Thymidine deoxyuridine effect

There appear also to be toxic effects. In animals, nitrous oxide has been shown to inactivate methionine synthetase which prevents the conversion of deoxyuridine to thymidine and thus has the potential for inducing megaloblastic anemia, leukopenia, and teratogenicity (44—46). A variety of epidemiologic surveys suggest positive correlations between exposure to nitrous oxide and spontaneous abortion in dental assistants (47). 

Methyl-2 -deoxycytidine (437) and 3-methyl-2 -deoxyuridine (438) were isolated from the Swedish sponge Geodia baretti. Compound 437 exhibits strong contractile activity in the isolated guinea pig ileum assay, whereas 438 had no effect on contractions (356). Thymidine-5 -carboxylic acid (439) and 2 -deoxyuridine-5 -carboxylic acid (440), which were previously known only as synthetic products, were found in extracts of the ascidian Aplidium fuscum of the East Pyrenean coast (357). 

Trimethylgermyl derivatives of 2,-deoxyuridine131 exhibit antimetabolic properties the ft-anomer possesses weak biological action, the a-anomers inhibits the replication of herpes simplex virus HSV-1131 132, reveal cytotoxic properties in vitro experiments on cell culture of human ovary carcinoma CaOv and fail to display antitumor action in vivo to leukemia P388 in mice. The a-anomer of 5-trimethylgermyl-2,-deoxyuridine suppresses the incorporation of 2,-deoxyuridine and thymidine into the DNA of hepatoma 22A cells in vitro more effectively (by 88 and 27%) than the ft-anomer (50 and 0%, respectively). 

K3. Killman, S. A., Effect of deoxyuridine on incorporation of tritiated thymidine Difference between normoblasts and megaloblasts. Acta Med. Scand. 175, 483-497 (1964). 

Site of action 5-FU per se is devoid of antineoplastic activity and must be converted to the corresponding deoxynucleotide (5-FdUMP, Figure 38.9), which competes with deoxyuridine monophosphate (dUMP) for thymidylate synthetase. 5-FdUMP acts as a pseudosubstrate and is entrapped with the enzyme and its N5,N10-methylene tetrahydrofolic acid coenzyme in a ternary complex that cannot proceed to products. DNA synthesis decreases due to lack of thymidine, leading to imbalanced cell growth and cell death. [Note Leucovorin is given with 5-FU because the reduced folate coenzyme is required in the thymidylate synthetase reaction. Lack of sufficient coenzyme reduces the effectiveness of the antipyrimidine.] 5-FU is also incorporated into RNA and low levels have been detected in DNA. 

Kiiiman S-A (1964) Effect of deoxyuridine on incorporation oftritiated thymidine difference between normobiasts and megaiobiasts. Acta Medica Scandinavica 175,483-8. 

A new series of 5-carboranyl-substituted-2 -deoxyuridine (25a) and deoxy-thymidine (25b) derivatives containing a range of alkyl spacers has been prepared to access a more effective use of boron neutron capture therapy. Evaluation of these derivatives as substrates for the human thymidine kinases TKl and TK2 showed that a decrease in the length of the spacer (from 8 methylene units to 4) between the carborane moiety and the pyrimidine base resulted in better substrate characteristics. 

Several inhibitors are known that bind to the adenosine site of PARP (19). These inhibitors include 6-bromo-2 -deoxyuridine, caffeine, 5-bromouracil, diadenosine-tetraphosphate, 1-methyladenine, 5-nitrouracil, theophylline, theobromine, thymidine, and other compounds. These compounds are not as well studied as the nicotinamide analogs. In addition, it is not known whether these compounds can interact with the adenosine (A,) receptors that are involved in modulation of synaptic transmission and neuroprotective effects. 

