Ribonucleotide reductase inhibitors

Hydroxyurea is a ribonucleotide reductase inhibitor that prevents DNA synthesis and traditionally has been used in chemotherapy regimens. Studies in the 1990s also found that hydroxyurea increases HbF levels as well as increasing the number of HbF-containing reticulocytes and intracellular HbF. Other beneficial effects of hydroxyurea include antioxidant properties, reduction of neutrophils and monocytes, increased intracellular water content leading to increased red cell deformability, decreased red cell adhesion to endothelium, and increased levels of nitric oxide, which is a regulator involved in physiologic disturbances.22... 

Nocentini, G., 1996, Ribonucleotide reductase inhibitors new strategies for cancer chemotherapy. Crit. Rev. Oncol. Hematol. 22 899126. 

Unlike ATM, which strongly prefers DSBs, ATR is a broad-spectrum signal initiator. Various types of replication interference, such as those induced by UV irradiation or ribonucleotide reductase inhibitor Hydroxyurea (HU), strongly elicit the ATR pathway. This versatility and the pivotal role of ATR in cell viability and genomic stability has prompted an intensive investigation into the mechanism(s) by which ATR senses different types of DNA damage and activates the checkpoint. 

Related to cytarabine, incorporated into DNA, inhibits DNA synthesis ribonucleotide reductase inhibitor interferes with DNA chain elongation... 

Raichurkar, A.V. and Kulkami, V.M. (2003) Understanding the antitumor activity of novel hydroxysemicarbazide derivatives as ribonucleotide reductase inhibitors using CoMFA and CoMSIA./. Med. Chem., 46, 4419-4427. 

The most obvious common feature of all ribonucleotide reductase inhibitors except for the least effective chelators desferrioxamine, EDTA, and EGTA is that all are aromatic or heterocyclic. The superior activity of aromatic compounds became evident in comparative studies with hydroxamate derivatives, too A corresponding hy-... 

The reactions of stable nitroxide radicals have been reviewed and have been the subject of intensive investigations 113). It should be emphasized that ribonucleotide reductase inhibitors are of special importance because of the possibility of applying them as immunoregu-latory drugs. 

Li et al. [149] have prepared ribonucleotide reductase inhibitors by coupling of vinyltributyltin with substituted 2-chloropyridines or the corresponding triflates. Quayle et al. [150] have carried out sequential couplings starting from 1,1-bis(tributylstannyl)-l-alkenes to afford ( )-configured vinylstannanes and hence defined trisubstituted alkenes. However, in certain cases involving bulky electrophiles, butyl migration is observed. 

Elford HL, Wampler GL and vanT Riet B (1979b) New ribonucleotide reductase inhibitors with antineoplastic activity. Cancer Res 39 844-851... 

Hydroxyurea, an inhibitor of ribonucleotide reductase inhibitor, is used to treat cancers such as chronic myeloid leukaemia. However, also increases foetal haemoglobin production which may be useful in the treatment of thal-assaemias and sickle cell disease [59 ]. A meta-analysis that analysed the effects and side effects of hydroxyurea therapy on patients with beta-thalassaemia was completed this year [60 ]. The report concluded that no randomised clinical trial had been performed. It also showed that haemoglobin levels after treatment showed modest but significant increases in both transfusion-dependent and transfusion-independent patients. 

Triapine is a ribonucleotide reductase inhibitor used as an anticancer agent [86 ]. However, symptomatic dyspnoea due to treatment-related methaemoglobinemia was a major dose-limiting toxicity in early clinical trials. A review discusses the mechanism of action of mefhaemoglobinemia developmenf due to Triapine [87 ]. 

Shao J, Zhou B, Chu B, Yen Y. 2006. Ribonucleotide reductase inhibitors and future drug design. Curr Cancer Drug Targets 6 409-431. 

