Search

Abstract: As a surrogate for 4′-hydroxy-5′-noraristeromycin and related carbocyclic nucleosides, an efficient, enantiodivergent synthetic route to both enantiomers of 5-(6-amino-9H-purin-9-yl)-3,3-difluorocyclopentane-1,2-diol (6 and ent-6) has been developed from a common starting material ((+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate, 10). Both compounds were assayed versus a series of viruses. The only response found was for compound 6 toward vaccinia and cowpox (EC50 of 143 and 94μM, respectively) and human cytomegalovirus (EC50 of 6.2μM). Both compounds were non-cytotoxic. While not as active as cidofovir toward the orthopox viruses and ganciclovir toward cytomegalovirus, compound 6 offers a new structural prototype upon which to build for uncovering new agents effective against these viral types. [Copyright &y& Elsevier]

Abstract: The potent antiviral potential of 5′-amino-5′-deoxy-5′-noraristeromycin (2) is limited by associated toxicity. To seek derivatives of 2 that circumvent this undesirable property, three amino substituted derivatives (acetyl, 3; formyl, 4; and methyl, 5) of 2 have been prepared in 4–7 steps from the same intermediate, (1S,4R)-4-(6-chloropurin-9-yl)cyclopent-2-en-1-ol (6). Key steps involved an improved Pd(0)-catalyzed allylic azidation and a novel Pd(0)-catalyzed allylic amidation. The three target compounds were evaluated against a large number of viruses and found to be inactive except for a very weak effect of 5 on human cytomegalovirus, varicella zoster virus, and Epstein–Barr virus. There was also no noteworthy cytotoxicity associated with the new derivatives. Thus, these results indicate variation of the cyclopentyl amine of 2 does not offer a means to improve upon its antiviral potential. [Copyright &y& Elsevier]

[Display omitted] In seeking to increase the library of fluorine containing adenine-derived carbocyclic nucleoside antiviral candidates, d -like and l -like 6′-fluoro-3-deazaneplanocin and its 3-bromo derivative lacking the 4′-hydroxylmethylene substituent (2 / 3 and 4 / 5 , respectively) are presented. Their synthesis was accomplished from d -ribose by developing a more facile precursor route than suggested by the literature. The 2 / 4 d -like pair displayed significant anti-filo virial properties while the enantiomeric l -like congeners 3 / 5 were inactive. Target compounds 2 / 4 also were active towards measles and norovirus. The effect of 2 / 4 is further evidence of the role fluoro-derived adenine carbocyclic nucleoside can play in antiviral drug discovery. Furthermore, the simplicity of their synthesis lends them to more efficacious analogs and to scale-up optimization. There were no other relevant antiviral properties for 2 / 3 and 4 / 5 (except BK polyomavirus for 3 / 5). [ABSTRACT FROM AUTHOR]

Abstract: Adenine is a poor substrate for the Mitsunobu process to carbocyclic nucleosides. However, N-6 amino bis-Boc-protected adenine is reported herein to undergo an efficient coupling under these conditions as a result of its increased solubility and the reduced competing nucleophilicity of the free adenine amino substituent. Products from this reaction are readily converted to aristeromycin, neplanocin, and analogs there from, including 5′-homoaristeromycin, a promising antiviral agent. [Copyright &y& Elsevier]

Abstract: A synthetic route to (1S,2S,3R,5S)-3-(6-amino-9H-purin-9-yl)-5-fluorocyclopentane-1,2-diol (that is, the 4′-fluoro derivative of 4′-deoxy-5′-noraristeromycin, 3) is described via a fluorinated cyclopentanol, which is in contrast to existing schemes where fluorination occurred once the purine ring was present. Compound 3 was assayed versus a number of viruses. A favorable response was observed towards measles (IC50 of 1.2μg/mL in the neutral red assay and 14μg/mL by the visual assay) but this was accompanied by cytotoxicity in the CV-1 host cells (21–36μg/mL). Among the viruses unaffected by 3 were human cytomegalovirus and the poxviruses (vaccinia and cowpox), which are three viruses that were inhibited by the 4′,4′-difluoro analog of 3 (that is, 2). [Copyright &y& Elsevier]