Synthesis and Antiviral Activity of Novel 5-(1-Cyanamido-2-haloethyl) and 5-(1-Hydroxy(or methoxy)-2-azidoethyl) Analogues of Uracil Nucleosides

Abstract

A new class of 5-(1-cyanamido-2-haloethyl)-2′-deoxyuridines (4-6) and arabinouridines (7, 8) were synthesized by the regiospecific addition of halogenocyanamides (X-NHCN) to the 5-vinyl substituent of the respective 5-vinyl-2′-deoxyuridine (2) and 2′-arabinouridine (3). Reaction of 2 with sodium azide, ceric ammonium nitrate, and acetonitrile-methanol or water afforded the 5-(1-hydroxy-2-azidoethyl)-( 10) and 5-(1-methoxy-2-azidoethyl)-2′-deoxyuridines (11). In vitro antiviral activities against HSV-1-TK + (KOS and E-377), HSV-1-TK -, HSV-2, VZV, HCMV, and DHBV were determined. Of the newly synthesized compounds, 5-(1-cyanamido-2-iodoethyl)-2′-deoxyuridine (6) exhibited the most potent anti-HSV-1 activity, which was equipotent to acyclovir and superior to 5-ethyl-2′-deoxyuridine (EDU). In addition, it was significantly inhibitory for thymidine kinase deficient strain of HSV-1 (EC 50 ) 2.3-15.3 µM). The 5-(1cyanamido-2-haloethyl)-2′-deoxyuridines (4-6) all were approximately equipotent against HSV-2 and were ∼1.5and 15-fold less inhibitory for HSV-2 than EDU and acyclovir, respectively. Compounds 4-6 were all inactive against HCMV but exhibited appreciable antiviral activity against VZV. Their anti-VZV activity was similar or higher to that of EDU and approximately 5-12-fold lower than that of acyclovir. The 5-(1-cyanamido-2-haloethyl)-(7,8) analogues of arabinouridine were moderately inhibitory for VZV and HSV-1 (strain KOS), whereas compounds 10 and 11 were inactive against herpes viruses. Compounds 5 and 6 also demonstrated modest anti-hepatitis B virus activity against DHBV (EC 50 ) 19.9-23.6 µM). Interestingly, the related 5-(1-azido-2-bromoethyl)-2′-deoxyuridine (1n) analogue proved to be markedly inhibitory to DHBV replication (EC 50 ) 2.6-6.6 µM). All compounds investigated exhibited low host cell toxicity to several stationary and proliferating host cell lines as well as mitogen-stimulated proliferating human T lymphocytes.

5-(1-Substituted) Alkyl Pyrimidine Nucleosides as Antiviral (herpes) Agents

“…None of the compounds were markedly inhibitory against HSV-1 strains (KOS, E-377), and HSV-2, which is not surprising in view of the inactivity of various other acyclic pyrimidine nucleosides [74,76,77]. In contrast, compounds 39-47 exhibited activity against VZV (EC 50 = 2.4 -52 µM), as compared to the reference drug ACV (EC 50 = 2.6 µM) [73]. Intriguingly, the acyclic derivatives of 5-(1-azido-2-haloethyl)uracil (39)(40)(41)(42)(43)(44)(45)(46)(47) also proved inhibitory to HCMV.…”

“…Reaction of 5-vinyl-2'-deoxyuridine with sodium azide, ceric ammonium nitrate, and acetonitrile-methanol or water afforded the 5-(1-hydroxy-2-azidoethyl)-(37) and 5-(1-methoxy-2-azidoethyl)-(38) analogs of 2'-deoxyuridine (Scheme 5) [73].…”

“…From antiviral evaluation studies, it was found that the 5-(1-cyanamido-2-haloethyl)-2'-deoxyuridines (32-34) exhibited significant inhibitory activity against HSV-1 (strains KOS and E-377), HSV-2 and VZV replication as shown in Table 7 [73]. The most potent compound of this series 5-(1-cyanamido-2-iodoethyl)-2'-deoxyuridine (34) inhibited HSV-1 strains (EC 50 = 1.6 -9.4 µM range) at concentrations which compared favourably with that of reference drug ACV (EC 50 = 2.2 -4.4 µM range).…”

“…It is interesting to note that the anti-HCMV activity of compounds 45-47 (EC 50 = 2.7 -14.4 µM range) was significantly improved compared to their 2'-deoxyribosyl analogs (4a-c), which were inactive, but equivalent to their 2'-arabinosyl derivatives (5-7) (EC 50 The observation that compounds 39-47 exhibited appreciable anti-VZV and anti-HCMV activity, and no toxicity to several host cells [73], suggests that they may be selectively phosphorylated in virus-infected cells by VZV-TK or UL-97, respectively, and inhibit viral DNA polymerase. Alternatively, compounds 39-47 may be phosphorylated by cellular kinases in both virus-infected and uninfected cells, but selectively inhibit viral DNA polymerase.…”

Capillary electrophoresis‐electrospray‐mass spectrometry of nucleosides and nucleotides: Application to phosphorylation studies of anti‐human immunodeficiency virus nucleosides in a human hepatoma cell line

“…Dideoxynucleosides (ddNs) lack both 2'-and 3'-hydroxyl groups, and can inhibit the replication of the human immunodeficiency virus (HIV), which is the etiologic agent of the acquired immunodeficiency syndrome (AIDS). Several ddNs and their analogs are currently used as a treatment for HIV infection either singly or in a combination therapy of homo-and heterodimeric derivatives of ddNs for increased antiviral effects [1][2][3][4]. ddNs are also important in treatment of other viral infections and in cancer chemotherapy.…”