Treatment via chelation has been observed for 2-acetylpyridine thiosemi-carbazone derivatives, which have been found to possess inhibitory activity for the RNA-polymerases of the influenza virus [133]. The iron(III) complexes were shown to be 3 to 6 times more active as inhibitors of partially purified ribonucleotide reductase (no added iron) compared to uncomplexed thiosemi-carbazone [128]. Raina and Srivastava [134] prepared and characterized low spin iron(III) complexes of 2-acetylpyridine thiosemicarbazone, [Fe(8-H)2A] (A = NO3, OH, Cl, N3, NCS or NO2), which were proposed as being seven-coordinate. However, all but the azide complex are 1 1 electrolytes in DMF and their solid ESR spectra are rhombic with the g-values being about 2.20,2.15 and 2.00. Of the six complexes, the azide ion seems to interact ihost strongly with the iron(III) center. 

The iron(III) complexes of 21 and 22 were shown to be 3 to 6 times more active as inhibitors of partially purified ribonucleotide reductase than un-complexed thiosemicarbazones [128]. The mechanism of antitumor action by these complexes still remains largely speculative, although some excellent preliminary studies have appeared. It has been postulated [148] that tridentate... 

HU is an inhibitor of ribonucleotide reductase, a rate-limiting enzyme which catalyzes the conversion of ribonucleotides into deoxyribonucleotides. HU is thus a cytotoxic agent as it has the ability to inhibit DNA synthesis. Consequently, H U can affect only cells that are actively synthesizing DNA and, therefore, a drug of S-phase cell-cycle specific. Moreover, HU-mediated inhibition of ribonucleotide reductase is reversible, implying that the action of HU will exhibit a relatively straight forward concentration-time course dependence [2—4-]. 

Heidel JD, Liu JY, Yen Y, Zhou B, Heale BS, Rossi JJ, Bartlett DW, Davis ME (2007) Potent siRNA inhibitors of ribonucleotide reductase subunit RRM2 reduce cell proliferation in vitro and in vivo. Clin Cancer Res 13 2207-2215... 

Initial insight of the role of CSN in cell-cycle control came from the finding that csnl and csn2 deletion S. pomhe strains have an S-phase delay [52]. Interestingly, this effect did not occur in strains missing other CSN subunits. The S-phase delay was caused by the accumulation of the cell-cycle inhibitor Spdl (S-phase delayed 1), which is involved in the misregulation of the ribonucleotide reductase (RNR). RNR catalyzes the production of deoxyribonucleotides for DNA synthesis and... 

One form of SOD is caused by inherited insufficiency of adenosine deaminase leading to accumulation of its substrate, deoxyadenosine, which is derived from DNA degradation and is converted to dATP, an allosteric inhibitor of ribonucleotide reductase. 

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. 

In addition to aconitases, nitric oxide is an inhibitor of many other enzymes such as ribonucleotide reductase [71], glutathione peroxidase [72,73], cytochrome c oxidase [74], NADPH oxidase [75], xanthine oxidase [76], and lipoxygenase [77] but not prostaglandin synthase [78]. (Mechanism of lipoxygenase inhibition by nitric oxide is considered in Chapter... 

Extremely large buildups of dATP in red I cells have been observed. [Note dATP is an 1 inhibitor of ribonucleotide reductase and,... 

Fontecave M, Lepoivre M, Elleingand E, Gerez C, Guittet O. 1998. Resveratrol, a remarkable inhibitor of ribonucleotide reductase. FEBS Lett 421 277-279. 

The regulation of ribonucleotide reductase is complex, with many feedback reactions used to keep the supplies of deoxynu-cleotides in balance. For example, dGTP and dTTP are feedback inhibitors of their own formation. Each is also an activator of the synthesis of the complementary nucleotide (dCDP or dADP), while dATP is an inhibitor of the reductions to make dADP, dCDP, dGDP, and dUDP. These control functions keep the supply of deoxynu-cleotides in balance, so that a roughly equivalent amount of each remains available for DNA synthesis. 

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. 

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