Inosine monophosphate dehydrogenase (IMPD) is the rate-limiting enzyme in guanine nucleotide biosynthesis. Inhibitors of this enzyme have been shown to possess antitumor, antiviral, and antiparasitic activity and several compounds in this class are currently used in man for the treatment of cancer or viral diseases. Mycophenolic acid (MPA), a mould metabolite, is one of the most potent IMPD inhibitors known, however the phenolic hydroxyl in MPA is metabolized so rapidly in man that therapeutic levels of the drug cannot be achieved.
The specific aim of the proposed research is to use MPA and other known IMPD inhibitors in the design, synthesis and evaluation of new drugs in this class. The goals of the project are to develop information relating to structural requirements for IMPD inhibition and to develop new, potent inhibitors of this enzyme which may be used in the treatment of cancer and/or viral diseases. The design of target compounds proposed in this project is based, in part, on molecular modelling and the potential relationship between MPA and the IMPD cofactor, NAD+. In addition, molecular modelling and theoretical calculations are used to develop a model of the enzyme reaction that can be used in the design of potential irreversible IMPD inhibitors and multisubstrate analogue inhibitors. Structure-activity relationship studies on MPA are proposed. Specifically, variants of the MPA lactone will be studied along with replacements for the metabolically labile MPA phenolic group by other, bioisoterically equivalent hydrogen-bond donor groups. Mono- and bicylic heteroaromatic compounds were designed as """"""""fixed-hydrogen-bonding heterocycles whereas substituted amines were designed to create a more flexible hydrogen-bonding group. Modifications of the MPA hexanoic acid side-chain are also proposed to study possible relationships between that moiety and a nucleotide ribose phosphate residue. Several """"""""lead"""""""" compounds are proposed to examine the potential application of the MPA hexanoic acid side chain on selected purines, pyrimidines and related heterocycles. The proposed compounds will be evaluated for antitumor activity in vitro against human tumor cell lines and selected active compounds will be further evaluated in vivo. The compounds will also be tested in a tumor- cell redifferentiation assay. All of the compounds will also be submitted to the NCI for antiHIV testing. The compounds will all be tested for IMPD- inhibitory activity and selected active inhibitors will be subjected to more extensive analysis to establish the nature of the inhibition. Potential drug candidates which evolve from the proposed studies will be evaluated for water solubility, chemical stability and other properties that must be assessed in new drug development studies.
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