SYNTHESIS OF ANTIFOLS AND MECHANISM-BASED INHIBITORS

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The project's long term objectives are the development of a new chemical class of antifolates. The specific aim is the preparation of potential antifolates based loosely on methotrexate in which the heterocyclic ring of methotrexate (i.e., pteridine) is replaced by the pyrimido(4,5-d) pyrimidine ring system, which is isomeric with pteridine. The presence of a reduced ring makes an enzyme process other than DHFR a more likely target. Some of these compounds will include N-C linages at both the heterocyclic and side chain sites. The rationale for this investigation is the need to provide an agent with fewer unwanted side effects than methotrexate as an antitumor chemotherapeutic agent. The formation of these compounds will result primarily from standard chemical methodology. In particular, heavy emphasis will be placed on the Mannich reaction to prepare some of the target molecules as well as some of the precursors. The usual chemical characterization of analysis and spectroscopy will be employed for all new structures. Biological evaluation will be conducted by acceptable and accredited laboratories, such as the National Cancer Institute.