5 -iodo-thymidine

Amino-5-iodo-2, 5 -dideoxyuridine [56045-73-9] (13) C2H22IN2O4, was synthesized ia 1975 (27) and was found effective against herpes keratitis ia rabbits (28). This compound is markedly less cytotoxic than IdU, iadicating that it may have a safer and more specific mode of antiviral activity. A potential limitation of this group of nucleosides is their specificity, for they fail to inhibit all strains of herpes vimses. The specific antiviral activity of (13) is considered to be a result of the incorporation of the 5 -Ai-phosphate into both viral and host DNA in infected cells, but not into the DNA of normal cells. Phosphorylation of (13) occurs only in herpes vims-infected cells, brought about by a vims-induced thymidine kinase (29). 

Selective replacement of primary hydroxyl groups in carbohydrates by iodine atoms has been achieved by using the Rydon reagent, namely, methyltriphenoxyphosphonium iodide.368 Treatment of methyl 3,4-O-isopropylidene-jS-D-galactopyranoside with the phosphonium salt in benzene for 48 hours at room temperature yielded 60% of the 6-deoxy-6-iodo derivative,369 and reaction of thymidine, uridine, and 2,2 -anhydrouridine in N,N-dimethylformamide afforded 5 -deoxy-5 -iodo derivatives in yields of 63, 65, and 31%, respectively.370... 

As a direct result of these anhydronucleoside studies, methods have been developed126,262 for the chemical synthesis of 2-deoxynucleosides of pyrimidines. It was noted126 that the 2-O-tosyluridine derivative LXXXVI, when caused to react with sodium iodide in hot 2,5-hexanedione (acetonylace-tone), is converted into a 5-0-acetyl-2-deoxy-2-iodo nucleoside which, upon reduction under alkaline conditions, yields 2-deoxyuridine (V, R = H). In analogous fashion, the 5-O-acetyl derivative of l-/S-D-ribofuranosyl-thymine68 is converted by sodium iodide to CVI which, after deacetylation followed by reduction in the presence of palladium catalyst, yields thymidine (V, R = CH,).126... 

Arylhalide 5 -iodo-2 -deoxy- uridine monophosphate Thymidine kinase Both iodine and nucleotide covalently incorporated. Only nucleotide incorporation parallels inhibition of enzyme activity (Chen et al., 1976). 

Another type of convertible nucleoside phosphoramidite, a derivative of (5 S)-5 -C-(5-bromo-2-penten-l-yl)-2 -deoxyribosylfuranosyl thymidine (49), has been reported. The synthesis of this phosphoramidite was stereoselective and involved a Sakurai reaction between 5 -C-thymidine aldehyde and allyltrimethylsilane. Seela has reported the synthesis of the ribosyl-phosphoramidite derivatives of 7-bromo- and 7-iodo-8-aza-7-deazapurine-2,6-diamine (50a,b) from advanced synthetic precursors and of the bromo- and iodo-derivatives at the 5-position of uracyl phosphoramidite (51a,b). He further described the effect on base-pair stability due to their incorporation into oligonucleotide duplexes. ... 

Idoxuiidlne, USF. Idoxuridinc. S-iodo-2 -dcoxyuridine (Stoxil, Herplex), was introduced in 1963 for the treatment of herpes simplex keratitis. - The drug is an iodinated analogue of thymidine that inhibits replication of a number of DNA viruses in vitro. The susceptible viruses include the herpesviruses and poxviruses (vaccinia). 

With a view to investigating its effect on the activity of thymidine kinase, 5-iodo-5 -amino-2, 5 -dideoxyuridine 5 -A-triphosphate (57) has been prepared by treating the amino-nucleoside with trimetaphosphate at pH 9.5. Below pH 8, first-order... 

Idoxuridine (5-iodo-2 -deoxyuridine) is an iodinated thymidine analog that inhibits the in vitro replication of various DNA viruses, including herpesviruses and poxviruses. 

FU, floxuridine (5-fluoro-2 -deoxyuridine, or 5-FUdR), aTK/idoxuridine (5-iodo-deoxyuridine) (see Chapter 49). lododeoxyuridine behaves as an analog of thymidine, and its primary biological action results from its phosphorylation and ultimate incorporation into DNA in place of thymidylate. In 5-FU, the smaller fluorine allows the molecule to mimic uracil biochemically. However, the fluorine-carbon bond is much tighter than that of C—H and prevents the methyla-tion of the 5 position of 5-FU by TS. Instead, in the presence of the physiological cofactor 5,... 

Other halogenated uridine derivatives have been reported to exhibit antiviral activity. Fluorodeoxyuridine has in vitro antiviral activity but is not used in clinical practice. Bromodeoxyuridine is used in subacute sclerosing panencephalitis, a deadly, virus-induced CNS disease. This agent appears to interfere with DNA synthesis in the same way as idoxuridine. The 5 -amino analogue of idoxuridine (5-iodo-5 -amino-2, 5 -dideoxyuridine) is a better antiviral agent than idoxuridine, and it is less toxic. It is metabolized in herpesvirus-infected cells only by thymidine kinase to di- and triphosphoramidates. These metabolites inhibit HSV-specific late RNA transcription, causing reduction of less infective abnormal viral proteins. 5-Bromo-2 -deoxyuridine has an action similar to that of other iodinated compounds. None of these compounds are commercially available in the United States. 

The third approach involves a short, elegant, free radical reaction of the 3 -deoxy-3 -iodo-5 -0-tritylthymidine 49 with hexamethylditin, t-butylisonitrile and azobisisobutyronitrile to give stereoselectively CNT 31. This synthetic pathway allows the stereocontrolled synthesis of CNT 31 in four steps and 22% overall yield from thymidine [79]. 

Deoxy-5 -iodo-2, 3 -0-isopropylidene-thymidine, prepared conventionally from thymidine, has been used to prepare the 5 -modified nucleosides illustrated in Scheme 1. ... 

In addition to thymidine, the enzyme will accept as substrates deoxyiui-dine and various 5-position derivatives including those with fluoro, bromo, and iodo substituents. The kinase is specific for deoxyribonucleosides and will not phosphorylate deoxycytidine. 

Iodo-2 -deoxy- uridine Thymidine kinase Enhanced activity loss on photolysis thymidine protects 124... 

Verheyden and Moffatt have prepared l-(5-deoxypent-4-enofuranosyl) derivatives of uridine, thymidine, cytidine, and 2 -deoxycytidine by dehydrohalogen-ation of the acetylated 5 -deoxy-5 -iodo-nucleoside with either silver fluoride in pyridine or DBN (Scheme 89). ° Similar treatment of 3, 5 -dideoxy-3, 5 -di-iodothymidine (235) furnished the dihydrofuran derivative (236). Addition reactions of 4, 5 -unsaturated derivatives of nucleosides are mentioned in Chapter 21. 

Similarly, l-j -D-2 -deoxyribofuranosyl-5-iodo-uracil (1-21) is an antagonist of l-j -D-2 -deoxyribofuranosyl thymine, or thymidine (1-22). That is, it is able to antagonize or prevent the action of the latter in biological... 

SaroHnycin (Fig. 1), a streptomycete antibiotic inhibits the DNA polymerase. It prevents the incorporation of thymidine into intact tumour cells, and into DNA primer in cell-free extracts. Sarcomycin probably blocks the thiol groups which are indispensable for the activity of the DNA-polymerase molecule. It is a noncompetitive inhibitor of the enzyme in the same way as iodoacetate or iodo-acetamide. Its action is prevented or reversed by 2-mercaptoethanoL... 

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