Truncated phosphonated C-1′-branched N,O-nucleosides: A new class of antiviral agents
TL;DR: Preliminary biological assays show that β-anomers are able to inhibit HIV in vitro infection at concentrations in the micromolar range and higher SI values with respect to AZT indicated that the compounds were endowed with low cytotoxicity.
About: This article is published in Bioorganic & Medicinal Chemistry.The article was published on 2012-06-01 and is currently open access. It has received 25 citations till now.
Summary (1 min read)
Introduction
- Preliminary biological assays show that b-anomers are able to inhibit HIV in vitro infection at concentrations in the micromolar range.
- 18,19 Several strategies to overcome the initial selective phosphorylation step have been designed;23 in particular, phosphonate analogues,20 by miming the nucleoside monophosphates, overcome the instability of nucleotides towards phosphodiesterase and enhance the cellular uptake by bypassing the initial phosphorylation step.
- In connection with their work addressed to the search of new and potent antiviral agents, the authors have extended their interest to the synthesis of the new generation of truncated phosphonated C-10branched N,O-nucleosides.
- The authors report in this paper the synthetic approach towards these derivatives and their preliminary biological evaluation.
2.1. Chemistry
- According to the retrosynthetic analysis shown in Scheme 1, the key step of the synthetic route involves the 1,3-dipolar cycloaddition of the N-methyl-C-nitrone 7 with the acrylate 8.
- The authors have designed an alternative methodology towards 7 (route b), which is based on the conversion of the phosphonated alcohol 13 into the corresponding mesylate 15; the subsequent reaction with N-methyl hydroxylamine afforded the derivative 16 which, by oxidation with MnO2, gave the target nitrone 7 in a 60% yield (Scheme 2).
- The anomeric configuration of obtained modified nucleosides was assigned on the basis of 1H NMR and NOE experiments.
2.2. Biological results
- For testing the potential activity of the new truncated phosphonated C-10-branched N,O-nucleosides against human retroviruses, the authors assessed their ability to inhibit both HIV and HTLV-1 in vitro infections.
- The results reported in Table 1 showed that compounds 11a and 11d were not active, while 11b and 11c inhibited HIV infection at an inhibitory concentration 50 (IC50) of 220 and 132 lM respectively.
- Actually this is summarized by the values of the selectivity index (SI) calculated on the basis of the ratio between the CC50 and IC50 values.
- Thus, the low cytotoxic effect of the compounds could balance their higher IC50 with respect to the positive control.
3. Conclusion
- Truncated phosphonated C-10-branched N,O-nucleosides have been synthesized in good yields by the 1,3-dipolar cycloaddition methodology, starting from the nitrone 7.
- Preliminary biological assays show that the b-anomers are able to inhibit infection of HIV at concentrations in the micromolar range.
- They are certainly less cytotoxic than AZT, as deduced from the calculated SI values.
- In addition, they seem to be rather specific in inhibiting HIV infection, while they were unable to exert the same effect on HTLV-1 infection.
- Truncated phosphonated represent a new template of cyclic nucleoside analogs which deserve further investigations as lead compounds for extending the current spectrum of antiviral activity of modified nucleosides, avoiding some unwanted side effects.
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TL;DR: A novel series of C-nucleosides, featuring the presence of a 1,2,3-triazole ring linked to an isoxazolidine system, has been designed as mimetics of the pyrimidine nucleobases, and an antiproliferative effect was observed.
Abstract: A novel series of C-nucleosides, featuring the presence of a 1,2,3-triazole ring linked to an isoxazolidine system, has been designed as mimetics of the pyrimidine nucleobases. An antiproliferative effect was observed for compounds 17a and 17b: the growth inhibitory effect reaches the 50% in HepG2 and HT-29 cells and increases up to 56% in the SH-SY5Y cell line after 72 h of incubation at a 100 µM concentration.
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References
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TL;DR: The CEM-GFP reporter cell line provides a simple, rapid, and direct method for monitoring HIV infectivity titers and antiretroviral drug susceptibility of syncytium-inducing strains.
Abstract: Determination of HIV infectivity in vitro and its inhibition by antiretroviral drugs by monitoring reduction of production of p24 antigen is expensive and time consuming. Such assays also do not allow accurate quantitation of the number of infected cells over time. To develop a simple, rapid, and direct method for monitoring HIV infection, we generated a stable T-cell line (CEM) containing a plasmid encoding the green fluorescent protein (humanized S65T GFP) driven by the HIV-1 long terminal repeat. Clones were selected that displayed low constitutive background fluorescence, but a high level of GFP expression upon infection with HIV. HIV-1 infection induced a 100- to 1,000-fold increase in relative fluorescence of cells over 2 to 4 days as monitored by fluorescence microscopy, cytofluorimetry, and flow cytometry. Addition of inhibitors of reverse transcriptase, protease, and other targets at different multiplicities of infection permitted the accurate determination of drug susceptibility. This technique also permitted quantitation of infectivity of viral preparations by assessment of number of cells infected in the first round of infection. In conclusion, the CEM-GFP reporter cell line provides a simple, rapid, and direct method for monitoring HIV infectivity titers and antiretroviral drug susceptibility of syncytium-inducing strains.
267 citations
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Abstract: Dipartimento Farmaco-Chimico, Università di Messina, Via SS Annunziata, 98168 Messina, Italy, Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125 Catania, Italy, and Laboratorio de Sintesis Asimetrica, Departamento de Quimica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza, CSIC, E-50009 Zaragoza, Aragon, Spain, Pedro Merino: pmerino@unizar.es
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Abstract: Enantiomers of 4‘-aza-2‘,3‘-dideoxynucleosides have been prepared by two different synthetic approaches, on the basis of 1,3-dipolar cycloaddition of a chiral nitrone. Cytotoxicity and apoptotic activity have been investigated. (5‘S)-5-Fluoro-1-isoxazolidin-5-yl-1H-pyrimidine-2,4-dione [(−)-AdFU], while showing low level of cytotoxicity, is a good inductor of apoptosis on lymphoid and monocytoid cells, acting as a strong potentiator of Fas-induced cell death.
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