Ribonucleosides, antiviral

Crotty S, Maag D, Arnold JJ, et al. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med 2001 6 1375-9. 

Figure 3 Binding site cavities of a series of antiviral ribonucleosides obtained by the REMOTDISC method. Each site is labeled note that in this example not all space belongs to a site and sites 1, 2, 4, 5, and 7 are not completely enclosed. Reprinted with permission from Ref. 156. Copyright 1989, American Chemical Society.

The other thiosemicarbazones are less well studied and as yet the link between antiviral action and chelation is not fully established. It has been proposed that the chelation of iron(II), a cofactor of ribonucleoside diphosphate reductase, could be the principal mode of action of the thiosemicarbazones300. However, other mechanisms are possible. Investigations of the ESR spectra of copper(II) complexes of thiosemicarbazones has been used to follow the intracellular reactions of the complexes - see Antholine et al.301 for a review. In Ehrlich cells the chelate becomes localized in the cell membrane302. This spectroscopic technique could also be used to monitor the antimala-rial action of 2-acetylpyridine thiosemicarbazones303. ... 

In 2001 a critical stndy published in Nature Medicine showed in vitro nse of ribavirin triphosphate by a model viral RNA polymerase, polioviras 3D pol. Ribavirin incorporation is mutagenic, because it serves as a template for incorporation of cytidine and uridine with equal efficiency (Figure 2-2). Ribavirin reduces infectious poliovirus production to as little as 0.00001 percent in cell culture. The antiviral activity of ribavirin correlates directly with its mutagenic activity. These data indicate that ribavirin forces the virus into error catastrophe. This study reveals a new concept about nucleoside analogs, that is, mutagenic ribonucleosides may represent an important class of anti-RNA virus agents. 

Nucleosides prepared conventionally from deoxy-sugars have included the antiviral nucleoside dihydro-5-azathymidine (12), the tritiated analogue (13), and the 6-substituted derivatives (14) (Scheme 2), [ C-2] and [ C-4]-2-deoxy-uridine, and 2-deoxy-ribonucleosides from 5-azapyrimidine derivatives, ... 

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). ... 

Zeynep A, Mehmet A, Canan K, SuLhiye Y, Eidem B, Hakan G (2006) Synthesis and potent antimicrobial activities of some novel retinoidal monocationic benzimidazoles. Arch Pharm Chem Life Sci 339(2) 74-80. doi 10.1002/aidp.200500168 Zhu L, Zhang M (2004) Ortho-selective nucleophilic aromatic substitution reactions of polyhaloanilines with potassium/sodium G-ethyl xanthate a convenient aeeess to halogenated 2(37f)-benzothiazolethiones. J Org Chem 69(21) 7371-7374. doi 10.1021/jo049056s Zou R, Ayres K, Drach J, Townsend L (1996) Synthesis and antiviral evaluation of certain disubstituted benzimidazole ribonucleosides. J Med Chem 39(18) 3477-3482. doi 10.1021/ jm960157v... 

A general method for the synthesis of 3 -azido -2, 3 -dideoxy-ribofuranosyl nucleosides involves the reaction of methyl 3-azido-2,3-dideoxy-5-0-toluoyl-D-ribose with the nucleoside base in the presence of TMSOTf. A range of 3 -azido- and 3 -amino-2, 3 -dideoxypyriraidine ribonucleosides have been prepared and evaluated as antiviral agents. 

Anticancer examples, Thiosemicarbazones have been mentioned above in connexion with their antiviral and antitubercular properties. They also have anticancer activity, as already mentioned for 5-hydroxypicolinic aldehyde thiosemicarbazone (4.18) in Section 4.0. Such substances powerfully inhibit ribonucleoside diphosphate reductase, the enzyme which converts ribo- to deoxyribo- nucleotides, leading to inhibition of DNA synthesis. Interaction with the enzymatically-required iron by these drugs in thought to lie at the root of their action (Agrawal, et al,y 1972). 

Modification other atoms or groups. Besides fluorine atoms, other atoms (such as C, N and O) and groups are also used to produce novel sugar-modified nucleoside monophosphates. 2-C-Methyl nucleosides are potential candidates with activity against Hepatitis C virus. Leisvuori et al ° prepared 3,5-cyclic phosphates (25a) and 3,5-cyclic thiophosphates (25h) of 2-C-methyl ribonucleosides as potential antiviral drugs. 

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