Arabinofuranosylcytosine

P-D-Arabinofuranosylcytosine [147-94-4] (ara-C, 16), C H N O, reportedly has had significant therapeutic effects in patients with localized herpes zoster, herpes eye infections, and herpes encephaUtis (33), although several negative results have also been reported (34) (Fig. 2). Ara-C, also known as cytarabine, is quite toxic and is only recommended for very severe viral infections. It is rapidly deaminated in humans to the relatively inactive ara-U Ara-C is converted in the cell to the 5 -monophosphate by deoxycytidine kinase, followed by formation of the corresponding di- and triphosphate. The triphosphate has been shown to inhibit DNA polymerase. 

B) Preparation of 1-0-D-Arabinofuranosylcytosine In a glass liner, a mixture of 1.16 g (3.0 mmol) of 1-(2,3,5-tri-0-acetyl-(3-D-arabinofuranosyl)-4-thiouracil prepared in (A) and about 60 ml of absolute methanol which had been saturated with anhydrous ammonia at 0°C was heated in a steel bomb at 98° to 105°C for 35 hours. After cooling to about 25°C and venting the bomb, the dark solution was filtered into a round-bottom flask. The methanol and excess ammonia were then removed under reduced pressure at about 25°C. The residual syrup was dissolved in absolute methanol, and the methanol was removed under reduced pressure at a bath temperature of about 40°C. This procedure of dissolving in absolute methanol and removing the solvent was repeated, and the residue was held under reduced pressure at a bath temperature of 45°C for 12 hours. 

The resulting semisoiid was triturated thoroughly with absolute methanol, and the resulting suspension was chilled at 0°C. A pale tan solid that separated was collected on a filter and washed repeatedly with methanol. After washing with anhydrous ether, there was obtained 430 mg of 1-(3-D-arabinofuranosylcytosine. 

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. 

MVE copolymer has been covalently linked with 5-fluorouridine (4, 5), daunomycin (6), adriamycin (6-8), p-D-arabinofuranosylcytosine (9) and... 

Eram, R. J., and Kufe, D., 1982, DNA strand breaks caused by irrhibitors ofDNA synthesis 1-beta-D-arabinofuranosylcytosine and aphidicoUtL Cancer Res. 42 4050-4053. 

Yuan, Z. M., S. Kharbanda, and D. Kufe., 1995, 1-beta-D-arabinofuranosylcytosine activates tyrosine phosphorylation of p34cdc2 and its association with the src-like p56/p531yn kinase in human myeloid leukemia cells. Biochemistry. 34 1058-1063. 

Figure 1 Chemical structures of the 5 —>5 phosphodiester duplex drugs Ara-C-NOAC, mol. wt. 801g/mol, 5-FdU-NOAC, mol. wt. 804g/mol, and ETC-NOAC, mol. wt. 825g/mol. Abbreviations-. Ara-C-NOAC, arabinocytidylyl-(5 —>5 )-lSr -octadecyl-l-P-D-arabinofuranosylcytosine 5-FdU-NOAC, 2 -deoxy-5-fluorouridylyl-(5 5 )-N" -octadecyl-l-P-D-arabinofuranosylcytosine ETC-NOAC, 3 -C-ethynylcytidylyl-(5 5 )-N" -octadecyl-l-P-D-arabinofuranosylcytosine.

Figure 2 In vitro cytotoxic activity on B16F1 melanoma cells of the duplex drugs in liposome formulations and of ETC dissolved in phosphate buffered saline. The corresponding IC50 values in mM are shown on the bars. Abbreviations ara-C-NOAC, arabinocytidylyl-N" -octadecyl-l-P-D-arabinofuranosylcytosine 5-FdU-NOAC, 2 -deoxy-5-fluorouridylyl-N" -octadecyl-l -P-D-arabinofuranosylcytosine ETC, ethynylcy-tidine [l-(3-C-ethynyl-P-D-ribopentafuranosyl)-cytosine] NOAC, ISf-octadecyl-ara-C PBS, phosphate buffered saline.

