Two crucial enzymes involved in nucleic acid metabolism and cellular proliferation are targeted for inhibition by synthetic nucleoside analogs. The cellular enzyme S-adenosyl-L homocysteine (AdoHcy) hydrolase catalyzes hydrolysis of AdoHcy (produced by methyl transfer from S- adenosylmethionine). Since AdoHcy is a potent feedback inhibitor of crucial transmethylation enzymes, the design of inhibitors of AdoHcy hydrolase represents a rational approach for anti-cancer and antiviral chemotherapy. The major objective is to develop specific inhibitors designed to exploit the 'hydrolytic activity' of the enzyme which might lead to generation of reactive electrophiles and type II (covalent) inhibition. Various derivatives with 3-, 4-, or 5-carbon extended conjugation to the furanosyl ring will be targeted for synthesis and testing. This will provide structural and mechanistic probes with different stereochemical and conformational attributes for binding as well as addition of enzyme-bound water. Ribonucleotide reductases (RNRs) are enzymes that execute 2'-deoxygenation of ribonucleotides in unique do novo biosynthetic pathways to DNA monomers. RNRs are tightly controlled and present attractive chemotherapeutic targets for intervention with replication of cancer cells and proliferation of viruses. The major objective will be developing new methods for the preparation of 3'[17O]- labeled 2'-substituted-2'-deoxynucleotides. These 3'[17O]-labeled 2'-azio- , 2'- mercapto- and 2'-fluoremethylene-2'-deoxy pyrimidine nucleotides should perturb the EPR spectra of the recently proposed protein- and/or substrate-delivered radicals, generated during inactivation of RNR by these inhibitors, in a predictable fashion. Chemical and biochemical basis for study of the proposed inhibitors and justification of the collaborative biological and mechanistic testing are presented. It is essential to understand these mechanisms to pursue rational design of new mechanism-based inhibitors.
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