Deoxycytidine analogs

S. Hildbrand and C. Leumann, Enhancing DNA triple helix stability at neutral pH by the use of oligonucleotides containing a more basic deoxycytidine analog, Angew. Chem. Int. Ed., 35 (1996) 1968-1970. 

Van Rompay, A.R. Johansson, M. Karlsson, A. Phosphorylation of deoxycytidine analog monophosphates by UMP-CMP kinase molecular characterization of the human enzyme. Mol. Pharmacol., 56, 562-569 (1999)... 

Gemcitabine is a fluorine-substituted deoxycytidine analog related structurally to cytarabine (see Table 124—11). Its activation and mechanism of action are similar to those of cytarabine. Gemcitabine is incorporated into DNA, where it inhibits DNA polymerase activity. It also inhibits ribonucleotide reductase. Compared with cytarabine. 

Scheme 6 illustrates the use of these protecting groups in the phosphorylation of 2 -deoxynucleosides by Michelson and Todd. 5 -0-Trityl-thymidine (110) was phosphorylated with dibenzyl phosphorochloridate (44) to (111), which, after treatment with 80% acetic acid, afforded thymidine 3-(benzyl phosphate) (112). Catalytic hydrogenolysis of (112) gave thymidine 3 -phosphate. Acetylation of (110) yielded the 3 -acetate (114) which, on detritylation to (115), followed by phosphorylation, catalytic reduction, and deacetylation, gave thymidine 5 -phosphate (116), identical with the thymidylic acid obtained by enzymic hydrolysis of 2 -deoxyribonueleic acid. A rather similar sequence was applied to the preparation of the 2 -deoxycytidine analogs of (113) and (116). 

Nakatani-Freshwater, T., Babayeva, M., Dontabhaktuni, A., Taft, D. R. (2006). Effects of trimethoprim on the clearance of apricita-bine, a deoxycytidine analog reverse transcriptase inhibitor, and Lamivudine in the isolated perfused rat kidney. The Journal of Pharmacology and Experimental Therapeutics, 319, 941—947. 

Lin KY, Jones RJ, Matteucci M (1995) Tricyclic 2 -deoxycytidine analogs - syntheses and incorporation into oligodeoxynucleotides which have enhanced binding to complementary RNA. J Am Chem Soc 117(13) 3873-3874... 

As was the case with the thymidine and uridine nucleosides, the addition of an azido or cyano group to the 4 -position of 2 -deoxycytidine led to very potent compounds. 4 -Azidocytidine, in comparison, was inactive. The 2 -deoxycytidine analogs in general were as potent as the thymidine derivatives and more potent than the 2 -deoxyuridine analogs. 4 -Cyano-2 -deoxycytidine was significantly more potent than was its 2 ,3 -dideoxycytidine counterpart. This trend was also observed in the thymidine series. 

The modification of DNA including differently protected alkyne-containing bases, which can be sequentially/selectively cleaved in order to click various tags on the same strand, has also been explored [74]. Thus, a DNA strand containing a 5-alkynyl uridine derivative along with TMS- and TIPS-protected 5-alkyne-2 -deoxycytidine analogs was synthesized, and after a series of... 

Decitabine (5-aza-deoxycytosine) is an analog of the nucleoside 2 -deoxycytidine. It is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and by inhibition of the enzyme DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. DNA hypomethylation is achieved at concentrations below those required to significantly inhibit DNA synthesis, which may promote restoration of function to genes associated with control of cellular differentiation and proliferation. Cytotoxicity in rapidly dividing cells may also result from covalent adducts between DNA methyltransferase and decitabine. 

The cytotoxic activities of the 2, 2 -difluoro analog (775) of 737 against Chinese hamster ovary and tumor cells, in comparison with those of 1- -d-arabinofuranosylcytosine ara-C, a drug for leukemia), have been studied 775 is transported the faster through membrane into cells, more effectively phosphorylated by the deoxycytidine kinase (to the 5 -mono-phosphate) and, after conversion into the 5 -triphosphate, more highly accumulated in the cells, with longer duration time, than is ara-C, but nevertheless 775 is incorporated into the DNA to a lesser extent than is ara-C. These characteristics of 775 were discussed. 

The 2 -chloro and 2 -bromo congeners of either 748 (FIAC) or 758 (FMAU) are more cytotoxic than FIAC and FMAU, suggesting that these chloro and bromo nucleosides, in contrast to the 2 -fluoro compounds, are comparatively better substrates for deoxycytidine kinase of human lymphocytes than the substrates for viral-specific thymidine kinase. The disposition of the 2 -fluoro group may also be important from the biological viewpoint. It should be noted that the structural difference between RNA and DNA is at the 2 -position. The ribo type of analog (738) of FIAC is 10 times less effective in suppression of HSV replication than is FIAC. Thus Fox, and Watanabe and coworkers concluded that the 2 - up fluorine disposition and the species of the substituent at C-5 are the two important factors influencing antiviral activity. Nevertheless, the mechanism of action of 2 -deoxy-2 -fluorocytidine (737) on certain herpes viruses, including HSV-1... 

Pyrrolo-dc and pyrrolo-c fluorescent analogs of cytidine and 2 -deoxycytidine for the study of oligonucleotides. Tet Lett 45 2457-2461... 

Pharmacology Zalcitabine, active against HIV, is a synthetic pyrimidine nucleoside analog of the naturally occurring nucleoside deoxycytidine in which the 3 -hydroxyl group is replaced by hydrogen. Within cells, zalcitabine is converted to the active metabolite, dideoxycytidine 5 -triphosphate (ddCTP), by cellular enzymes. ddCTP inhibits the activity of the HIV-reverse transcriptase both by competing for utilization of the natural substrate, deoxycytidine 5 -triphosphate (dCTP), and by its incorporation into viral DMA. 

Hudarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine. Its cytotoxicity is not well understood. It is rapidly dephospho-rylated at the cell membrane level and then rephos-phorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative. It inhibits DNA polymerase and DNA primase. It is also incorporated into DNA and RNA. Hudarabine is administered intravenously by infusion over 30-120 min. It is eliminated by renal excretion with a terminal half life 10 hours. Adverse effects include myelosuppres-sion, nausea, vomiting, chills and fever. The number of CD4 positive cells is reduced and the incidence of opportunistic infections is increased. 

Gaubert, G. Gosselin, G. Boudou, V. Imbach, J.L. Eriksson, S. Maury, G. Low enantioselectivities of human deoxycytidine kinase and human deoxyguanosine kinase with respect to 2 -deoxyadenosine, 2 -deoxyguanosine and their analogs. Biochimie, 81, 1041-1047 (1999)... 

Cytosine arabinoside (Cytarabine, Cytosar, and Ara-C) is an analog of deoxycytidine, differing only in its substitution of sugar arabinose for deoxyribose. It is converted to Ara-CTP, and thereby inhibits DNA polymerase according to the following reactions ... 

Berry, D., Jung, K., Wise, D., Sercel, A., Pearson, W., Mackie, H., Randolph, J., and Somers, R. (2004). Pyrrolo-dC and pyrrolo-C Fluorescent analogs of cytidine and 2 -deoxycytidine for the study of oligonucleotides. Tetrahedron Lett. 45, 2457—2461. 

Fischhaber, P. L., et al. (1997). Synthesis of duplex DNA containing a spin labeled analog of 2 -deoxycytidine. Nucleosides Nucleotides 16, 365-377. 

Nucleoside analog 5 - Aza-2 Deoxycytidine Differentiation and cell cycle... 

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