key: cord-0709734-dhuznzal authors: Chen, Qi; Liu, Chong; Bowlin, Terry L.; Schneller, Stewart W. title: 5′-Hydroxy-5′-homoaristeromycin: Synthesis and antiviral properties date: 2018-05-15 journal: Bioorg Med Chem Lett DOI: 10.1016/j.bmcl.2018.03.088 sha: 49299c3586fd3c3afa8b43f41ef23066d32f8c0c doc_id: 709734 cord_uid: dhuznzal Synthetically combining the C-4′ side-chain structural features of the antiviral candidates 5′-methylaristeromycin and 5′-homoaristeromycin into a diastereomeric pair of C-4′ side-chain dihydroxylated aristeromycins (6 and 7) is reported. Broad antiviral analyses of the both targets found promising effects towards HBV (6, 6.7 μM and 7, 7.74 μM) and HCMV (only 7, 0.72 μM). No other activity was found. Neither of the diastereomers was cytotoxic in the assays performed. Synthetically combining the C-4 0 side-chain structural features of the antiviral candidates 5 0 -methylaristeromycin and 5 0 -homoaristeromycin into a diastereomeric pair of C-4 0 side-chain dihydroxylated aristeromycins (6 and 7) is reported. Broad antiviral analyses of the both targets found promising effects towards HBV (6, 6.7 lM and 7, 7.74 lM) and HCMV (only 7, 0.72 lM). No other activity was found. Neither of the diastereomers was cytotoxic in the assays performed. Ó 2018 Elsevier Ltd. All rights reserved. While the report of biologically inactive carbocyclic thymidine (1) in 1962 1 introduced a new class of nucleosides, it was the synthesis of racemic carbocyclic adenosine (aristeromycin, 2) 2 and subsequent isolation of the (À)-enantiomer from Streptomyces citricolor 3 that the era of carbocyclic nucleosides began and became a focal point for the pursuit of carbocyclic nucleosides as therapeutic candidates and as probes for biological processes. 4 Our interest in aristeromycin and analogs therefrom began with the report of 5 0 -noraristeromycin (3) with activity towards human cytomegalovirus. 5 Over the years 6 since 1992 we have looked back to see what analogs lie in the wake of our work that suggested a further look into structural possibilities. Recently, in that regard, we were drawn to our reports that 5 0 -methylaristeromycin (4) 7 and 5 0 -homoaristeromycin (5) 8 have meaningful antiviral properties that had not been developed through analog design. This stimulated us to consider combining the two side chain features of 4 and 5 into diastereomers 6 and 7 (whose designation is derived from 5 0 -homoaristeromycin in blue possessing a 5 0 -hydroxyl). The outcome of that pursuit is presented here (see Fig. 1 ). Oxidation of alkenes to glycols is well established in the synthetic organic toolbox. Thus, for this investigation, the known N-6 protected carbocyclic adenine nucleoside with the unsaturated C-4 0 side chain 8 (available from D-ribose) 9 served as the starting point. To achieve the requisite diastereomers 9a and 9b ADmix-a (for 9a) and ADmix-b (for 9b) were employed, respectively. Deprotection of 9a and 9b with 2 N hydrochloric acid produced 6 and 7. The stereochemistry of 6 and 7 was determined by mesylation of 9a/9b to 10a/10b that were deprotected to 11a/11b. Reductive removal of the 6 0 -mesylate with lithium aluminum hydride yielded 12a/12b (a convenient, alternative synthesis of those diastereomers). The spectroscopic properties of 12a were identical to that previously reported for 4 (same as 12a). 7 To address any possible structural ambiguity in this study, confirmation of 6 was achieved by an X-ray structural analysis. 10 In an antiviral analysis, 11 both 6 and 7 showed moderate activity towards hepatitis B (EC 50 7.1 lM and 7.4 lM, respectively; CC 50 >100 lM)) while only 7 was potent against human cytomegalovirus (EC 50 0.72 lM; CC 50 >300 lM). Compound 6 was found to lack the significant yellow fever properties reported for 4 indicating addition of a hydroxyl to the methyl carbon of 4 (12a), resulted in an undesirable outcome for future development of 4 as a yellow fever antiviral candidate. A similar conclusion can be reached for the loss of the orthopox activity of 5 due to the presence of the extra hydroxyl group on the C-5 0 position of both diastereomers 6 and 7 (see Scheme 1.). In an antiviral analysis, 11 both 6 and 7 showed moderate activity towards hepatitis B (EC 50 7.1 lM and 7.4 lM, respectively; CC 50 >100 lM)) while only 7 was potent against human cytomegalovirus (EC 50 0.72 lM; CC 50 >300 lM). Compound 6 was found to lack the significant yellow fever properties reported for 4 indicating addition of a hydroxyl to the methyl carbon of 4 (12a), resulted in an undesirable outcome for future development of 4 as a yellow fever antiviral candidate. A similar conclusion can be reached for the loss of the orthopox activity of 5 due to the presence of the extra hydroxyl group on the C-5 0 position of both diastereomers 6 and 7. Compounds 6 and 7 were inactive towards polio virus, SARS coronavirus, respiratory syncytial virus, hepatitis C virus, herpes simplex 1 and 2 viruses, vaccinia virus, dengue, Rift Valley fever, Venezuelan equine encephalitis, H1N1 influenza A virus, and West Nile virus. No cytotoxicity was found for either 6 or 7 in the assays conducted. In conclusion, a convenient synthesis of the diastereomeric hybridization of 5 0 -methylaristeromycin (4) and 5 0 -homoaris-teromycin (5) to 5 0 -hydroxy-5 0 -homoaristeromycin (6 and 7) has provided a new C-4 0 structural entity for the aristeromycin family of analogs that showed potent HBV (6 and 7) and moderate HCMV activities (7) . It should be noted that the hydroxyl substituents offer the opportunity of making substituent changes at those centers for possible new aristeromycin structural variations. Crystallographic data (excluding structure factors) for 6 has been deposited with the Cambridge Crystallographic Data Centre with deposition number CCDC 1578521. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road hepatitis B (ayw, 2.2.15), polio virus (type 1, LLC-MK2 clone 7.1), SARS coronavirus (Toronto-2, Vero 6), respiratory syncytial virus (A, Hep 2), hepatitis C virus (CON-1, Huh-Luc/Neo), herpes simplex 1 (E-377, HFF) and 2 (G, HFF), vaccinia virus (Copenhagen, HFF), dengue (Type 2/New guinea, Vero76), Rift Valley fever (MP-12, Vero 76), Venezuelan equine encephalitis (TC-83, Vero), H1N1 influenza A virus For the assay methods see reference 12 in Chen Q We are grateful to the Molette Fund and Auburn University for support. We are also indebted to the NIAID in vitro assay team for the viral data presented herein. 11 Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.bmcl.2018.03.088.