Synthesis of Homoaristeromycin Analogues as Potent antiviral agents

Abstract

(-)-Aristeromycin (1) exhibits significant antiviral activity through inhibition of S-adenosylhomocysteine (SAH) hydrolase, which has been a promising target for many broad antiviral agents. However, its therapeutic utility has been limited due to its the significant toxicity. This cytotoxicity arise from 5'-phosphorylation to the corresponding nucleotides by cellular kinase. To lower cytotoxicity, an approach of extending the C-5' hydroxymethyl side chain by one carbon homologation was made to provide the C-5' homolog of (-)-aristeromycin. Furthermore, we thought that introduction of fluorine atom at 6'-position which is bioisostere with hydrogen atom improves antiviral activity by SAH hydrolase inhibitory effect. Based on these strategy, 6'-fluoro-homoaristeromycin analogues were designed and synthesized via Michael reaction and stereoselective electrophilic fluorination as key steps. (‒)-6'-b-Fluoro-homoaristeromycin (3) showed potent inhibition of SAH hydrolase (IC50 = 0.36 nM), high anti-Chikungunya activity (EC50 = 0.12 uM) and low cytotoxicity (CC50 > 250 uM). Selectivity index is more than 2087. In brief, the (‒)-6'-b-fluoro-homoaristeromycin (3) showed potent activity against Chikungunya virus and low toxicity. This study can be extensively applied to the development of potent antiviral agents.