Novel Isoxazolidine and γ-Lactam Analogues of Homonucleosides.

Dorota G Piotrowska,Robert Snoeck,Iwona E Głowacka,Graciela Andrei,Joanna Gotkowska,Dominique Schols

doi:10.3390/molecules24224014

Dorota G Piotrowska, Robert Snoeck + Show 4 more

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https://doi.org/10.3390/molecules24224014

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Abstract

Homonucleoside analogues cis-16 and trans-17 having a (5-methoxycarbonyl)isoxazolidine framework were synthesized via the 1,3-dipolar cycloaddition of nucleobase-derived nitrones with methyl acrylate. Hydrogenolysis of the isoxazolidines containing thymine, dihydrouracil, theophylline and adenine moieties efficiently led to the formation of the respective γ-lactam analogues. γ-Lactam analogues having 5-bromouracil and 5-chlorouracil fragments were synthesized by treatment of uracil-containing γ-lactams with NBS and NCS. Isoxazolidine and γ-lactam analogues of homonucleosides obtained herein were evaluated for activity against a broad range of DNA and RNA viruses. None of the compounds that were tested exhibited antiviral or cytotoxic activity at concentrations up to 100 µM. The cytostatic activities of all compounds toward nine cancerous cell lines was tested. γ-Lactams trans-15e (Cl-Ura) and cis-15h (Theo) appeared the most active toward pancreatic adenocarcinoma cells (Capan-1), showing IC50 values 21.5 and 18.2 µM, respectively. Isoxazolidine cis-15e (Cl-Ura) inhibited the proliferation of colorectal carcinoma (HCT-116).

Highlights

Nucleoside analogues belong to a group of important antiviral and antitumor drugs [1,2,3,4]
The introduction of a methylene bridge between a nucleobase and the sugar partly led to the formation of homonucleosides, which are known for their resistance to hydrolytic or enzymatic cleavage, as well as for the rotational freedom when compared with the natural nucleosides
It was shown that homonucleosides are substrates for cellular kinases and are able to pair with other nucleosides by Watson–Crick interactions without appreciable modifications of the structure of DNA molecules [18]. 10 -Homonucleosides containing adenine 1 or guanine 2 were found to be active against herpes simplex virus (minimum inhibitory concentration (MIC) = 5–20 μg/mL) and vaccinia virus [19,20,21], while compound 3 (IC50 = 25.2 μg/mL) showed activity against the influenza type virus AH1N1 (Figure 2) [22]

Summary

Introduction

Nucleoside analogues belong to a group of important antiviral and antitumor drugs [1,2,3,4]. Structural modifications of available drugs from a class of nucleoside analogues, including sugar and/or nucleobase residues, resulted in the discovery of a variety of therapeutically-useful antiviral [5]. The introduction of a methylene bridge between a nucleobase and the sugar partly led to the formation of homonucleosides, which are known for their resistance to hydrolytic or enzymatic cleavage, as well as for the rotational freedom when compared with the natural nucleosides. 10 -Homonucleosides containing adenine 1 or guanine 2 were found to be active against herpes simplex virus (minimum inhibitory concentration (MIC) = 5–20 μg/mL) and vaccinia virus [19,20,21], while compound 3 (IC50 = 25.2 μg/mL) showed activity against the influenza type virus AH1N1 (Figure 2) [22].

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