1-P-D-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. 

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. 

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. 

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. 

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. 

B) Preparation of 1-p-D-Arabinofuranosylcytosine In a glass liner, a mixture of 1.16 g (3.0 mmol) of l-(2,3,5-tri-0-acetyl-p-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 semisolid 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-p-D-arabinofuranosylcytosine. 

Recently, we further modified NOAC by the synthesis of new duplex drugs by combination of the clinically used cancer drugs ara-C, 5-fluorodeoxyuridine (5-FdU) and the highly active new compound ethynylcytidine (l-(3-C-ethynyl-P-D-ribopentofuranosyl)-cytosine, ETC) with NOAC, yielding the heterodinucleoside phosphates arabinocytidylyl- N -octadecyl-1 -P-D-arabinofuranosyl-cytosine (ara-C-NOAC), 2 -deoxy-5-fluorouridylyl-N -octadecyl-l-P-D-arabinofiiranosylcytosine (5-FdU-NOAC) and ETC-NOAC ( 3 -C-ethynylcytidylyl-(5 5 )- octadecyl-1-p-D-arabinofuranosylcytosine) as shown in Fig. 2 (28-32). 

Horber DH, Schott H, Schwendener RA (1995) Cellular pharmacology of N -hexadecyl- 1-P-D-arabinofuranosylcytosine (NHAC) in the human leukemic cell lines K-562 and U-937. Cancer Chemother Pharmacol 36 483 92... 

Koller-Lucae SKM, Surer MJ, Rentsch KM, Schott H, Schwendener RA (1999) Metabolism of the new liposomal anticancer drug W-octadecyl-1-P-D-arabinofuranosylcytosine (NOAC) in mice. Drug Metab Dispos 27 342-350... 

Low density lipoprotein and liposome mediated uptake and cytotoxic effect of W-octadecyl-1-P-D-arabinofuranosylcytosine (NOAC)inDaudi lymphoma cells. Br JCancer 80 1542-1549... 

Horber DH, Cattaneo-Pangrazzi RM, von BaUmoos P, Schott H, Ludwig PS, Eriksson S, Fichmer I, Schwendener RA (2000) Cytotoxicity, ceU cycle perturbations and apoptosis in hmnan tumor cells by Upophilic W-aUcyl- 1-P-D-arabinofuranosylcytosine derivatives and the new heteronucleoside phosphate dimer arabinocytidylyl-(5 —>5 )-AP-octadecyl-l-P-D-ara-C. J Cancer Res CKn Oncol 126 311-319... 

P-D-Arabinofuranosylcytosine has been prepared in one step in 47.5% yield by reaction of cytidine with diphenyl carbonate in DMF at 120°C in the presence... 

A comparison of 1-p-D-arabinofuranosylcytosine and 1-P-D-arabinofuranosyl-5-fluorocytosine as inhibitors of herpes keratitis infection in rabbits and of vaccinia in tissue culture indicated comparable activity. The compound,... 

Anti-cancer 1 -P-D-arabinofuranosylcytosine has been isolated from the mushroom Xerocomus nigromaculatus. The broth of Nocardia brasiliensis SF2457 has yielded the antibiotic SF2457 13, a close relative of amicetin. Liposidomycins A-C 14 bave been isolated from S. griseosporeus," and a stereospecific synthesis of a stereoisomer of the ribosyl-diazepanone unit has been described in an attempt to elucidate the stereochemistry of the B component. ... 

In the field of pyrimidine nucleosides HPLC methods have been used to assay 1-P-D-arabinofuranosylcytosine in biological samples, its 5 -stearyl phosphate derivative, which is a pro-drug, and A -hexadecyl- and A -octadecyl derivatives... 

Preliminary studies with azauridine suggest that this material was effective for the treatment of herpes simplex and zoster infections of the human eye (69). Rabbits infected with vaccinia virus vaccine were com-pletely protected from pustule formation and erythema by 2-3 grams of compound injected IV (70). This material apparently has a low order of toxicity. 5-Bromo-2-deoxyuridine was found to inhibit a new virus, equine herpes 3, in rabbit kidney cells as well as pseudorabies, a DMA. virus, whereas vesicular stomatitis, an RNA virus, was resistant (71). A large number of nucleosides have been synthesized and tested in various systems for antiviral activity. 1-p-D-Arabinofuranosylcytosine (cytarabine ara-C) blocked DNA synthesis of herpes-infected cells (72) while a number of structurally related compounds showed some antiviral activity, although less than the parent compound (73,74,75,76). It is still too early to determine the ultimate value of these newer agents as "antiviral" drugs. 

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