Ribonucleotide diphosphate reductase inhibitors

C10H12FN3O4 257.221 Ribonucleotide-diphosphate reductase inhibitor. Antineoplastic agent. Designated an orphan drug by FDA (2003) for treatment of cancer of the oesophagus and stomach. USAN name refers to the monohydrate. 

Fluoro and 3, 3-difluoromethylene nucleosides have been prepared as inhibitors of ribonucleotide diphosphate reductase (cf. Chapter 7). ... 

E.C. Moore and A.C. Sartorelli, in Inhibitors of Ribonucleotide Diphosphate Reductase Activity, International Encyclopedia of Pharmacology and Therapeutics, Section 28, eds. J.G. Cory and A.H. Cory, Pergamon Press, New York, 1989, p. 203. 

Cory, J. G. (1989). Role of ribonucleotide reductase in cell division. In Inhibitors of Ribonucleoside Diphosphate Reductase Activity (J. G. Cory and A. H. Cory, eds.), pp. 1-16. Pergamon, New York. 

The critical and rate-controlling step in the pathway leading to the synthesis of DNA is focused on ribonucleotide reductase (RR). Inhibitors of RR would have great utility as a therapeutic agent against cancer. One such potent inhibitor of ribonuclease diphosphate reductase is 3-AP 196, and a Suzuki methylation reaction that converted 194 into 195 began the synthesis of this compound [69]. 

Inhibition of DNA synthesis is brought about by the action of dTTP as an allosteric inhibitor of ribonucleotide reductase (Reichard et al., 1961 Moore and Hurlbert, 1966 Brown and Reichard, 1969 Rummer et al., 1978). This enzyme is responsible for reducing all four ribonucleoside diphosphates (NDP) to the corresponding de-oxyribonucleoside diphosphates (dNDP). It is subject to a complex allosteric control which has been most studied with the bacterial enzyme. Most studies with the mammalian enzyme show it to be similar to the bacterial enzyme (Fig.11.7). 

The enzyme contains two catalytic sites, two regulatory sites and two specificity sites. The catalytic site binds the substrates, thioredoxin (reduced by NADPH + H+) and the nucleoside diphosphates. The allosteric regulatory site binds ATP as an activator in competition with dATP as an inhibitor. The specificity site binds dGTP, dTTP and dATP but not dCTP and modulates ribonucleotide reductase activity selectively for the four NDP substrates to balance the four dNTP pools. 

An unprecedented example of the application of an organic azide as an enzyme inhibitor derives from the elegant studies of Stubbe and coworkers at MIT, who have investigated the mechanism of action of ribonucleotide reductase (RNR) using several mechanism-based inhibitors including 2 -azido-2 -deoxyuridine-5 -diphosphate (NjUDP) (71) [82]. RNR plays a... 

FIGURE 48-2 Action of flucytosine in fungi. 5-Flucytosine is transported by cytosine permease into the fungal cell, where it is deaminated to 5-fluorouracil (5-FU). The 5-FU is then converted to 5-fluorouracil-ribose monophosphate (5-FUMP) and then is either converted to 5-fluorouridine triphosphate (5-FUTP) and incorporated into RNA or converted by ribonucleotide reductase to 5-fluoro-2 -deoxyuridine-5 -monophosphate (5-FdUMP), which is a potent inhibitor of thymidylate synthase. 5-FUDP, 5-fluorouridine-5 -diphosphate dUMP, deoxyuridine-5 -monophosphate dTMP, deoxyuridine-5 -monophosphate UPRTase, uracil phosphoribosyl transferase. 

R. Resvik, 2 -Deoxy-2 -methylenecytidine and 2 -deoxy-2, 2 -difluorocytidine 5 -diphosphates Potent mechanism-based inhibitors of ribonucleotide reductase,/. Med. Chem. 34 1879 (1991). 

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