Schwendener RA, Schott H. Treatment of L1210 murine leukemia with liposome-incorporated N -hexadecyl-l-P-D-arabinofuranosylcytosine. Int J Cancer... 

Horber DH, et al. Pharmacokinetic properties and interactions with blood components of N -hexadecyl-l-P-D-arabinofuranosylcytosine (NHAC) incorporated into liposomes. J Pharm Pharmacol 1995 47 282. 

Horber DH, Schott CH, Schwendener RA. Cellular pharmacology of a liposomal preparation of ISf-hexadecyl-l-P-D-arabinofuranosylcytosine, a lipophilic derivative of 1-P-D-arabinofuranosylcytosine. Br J Cancer 1995 71 957. 

Horber DH, Schott H, Schwendener RA. Cellular pharmacology of N" -hexade-cyl-l-P-D-arabinofuranosylcytosine (NHAC) in the human leukemic cell lines K-562 and U-937. Cancer Chemother Pharmacol 1995 36 483. 

Schwendener RA, et al. Preclinical properties of N -hexadecyl- and N -octadecyl-1-P-D-arabinofuranosylcytosine in liposomal preparations. J Liposome Res 1995 5 27. 

Koller-Lucae SKM, Schott H, Schwendener RA. Pharmacokinetic properties in mice and interactions with human blood in vitro of liposomal N" -octadecyl-l-P-D-arabinofuranosylcytosine (NOAC), a new anticancer drug. J Pharmacol Exptl Therap 1997 282 1572. 

Koller-Lucae SM, et al. Metabolism of the new liposomal anticancer drug N -octadecyl-l-P-D-arabinofuranosylcytosine (NOAC) in mice. Drug Metabol Dispostion 1999 27 342. 

Horber DH, et al. Cytotoxicity, cell cycle perturbations and apoptosis in human tumor cells by lipophilic N" -alkyl-l-P-D-arabinofuranosylcytosine derivatives and the new heteronucleoside phosphate dimer arabinocytidylyl-(5 5 )-N" -octadecyl-l-P-D-ara-C. J Cancer Res Clin Oncol 2000 126 311. 

Schwendener RA, Schott H. Lipophilic 1-P-D-arabinofuranosylcytosine derivatives in liposomal formulations for oral and parenteral antitleukemic therapy in the murine L1210 leukemia model. J Cancer Res Clin Oncol 1996 122 723. 

Schott H, Schwendener RA. Synthesis of liposomal phospholipid-(N" -palmitoyl-l-P-D-arabinofuranosylcytosine)-conjugates and evaluation of their cytostatic activity against L1210 murine leukemia. Liebigs Annalen Chemie 1996 365. 

Allen TM, Mehra T, Hansen C, et al. Stealth liposomes an improved sustained release system for 1-P-D-arabinofuranosylcytosine. Cancer Res 1992 52 2431. 

Freemerman AJ, Turner AJ, Birrer MJ, Szabo E, Valerie K, Grant S (1996) Role of c-jun in human myeloid leukemia cell apoptosis induced by pharmacological inhibitors of protein kinase C. Mol Pharmacol 49 788-795 Freund A, Boos J, Harkin S, Schultze-Mosgau M, Veerman G, Peters GJ, Gescher A (1998) Augmentation of l-beta-D-arabinofuranosylcytosine (Ara-C) cytotoxicity... 

Wang S, Vrana JA, Bartimole TM, Freemerman AJ, Jarvis WD, Kramer LB, Krystal G, Dent P, Grant S (1997) Agents that down-regulate or inhibit protein kinase C circumvent resistance to 1-beta-D-arabinofuranosylcytosine-induced apoptosis in human leukemia cells that overexpress Bcl-2. Mol Pharmacol 52 1000-1009 Wang XY, Repasky E, Liu HT (1999a) Antisense inhibition of protein kinase C alpha reverses the transformed phenotype in human lung carcinoma cells. ]q> Cell Res 250 253-263... 

Heinemann V, Hertel LW, Grindey GB, et al. Comparison of the cellular pharmacokinetics and toxicity of 2, 2 -difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. Cancer Res 1988 48(14) 4024-4031. 

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