Cytosine antiviral derivatives

Cytosine Derivatives. l-/j-D-Arabinoiuranosylcytosine (ara-C). G)H 3N3C>5 reportedly has had significant therapeutic effects in patients with localized herpes zoster, herpes eye infections, and herpes encephalitis. although several negative results have also been reported, Ara-C. also known as cytarabine. is quite toxic and is only recommended for very severe viral infections. A number of derivatives of ara-C have been prepared in an effort to improve on antiviral activity and to reduce the toxicity. 

Table VII summarizes additional examples of allylations of 190 and 191 as well as of cytosine 200 and 5-methylcytosine 201 (Scheme 44) with electrophiles 74, rac-166, and rac-204 together with the targeted final products. Reactions with glycoside 74 and with vinyl epoxide 204 always occur with overall retention of configuration. The reactions with cyclopentene derivatives are related to the preparation of synthetic carbanucleosides with antiviral action.

Biological activities— The 5-halo derivatives and the mercapto analogues of cytosine have been discussed in Part I of this review. Cytosines with fraudulent sugars have received extensive study. Although a discussion of this type of modification is beyond the scope of this review, the fact that cytosine arabinoside [285, 286] (LVI, l-/S-D-arabinofuranosylcytosine, Ara-C, CA, cytarbine) is a potent antiviral agent against herpes and vaccinia virus [287-293] as well as a potent antileukaemia agent must not escape mention. In the latter case cytosine arabinoside is not only effective in transplantable... 

Cytosine arabinoside is enzymatically deaminated in the liver. The resulting product, uracil arabinoside, no longer possesses antileukaemia or antiviral activity [291, 292, 340, 341]. A variety of cytosine derivatives have been studied as deaminase inhibitors. The most active of these was a 4-hydroxylamino derivative, iV -hydroxy-5-methyl-2 -deoxycytidine [342]. 

Another cytosine derivative with antiviral activity is the 5-(4-aminophenyl) cytosine (LVII). This substance, according to results of clinical trials, possesses good prophylactic activity against influenza A2 [343]. The LD50... 

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 number of H-phosphonate derivatives of 3 -azido-2, 3 -dideoxynucleosides with adenine, guanine, and cytosine [59,63-65] exhibit antiviral acivities with selectivity similar to or higher than that of the corresponding nucleoside. 

Cyclic 3, 5 -phosphates of ara-A (7, B = adenyl) [12], ara-C (7, B = cytosyl) [15] and thioinosine (8, R = H) have been synthesized [16]. The acylated thioinosine derivative (8, R = Me(CH2)i4CO, ECso 6 //M) has been shown to readily enter S49 mouse lymphoma cells and then be metabolized to thioinosine 5 -monophosphate catalyzed by phosphodiesterase and deacylation. More recently, the cyclic phosphonate analogue (9) of the antiviral (5)-l-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) has been prepared and shown to have comparable activity against HSV-2, both in vitro in MA-104 and MRC-5 cells and in vivo in a mouse encephalitis model, to that of the parent drug [17]. The cyclic phosphonate (9) was converted to HPMPC inside the cells, before phosphorylation to the active diphosphate. 

Both analogues can sm e to iUustrate an important problem frequently associated with design of new biologically active nucleoside analogues, namely, base selectivity. Thus, the antiviral effect of acyclovir (la), a guanine derivative, is unique. The corresponding adenine analogue (Ic), which is historically the first compound of this series, is much less effective. The thymine and cytosine derivatives lb. Id have virtually no antiviral activity. ... 

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