Ribonucleotide-diphosphate reductases

Hydroxyurea is an oral agent that inhibits ribonucleotide diphosphate reductase and interferes with the synthesis of DNA, specifically the S phase of the cell cycle. Sinclair et al. have demonstrated in preclinical animal models that hydroxyurea may inhibit cells from leaving the Gj radiosensitive phase and entering the radioresistant S phase (9). Early studies have demonstrated little or no efficacy associated with the use of single-agent hydroxyurea (10). It has received FDA approval in the use of head and neck cancer when administered concomitantly with radiotherapy based upon promising results from earlier studies (11). 

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

Mao, S. S., Yu, G. X., Chalfoun, D., and Stubbe, J., 1992, Characterization of C439SR1, a mutant of Escherichia coli ribonucleotide diphosphate reductase evidence that C439 is a residue essential for nucleotide reduction and C439SR1 is a protein possessing novel thioredoxin-like activity, Biochemistry 31 9752n9759. 

From their key role in DNA synthesis it is not surprising that the ribonucleotide reductases are ubiquitous in nature. However, three different types of ribonucleotide reductases are now known, each with variations in their cofactor requirements. The most extensively studied and characterized are the ribonucleotide-diphosphate reductases (RDPRs), in particular the enzyme from Escherichia coli. This reductase consists of two nonidentical subunits, proteins B1 and B2, which form an active 1 1 complex where the interface between these subunits forms the active site, and each subunit alone is devoid of catalytic activity (9). Protein B2 (Mr 78,(XK)) is a dimer and contains two atoms of tightly... 

Scheme 2. Cofactor center of ribonucleotide-diphosphate reductases.

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. 

In a study related to the mechanism of inactivation of ribonucleotide diphosphate reductase (RDPR) by 2 -deoxy-2 -substituted nucleotide analogues, it was found that treatment of nucleosides of type 57 (B=Ura, Ade, X=I, Br, Cl, SMe, N3) with tributylstannane and AIBN gave the d4 products 58, whilst with X=F, OMs or OTs, the 3 -deoxysystem 59 was the product. The results pointed to the loss of radicals rather than anions from C-2 during mechanism-based inactivation of RDPR, and the authors suggest some modifications to Stubbe s mechanistic proposals. ... 

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. 

Scheme 14.11. A proposal for the use of ribonucleoside diphosphate reductase (ribonucleotide diphosphate reductase, EC 1.17.4.1) to convert adenosine diphosphate (ADP), uridine diphosphate (UDP), and cytidine diphosphate (CDP) into their respective 2 -deoxy analogues deoxyadenosine diphosphate (dADP),deoxyuridine diphosphate (dUDP),and deoxy-cytidine diphosphate (dCDP), or, in general, ribonucleic acids (RNAs) into the corresponding deoxyribonucleic acids (DNAs) (after Stubbe, J. 7. Biol. Chem., 1990,265, 5330).

Deoxy-2 -difluoromethylene nucleosides, also of interest in connection with the inhibition of ribonucleotide diphosphate reductase, have been made by a modified Julia synthesis as outlined in Scheme 13 the cytosine analogue was also reported. 0 OEt... 

Hydroxyurea (Fig. 13) inhibits the growth of a number of tumours, and has a rapid but temporary effect on DNA synthesis without concomitant effects on RNA or protein s3mthesis. This derivative appears to act by inhibiting ribonucleotide diphosphate reductase, which is responsible for converting ribonucleotide diphosphates to their corresponding deoxyribonucleotides. The evidence for this mechanism is that its effects can be reversed by deoxyuridine, deoxycytidine, and thymidine. 

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