Synthesis and Comparative Study of Anti-Adenoviral Activity of 6-Azacytidine and Its Analogues

Abstract

This paper presents the results of synthesis and study of cytotoxicity and the anti-adenoviral activity of new N4-derivatives of 6-azacytidine and its α-L-glycopyranosyl analogues obtained by the simplified one-pot version of the silyl condensation method. The resulting acylated 4-methylmercapto-1,2,4-triazin-3(2Н)-one glycosides then underwent the amination and/or ammonolysis to provide 6-azacytidine glycoside analogues (2-6, 12, 15, 17) and compounds with modifications at both base and sugar fragments (11, 15). The evaluation of cytotoxicity and antiviral activity of new compounds against AdV5 showed high selectivity indexes for N4-methyl-6-azacytidine (2) and N,O-tetraacetyl-6-azacytidine (8). High anti-adenoviral activity of N4-methyl-6-azacytidine as well as very low cytotoxicity may suggest its further investigation as potential compound for the therapy of AdV infection.

Selected nucleos(t)ide-based prescribed drugs and their multi-target activity

“…Experimental studies have shown that azacitidine is a potent, broadspectrum antiviral agent. The range of viruses against which it shows activity includes AdV (Alexeeva et al, 2001(Alexeeva et al, , 2015, human metapneumovirus (HMPV) (Bösl et al, 2019), HIV-1 (Dapp et al, 2009;Rawson et al, 2016a), HIV-2 (Beach et al, 2014), Rift Valley fever virus (RVFV) (Ianevski et al, 2018, human T-lymphotropic virus (HTLV-1) (Diamantopoulos et al, 2012), HSV-1, and FLUAV (Ianevski et al, 2018). A study of azacytidine activity against HIV-1 and HIV-2 revealed that it primarily targets reverse transcription (in the form of 5azacytidine-triphosphate or 5-aza-2′-deoxycytidine triphosphate).…”

“…The synergism was explained by the reduced accumulation of reverse transcription products rather than increased viral mutagenesis (Rawson et al, 2016b). A recent study on human adenoviruses revealed that azacytidine itself was an effective antiviral agent over a wide range of concentrations but its derivatives showed even better results, namely, N 4 -methyl-6-azacytidine and N 4 ,O-tetraacetyl-6-azacytidine, for which high selectivity against AdV and low cytotoxicity were observed (Alexeeva et al, 2015).…”

“…Myelodysplastic syndrome (2004) AdV (Alexeeva et al (2001); (Alexeeva et al, 2015) HMPV (Bösl et al, 2019) HIV-1 (Dapp et al, 2009;Rawson et al, 2016a) HIV-1 -synergy in combination with resveratrol (Rawson et al, 2016b) HIV-2 (Beach et al, 2014) RVFV ( (Clouser et al, 2012) HIV-1 -synergy in combination with decitabine (Clouser et al, 2010) MuLV (Clouser et al, 2012) HIV-2 (Beach et al, 2014) ZIKV (Kuivanen et al, 2017) Enteroviruses including poliovirus (Kang et al, 2015;Zhang et al, 2017) Enteroviruses -synergy with ribavirin (Kang et al, 2015) Rhinoviruses (Song et al, 2017) HCV (Beran et al, 2012) Coronaviruses (Dyall et al, 2014) SINV, HSV-1, FLUAV (Denisova et al, 2012) Gram-positive bacteria (Jordheim et al, 2012;Sandrini et al, 2007;…”

USC-087 protects Syrian hamsters against lethal challenge with human species C adenoviruses

“…Very recently, a number of other compounds and agents have been shown to have anti-HAdV activity in cell culture. These include cardiotonic steroids (Grosso et al, 2017), 3-hydroxy-quinazoline-2,4(1 H ,3 H )-diones (Kang et al, 2016), phenols in black tea extract (Karimi et al, 2016), dioscin, a compound extracted from air potato (Liu et al, 2013), 6-azacytidine (Alexeeva et al, 2015), and pyrrole and pyrrolopyrimidine compounds (Hamdy and El-Senousy, 2013; Mohamed et al, 2015).…”

Approach to Artificial Nucleosides from Glycoside Isothiocyanates: Synthesis of Original N‐Glycosylated Heterostructures by Cyclocondensation Reactions

“…Modified nucleobases have provided interesting progress in pharmaceutical applications . For example, 5‐azacytidine and 6‐azacytidine exhibit strong activity by means of their triazine skeletons (Figure ) . Modulation of the sugar part has also found many applications in the pharmaceutical field.…”