Selenoacyclovir and Selenoganciclovir: Discovery of a New Template for Antiviral Agents

Abstract

On the basis of the potent antiviral activity of acyclovir and ganciclovir, selenoacyclovir (2a) and selenoganciclovir (2b) were designed based on bioisoteric rationale and synthesized via the diselenide 7 as the key intermediate. Compound 2a exhibited potent anti-HSV-1 and -2 activities while 2b exerted moderate anti-HCMV activity, indicating that these nucleosides can serve as a novel template for the development of new antiviral agents.

Structure-Activity Relationships of Acyclic Selenopurine Nucleosides as Antiviral Agents

“…Scheme 1 illustrates the synthesis of 6-chloro- and 2-amino-6-chloropurine derivatives 11 and 12 , which serve as the versatile intermediates for the synthesis of various seleno-acyclovir analogues [ 11 ]. 2-Bromoethanol ( 5 ) was converted to the glycosyl donor 8 according to our previously reported procedure [ 12 ]. 2-Bromoethanol ( 5 ) was treated with selenium dianion prepared in situ by heating with selenium powder and hydrazine hydrate in aqueous KOH solution to afford the diselenide 6 , which was protected with the tert -butyldiphenylsilyl (TBDPS) group to give 7 .…”

“…Treatment of 11 and 12 with 2-mercaptoethanol and NaOMe in MeOH yielded seleno-inosine derivative 3a (80%) and seleno-acyclovir 4a [ 12 ] (94%), respectively. The N 9 -isomer 4a was further confirmed by comparing the C5 signal (δ 116.73 ppm) of 4a with that (δ 116.73 ppm) of acyclovir ( 1 ) [ 12 ]. Compounds 11 and 12 were also converted to the N 6 -methyladenine derivative 3b and the 2-amino- N 6 -methyladenine derivative 4b , respectively, by heating with 40% aqueous methylamine solution in MeOH.…”

“…For the synthesis of seleno-ganciclovir analogues, the key intermediates 6-chloropurine derivative 20 and 2-amino-6-chloropurine derivative 21 were first synthesized, starting from glycerol ( 13 ), as depicted in Scheme 3 [ 12 ]. Glycerol ( 13 ) was converted to the glycosyl donor 17 according to our previously reported procedure [ 12 ]. Glycerol ( 13 ) was protected with the 1,3-benzylidene group by treating with benzaldehyde in the presence of p -TsOH to give 14 , which was treated with MsCl to give the mesylate 15 .…”

“…In preliminary accounts, we synthesized the selenium analogues 3 (X = H, R 1 = OH, R 2 = NH 2 , seleno-acyclovir) and 4 (X = CH 2 OH, R 1 = OH, R 2 = NH 2 , seleno-ganciclovir) of 1 and 2 because they are in bioisosteric relationships; we also evaluated them for antiviral activity [ 12 ]. As expected, seleno-acyclovir exhibited potent anti-HSV activity, while seleno-ganciclovir exerted significant anti-HCMV activity [ 11 ].…”

Synthesis of Acyclic Selenonucleoside Phosphonates as Potential Antiviral Agents

“…Selenium belongs to the same group in the periodic table as oxygen, group 16, and is a chemical isostere of oxygen that has similar physicochemical properties . Recently, we have reported seleno‐acyclovir as a potent anti‐herpes simplex virus (HSV) agent, indicating that selenium can serve as the bioisostere of oxygen . Furthermore, selenium is more lipophilic than oxygen and its presence can result in better penetration across the cell membrane, including the blood‐brain barrier (BBB), resulting in better oral bioavailability.…”