The deoxyuridine suppression test measures the effect of prior addition of deoxyuridine on the uptake of radiolabeled thymidine into the DNA of cultured bone marrow cells, peripheral blood lymphocytes, or whole blood. Normal samples that contain vitamin B12 can convert deoxyuridine to thymidine and therefore do not take up as much thymidine. Samples from patients who are deficient in vitamin B12 show less suppression than in normal patients. Because it is relatively time consuming, the deoxyuridine suppression test is not widely available for use as a diagnostic test. ... 

When 5 -0-tritylthymidine-3 -phosphate is treated with excess tri-isopropyl benzenesulphonylchloride (TPS) and thymidine, and then deprotected, the trinucleoside monophosphate (7a) is obtained. The 5-bromo- and 5-fluoro-deoxyuridine analogues (7b) and (7c) are prepared similarly. All are resistant to snake venom and spleen phosphodiesterases, and hydrolyse too slowly under physiological conditions for the cytotoxic moiety to be effective. When protected UpU is treated with bis-(4-nitrophenyl) phosphorochloridate, and subsequently with an amine or amino-acid ester, the dinucleoside phosphor-amidates (8) are formed. Although the compounds investigated split the P—N bond under the conditions required for protecting-group removal, the method has potential for the preparation of easily fissionable neutral phospho-triesters. 

The form of the enzyme found in the cytosol acts only on deoxythymidine. The thymidine kinase found in the mitochondria acts on deoxythymidine, deoxycytidine, and deoxyuridine. The mitochondrial thymidine kinase s activity is sufficiently broad that it will also act on the anti-HIV drug, 3 -azido-2 3 -dideoxythymidine (AZT). Evidence suggest that deoxyribonucleotides of AZT interfere with mitochondrial function, possibly by inhibiting mitochondrial DNA replication or transcription, which may explain some of the side effects of cardiotoxicity observed with its use. 

A number of nucleosides were therefore tested for delaying effects on division 2 when added at EH in combination with methotrexate. It appears that 8 out of 10 nucleosides when tested at a 5 mM concentration have a delaying effect. Only the 2 methylated nucleosides, thymidine and 5-methyldeoxycytidine, do not. Uridine and deoxyuridine both delay division number 2 by 125 to 135 minutes. By itself methotrexate causes a delay of 5 minutes and uridine alone causes no delay. Uridine was used in all later experiments because it is cheaper than deoxyuridine. (Uracil or uridylic acid will not replace uridine in these tests). 

It was found in early studies that the folic acid analogues, methotrexate (amethopterin) and aminopterin very effectively blocked the incorporation of labeled deoxyuridine and of labeled formate into DNA thymine however, the incorporation of thymidine was not blocked. It was apparent, therefore, that the analogues interfered with the introduction of the methyl group into thymine, a process known to involve H -folate. When it became established that the antifolic agents were exceedingly potent inhibitors of tetrahydrofolate dehydrogenase (see Chapter 5), the mechanism of their inhibition of DNA synthesis was apparent. 

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. 

Various 2 -C -alkylated derivatives of carbocyclic 5-methyluridine have been prepared, as have 6 -alkoxy and -acyloxy-derivatives of carbocyclic thymidine (119), in order to test the effect of the structural alterations on DNA/RNA duplex stability. A short and high-yielding synthesis of carbocyclic bromo-vinyl-deoxyuridine (BVDU) has been described, involving a cyclopentylamine derivative as an intermediate. Carbocyclic BVDU and carbocyclic 2 -deoxy-guanosine have been made by a modification of an earlier route to carbocyclic 2 -deoxynucleosides, involving a microbiological reduction. Racemic difluoro-carbocyclic nucleosides of type 120 have been made via the fluorination of ( )-JV-Boc-2-azabicyclo[2.2.1]hept-5-en-3-one (see Vol.28, p.284), and the (+)-enan-tiomer of 2-azabicyclo[2.2.1]hept-5-en-3-one has been converted into the (—)-enomtiomer, which is of considerable use in the synthesis of carbocyclic nucleosides in the o-series. ... 

---