Carbocyclic nucleosides antiviral activities

Deoxy-5 -fluoroadenosine (911) and the analogs 910, 912, 913 were prepared by coupling of 5-deoxy-5-fluoro-D-ribofuranose and 6-chloro-purine. 2, 5 -Dideoxy-5 -fluoroadenosine (914) was prepared through a displacement reaction of the corresponding 5 -0-tosyl precursor with fluoride (BU4NF in DMF). The carbocyclic nucleosides 915 and 916 have been prepared and their antiviral activities evaluated. 

Agrofoglio, L. et al. Synthesis of a New Exocyclic Amino Carbocyclic Nucleoside with Potential Antiviral Activity. 2.4 1993 [103]... 

Brothwick, A. D., Evans, D. N., Kirk, B. E., et al. (1990) Fluoro carbocyclic nucleosides synthesis and antiviral activity of 2 -and 6 -(luoro carbocyclic pyrimidine nucleosides including carbocyclic l-(2-deoxy-2-fluoro-P-d-arabinofuranosyl)-5-methyluracil and carbocyclic l-(2 -deoxy-2-fluoro-P-d-arabinofuranosyl)5-iodouracil. J. Med. Chem., 33, 179-186. 

Carbocyclic nucleoside analogues have also attracted considerable attention because of their antiviral and antitumor activities. Of particular interest are cyclohexenyl nucleosides, whose conformation resembles that of natural nucleosides. They can hybridize with nucleic acids and may therefore hold promise as components of antisense oligonucleotides.46-52... 

Neplanocins. Neplanocins A—D and F (37—41) are carbocyclic nucleoside antibiotic products of Ampullariella regularis (1,4) that are structurally related to (36) in that they contain either a cyclopentene or epoxy cyclopentane ring (121,122). The chemical syntheses of (37—41) and the 3-deazaneplanocins have been reported (123—126). Compound (37), which is converted to its 5 -triphosphate, has potent antitumor and antiviral activities (127—129). It strongly inhibits SAM in cells and viruses (128—131) and is converted to the 3 -keto derivative by Tadenosylhomocysteine hydrolase (132,133). 

Ohno has reviewed the work of his group on the enantioselective synthesis of, inter alia, nucleosides, C-nucleosides and carbocyclic nucleoside analogues using chiral synthons derived by asymmetric hydrolysis of meso-diesters with pig liver esterase. Although acyclonucleosldes are not discussed in detail in these volximes, we note an extensive review of the chemistry and antiviral activity of such compounds. ... 

Resolution of an Af-acetylaminocyclopentene carboxylate shown in Scheme 2.34 was used to access optically pure starting material for the synthesis of carbocyclic nucleoside analogs with promising antiviral activity [241]. The bulky tricyclic monoester was required for natural product synthesis [242]. 

Secrist JA, Montgomery JA, Shealy YF, O Dell A, Clayton SJ. Resolution of racemic carbocyclic analogues of purine nucleosides through the action of adenosine deaminase. Antiviral activity of the carbocyclic 2 -deoxyguanosine enantiomers. J Med Chem 1987 30 746-749. 

The cyclobutyl nucleosides (149) have been prepared they are related structurally to carbocyclic oxetanocin analogues of known antiviral activity (Vol. 23, p. 197-8), but were inactive.2 3 Other references to oxetanocin analogues are given in Chapter 19. 

Carbocyclic nucleosides are structural analogues of natural and synthetic nucleosides, which often exhibit powerful antitumor and antiviral activities. In the course of synthesising chiral members of this family of compounds, Castillon et al. have developed the DKR of a 3-hydroxymethyl-cyclopentanol intermediate as key step, providing the corresponding acetate which constituted the key intermediate of this synthesis. This DKR process was... 

In the area of carbocyclic nucleoside antibiotics, hydrolysis of the racemic esters 40 (R= n-Bu or ii-CeHis) by the lipase from Candida rugosa proceeds with very high enantiomeric selectivity, and from the resolved materials both enantiomers of aristeromydn were made by an established route. The authors report that a previous similar method (Vol.21, p. 182) is not as enantioselective. In a new synthesis of neplanocin A (43), the alcohol 41, derived from D-ribose, was converted to the cyclopentene 42 using an intramolecular insertion reaction of an alkylidene carbene. The new stereocentre in 42 was mostly of the wrong P-configuration, but could be corrected by a process of desilylation, oxidation and borohydride reduction. The biosynthesis of neplanocin A (43) and aristero-mycin has been reinvestigated, and the cyclopentenone 44 has been proposed as an intermediate, which is converted to aristeromycin via neplanocin A without any bifurcation. The 3-deaza-analogue 45 of 5 - or-aristeromydn has been prepared, and the antiviral activity of it and of the 7-deaza-compound (Vol.27, p. 235) are reported. ... 

Unsaturated and carbocyclic nucleoside analogues Synthesis, antitumor, and antiviral activity, J. Med. Chem. 34 421 (1991). 

Nucleosides in which the ribofiiranosyl oxygen is replaced by a methylene to result in a cyclopentane ring are referred to as carbocyclic nucleosides. The first such conopound was carbocyclic adenosine (1, aristeromycin), which was synthesized in its racemic form prior to isolation of the (-)-enantiomer from Streptomyces citricolor. The antiviral activity of has stimulated the search for other carbocyclic nucleosides that would display a more favorable therapeutic index. ... 

The naturally occurring oxetanocin A (18) and synthetic oxetanocin G (19) represent a novel class of nucleosides possessing antiviral propmies. Modification of die unique oxetanosyl-lV-glycoside structural feature of 18 and 19 into the carbocyclic nucleoside framework led to the synthesis of 20 and 21 as racemates and enantiomers, which have shown activity against herpesviruses and HIV.22b,c,24,25 in view of the potent and selective anti-HCMV properties of the l -enantiomer of 21, the synthesis of the R sto eoisomer 22 was undertaken and accomplished. 

Except for the oxetanocin G analogue 22, carbocyclic 7-deazaguanosines do not seem to provide a fruitful source of potential antiviral agents. This obs ation agrees with others who have noted decreases in antiviral activity when carbocyclic 7-deazapurine nucleosides are compared to their purine parent systems. This correlation carries over into the cytotoxicity results in that the carbocyclic 7-deazaguanosines reported hoein showed no cytotoxicity, which is in contrast to what is often seen in the 7-deaztq)urine nucleoside series. 

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