Arabinosyl cytosine

DNA, RNA and protein synthesis at concentrations close to those at which viral growth was inhibited and hence they have both low antiviral selectivity and therapeutic index. Some improvements in the therapeutic index have been achieved through structural modifications [156]. Two synthetic antiviral agents are currently under clinical use ara-A (9P-D-arabinofuranosyladenin, 200) and ara-C (1-P-D-arabinosyl-cytosine, 201) are related to the arabinosides isolated in the early 1950s from the marine sponge Cryptotethia crypta, (Table 10) [155]. 

Numerous syntheses have also been reported for arabinofuranosyl nucleoside analogues, prepared either conventionally from arabinofuranosyl derivatives or via 2,2-anhydro-nucleosides obtained from appropriate ribonucleosides. 5-Aza-cytosine-D-arabinoside has been synthesized and found to show similar antiviral activity to Ara-C(arabinosyl-cytosine). 7-a-, 7-<3-, 9-0 -, and 9- 3-arabino-furanosyl derivatives of 3-deazaguanine have also been prepared, but none showed any anti-tumour activity. 9-(o -D-Arabinofuranosyl)-8-aza[2- C]-adenine, 7-(/3-D-arabinofuranosyl)-pyrrolo[2,3-d]pyrimidine-4(3//)-one (15)," l-(a-D-arabinofuranosyl)- and l-(/3-D-xylofuranosyl)-4-nitropyrazole, and Ot-arabino-nucleosides of 5-fluoro-cytosine and -uracil derivatives have also been prepared. An improved synthesis of 9-(/3-D-arabinofuranosyl)-2-fluoro-adenine has been reported. The ratio of o to 3 anomers obtained by phase-transfer reaction of 2,3,5-tri-O-benzyl-D-arabinofuranosyl bromide with 6-chloro-2-thiomethyl-7-deazapurine varied with the quaternary ammonium salt used as a catalyst, although the jU-anomer predominated in every case. 2,2-Anhydro-nucleosides have been used to prepare l-j3-D-arabinofiiranosyl derivatives of 5-alkylthio-uracils, 5-ethyl-cytosine, and 5-ethyl-uracil, 8-alkylamino-purines, and 2-aralkylamino-l,4-dihydro-4-imino-pyrimidine hydrochlorides (16). ... 

A very intense search for antiviral and cancerostatic agents has led to the synthesis of countless nucleoside analogues. Virtually all possible chemical modifications (on the bases, sugars, and even the phosphate) have been made and tested in vitro and in vivo. Two of the most intensively studied antimetabolites are arabinosyl cytosine (araCyd) and formycin A (see Fig. 3-1). The former is used in the clinical treatment of oncogenic viruses and leukemia. After transformation to the triphosphate it is incorporated into DNA, where it may be a chain terminator. Formycin A and B (A is the Ado analogue, B the Ino analogue) are both in the syn conformation and have strong antiviral activity. 

The utility of pyrimidine and purine analogs in cancer chemotherapy (e.g. 6-mercaptopurine, 5-fluorouracil, arabinosyl cytosine) serves as a continued stimulus for the preparation of new compounds of this type. Among these,3-deaza-uridine [l-(j3-p-ribofuranosyl)-4-hydroxy-2-pyridone] was markedly active... 

Haurani, R. Kyle, J.L. Hutchison, R.J. Forcier, and J.H. Moon, Arabinosyl cytosine a useful agent... 

Moreover, where studied (3,i), the 2 -fluoro nucleosides were resistant to catabolic cleavage by nucleoside phosphorylases, presumably a result of the increased metabolic stability of the N-glycosyl linkage imposed by this electronegative 2 -substituent. Of the several 2 -fluoro—5-substituted—arabinosyl pyrimidine nucleosides synthesized (1.), l-(2 -deozy-2 -fluoro-3-D-arabinofuranosy 1 )-5-iodo-cytosine [FIAC] has demonstrated clinical efficacy against Herpesvirus infections in Phase 1 (5,) and against Varicella zoster virus in Phase 2 ( ) clinical trials in immunocompromised cancer patients. 

Deoxy-2-halogeno-arabinosyl bromides have been used to prepare halo-nucleosides from 5-substituted-uracil or -cytosine bases leading to 2 -bromo, 2 -chloro, and 2 -fluoro-arabino-nucleoside analogues the 2 -fluoro analogues were most effective as anti-viral 48... 

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