Thymidine 4 -thio derivative

There are five dihydropyrimidines. The 1,4- and the 1,6-dihydropyrimidines can readily interconvert by tautomerism because of the mobile NH proton. The common metals to effect hydrogenation can be used . Platinum has been the catalyst of choice for the reduction of the 5,6-double bond of uracils, for example, in the addition of deuterium to uracil to produce [5,6- H2]5,6-dihydrouracil. But in the reduction of 2(l/f)-pyrimidinone and its iV-methyl derivative it is the 1,6-dihydro derivatives which are formed. The addition of hydrogen to the 5,6-bond of thymidine and other 5-substituted uridines is stereospecific with rhodium-on-alumina as catalyst. Rhodium-on-charcoal has been useful for hydrogenation of the 5,6-double bond in uracils, uridine, and isocytosine. Raney nickel readily promotes saturation of the 5,6-double bond. Thio derivatives may either be dethiated or taken further to reduced forms by Raney nickel catalysts . 

Reist and coworkers [9,10] described the first sulfur-containing furanose rings. They prepared 4-thio-D-ribofuranose 14 (Figure 9.4) and 4-thio-L-ribofuranose via nucleophihc displacement of the tosylate in 2,3-(9-isopropylidene-4-(9-toluenesulfonyl-a-D- and -a-L-lyxopyranosides, respectively, with potassium thiobenzoate in DMF. Several nucleosides of 4-thiofuranoses were subsequently synthesized. For example, the 4 -thio analog 15 of natural thymidine and the corresponding derivative of cytidine were prepared by Whistler and coworkers [11]. 

Moorthy et al. [32] have synthesized 5-isopropylidiene derivatives of 3-dimethyl-2-thio-hydantoin XXVI, 3-ethyl-2-thio-2,4-oxazoIidinedione XXVII, and 5-benzilidene-3-ethyl rhodanine XXVIII, which are cytotoxic against leukemic cell line in concentration-dependent manner. The results of the trypan blue and MTT assays indicated that the compound XXVIII found to be fivefold to sevenfold more potent than XXVI and XXVII with IC5o<10 pM. XXVIII found to affect DNA replication by inducing a block at S phase on the basis of cell cycle analysis and tritiated thymidine assays. Moreover, the treatment of XXVIII led to increased level of reactive oxygen species (ROS) production and DNA strand breaks. This suggests the activation of apoptosis for induction of cell death. 

One group of compounds that have proved to be particularly effective in interfering with DNA synthesis of tumour cells are the mercapto-purines and pyrimidines and their alkyl derivatives 6-mercaptopurine (6-MP) blocks the de novo synthesis of purines 9-(jS-D-arabinofuranosyl)-—9H—purine—6-thiol (ara—6-MP) inhibits the incorporation of L-aspartic acid and orotic acid into DNA cystosine 9-OS-D-xylo-furanosyl)—9H—purine—6-thiol (xyl—6-MP) inhibits the utilization of exogenously administered guanine the periodic acid oxidation product of 9-(/S-D-ribosyl)—6-methyl—thio purine (MMPR—OP) blocks the incorporation of thymidine into DNA . The effective clinical use of thiols... 

Among the 3 -azido analogues of pyrimidine deoxyribonucleosides, 3 -azido-3 -deoxy-thymidine (2, AZT) was the most active against HIV-1 in vitro with an EC50 value of 0.002 jaM. Conversely, 3 -azido-3 -deoxy-6-azathymidine (37) was practically inactive (EC50 >100 aM). The 3 -azido derivatives of 3 -deoxy-3-(3-oxo-l-propenyl)thymidine (36), 2 -deoxyuridine (1), 5-bromo-2 -deoxyuridine (5), 2 -deoxy-5-fluorocytidine (8), 2 -deoxy-5-iodouridine (6), 2 -deoxycytidine (7), 2 -deoxy-5-fluorouridine (4), 2 -deoxy-5-thio-... 

Didehydro-2 ,3 -dideoxythymidine (d4T) was more active and selective than its saturated counterpart ddT, having an ED,o which ranged from 0.009 to 4.1 nM and an SI which varied from 27 to >7700. Replacement of the oxygen at position 4 of the heterocycle by a sulfur (4-thio-d4T) diminished activity 50-foId. The 2 -fluoro derivative of d4T was inactive, whereas 3 -F-d4T retained moderate activity, albeit less in magnitude than that exhibited by 3 -F-ddT. The 4 -hydroxymethyl and 4 -azidomethyl congeners of d4T were inactive, in contrast to the marked activity shown by the analogously substituted thymidines. 

Substitution of various nucleotides by 4 -thio-ribonucleotides into an siRNA sequence led to increased thermal and nuclease resistance, resulting in a longer term RNAi effect. A series of thymidine derivatives has been reported bearing C4 -carbo3q l-, metho q carbonyl-, carbamoyl-and methylcarbamoyl-substituents and evaluated for hybridisation properties with complementary DNA and RNA. Of note was a C4 -carbo)q -derivative that adopted an S-conformation resulting in an increase in thermal stability with RNA. ° 4 -C-Aminomethyl-2 -0-methylthymidine triphosphate has been shown to be incorporated into DNA using the thermophilic DNA polymerases Pfu and Therminator III. The incorporation of the C4 -modification resulted in an increased resistance towards exonuclease activity compared with the known 2 -0-methyl modification. ... 

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