Synthesis and antiviral activity of novel acyclic nucleosides in the 5-alkynyl- and 6-alkylfuro[2,3-d]pyrimidine series
Graphical abstract
The synthesis of series of hitherto unknown 5-alkynyl pyrimidine acyclic nucleosides and their furopyrimidine analogues is described. The in vitro antiviral activity (HIV, HSV-1) and toxicity in different cell lines are reported.
Introduction
Among the antiviral agents developed for several life threatening infections, acyclic nucleosides have been a focus of several recent studies, including variations both of the acyclic glycone and of the heterocyclic base.1, 2 Acyclovir (ACV, 1a)3 and ganciclovir (GCV, 1b)4 are two important acyclic drugs (Fig. 1) active against herpes simplex virus (HSV), varicella-zoster virus (VZV) and/or cytomegalovirus (CMV). The success of ACV and GCV as antiviral drugs has prompted intensive efforts by several groups to prepare and evaluate many structurally related acyclic nucleoside analogues. In another area, many nucleoside analogues substituted at various positions on the heterocycle,5 are known to have potent biological properties and have been investigated, for instance, as antiviral agents (against HSV, VZV, CMV, HIV, HBV and HCV), non-radioactive fluorescent labels for DNA and as anticancer drugs. Among them, extensive studies have been carried out on 5-substituted uracils,6 starting from the anti-HSV BVDU agent, 2.6e Bicyclic pyrimidine nucleosides such as (3),7 oxazolo- (4a)8a, thieno (4b)8b or imidazo (5)8(c), 8(d), 8(e) have demonstrated antiviral and antileukemic activity in vitro, which has led to increased interest in preparation of corresponding nucleoside analogues (Fig. 1). Thus, as part of an ongoing program in our drug discovery group, we initiated the preparation of different, hitherto unknown, acyclic analogues of ACV and other bicyclic nucleosides. In the present report, we present the full experimental details and biological evaluation of the first 18 analogues of these novel acyclic nucleosides in the 5-alkynyl- and 6-alkylfuro[2,3-d]pyrimidine series with hydrophobic functional groups.
Section snippets
Chemistry
The preparation of the desired 5-alkynyl analogues of acyclovir is illustrated in Scheme 1. Thus, starting from the known acetylated uracil analogue of acyclovir 6, synthesized following a well-known procedure,9 an iodo group was selectively introduced at the C-5 position on the heterocyclic moiety using I2/CAN.10 Different substituents were then introduced by reaction of the 5-iodo acyclic nucleoside 7 under optimized Sonogashira Pd(0)-catalyzed reactions.11, 12 It is important to note that
Biological assay
All synthesized compounds, the C5-alkynyl derivatives 9a–d, 14a–b, 15a,b, the C5-acetyl derivatives 18 and 19 and the 6-alkylfuro[2,3-d]pyrimidine (21a–d, 23a,b and 24a,b) along with the known antiviral compounds (acyclovir for HSV and AZT for HIV), were tested for their antiviral activities in vitro (results shown in Table 1). The antiviral16 and cytotoxicity17 assays were performed as previously described. For the anti-HIV activity, among the C-5-alkynyl acyclonucleoside analogues, 9a,b, 14a,b
General procedures
Commercially available chemicals and solvents were reagent grade and used as received. Dry tetrahydrofuran, pyridine and dichloromethane were obtained from distillation over CaH2 or Na, and dry N,N-dimethylformamide over BaO. Reactions were monitored by thin-layer chromatography (TLC) analysis using silica gel plates (Kieselgel 60 F254, E. Merck). Compounds were visualized by UV irradiation and/or spraying with 20% H2SO4 in EtOH, followed by charring at 150 °C. Column chromatography was
Acknowledgements
We thank J. Grier, M. Bennett and K. Rapp for excellent technical assistance. L.A.A. thank the CNRS and MENRT for financial support. F.A. thanks the MENRT for a Ph.D. fellowship. For work performed at the University of New Orleans, S.P.N. gratefully acknowledges the National Science Foundation for generous support. R.F.S. was supported by Emory’s Center for AIDS Research NIH grant 2P30-AI-50409 and by the Department of Veterans Affairs.
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