed a good, but less than perfect, correlation. Thus the use of HPLC to estimate the partition coefficients of moderately polar to very polar compounds is not as good as the direct determination of log P using our previously developed micro-shake flask method.