Synthesis and antiviral activity of novel acyclic nucleosides in the 5-alkynyl- and 6-alkylfuro[2,3-d]pyrimidine series

doi:10.1016/j.bmc.2004.11.057

Bioorganic & Medicinal Chemistry

Volume 13, Issue 4, 15 February 2005, Pages 1239-1248

https://doi.org/10.1016/j.bmc.2004.11.057 Get rights and content

Abstract

The synthesis of novel acyclic nucleosides in the 5-alkynyl and 6-alkylfuro[2,3-d]pyrimidine series is described. These compounds were evaluated against HIV and HSV in order to determine their spectrum of antiviral activity. Their cytotoxicities against PBM, CEM and VERO cells were also determined. Compounds 21d and 24b displayed moderate EC₅₀s of 2.7 and 4.9 μM, respectively, against HIV-1 and of 6.3 and 4.8 μM, respectively, against HSV. Nevertheless, these compounds also showed cellular toxicity, suggesting that the antiviral effects are secondary to the toxic effects.

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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Synthesis and antiviral activity of novel acyclic nucleosides in the 5-alkynyl- and 6-alkylfuro[2,3-d]pyrimidine series

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Biological assay

General procedures

Acknowledgements

Antimicrob. Agents Chemother.

Acyclic, Carbocyclic and l-Nucleosides

J. Heterocycl. Chem.

Nature

Antiviral Chem. Chemother.

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

J. Proc. Natl. Acad. Sci. U.S.A.

Nature

Antimicrob. Agents Chemother.

Proc. Nat. Acad. Sci. U.S.A.

Antimicrob. Agents Chemother.

J. Med. Chem.

Can. J. Chem.

Chem. Rev.

J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem. Lett.

J. Med. Chem.

Proc. Natl. Acad. Sci. U.S.A.

J. Med. Chem.

J. Med. Chem.

Bioorg. Med. Chem. Lett.

Drugs Future

J. Med. Chem.

J. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Nucleosides Nucleotides