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Nucleotide Analogues: Modifications, Biological Activities and Applications

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 17501

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Special Issue Editor

Prof. Dr. Roberto Romeo

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Guest Editor

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, Università degli Studi di Messina, Messina, Italy
Interests: organic synthesis; radical processes; pericyclic reactions; drug discovery; modified nucleosides; nanomaterials

Special Issue Information

Dear Colleagues,

Nucleosides play a very important role in many biological processes; accordingly, modifications of the nucleoside structure are widely exploited for the design and development of new drugs, especially in the fields of virology and cancer research. In this search, structural modifications on the sugar moiety of natural nucleosides and/or modifications of the heterocyclic base can be performed.

The first option involved changes in the (2-deoxy)-D-ribofuranose moiety as the inversion of hydroxyl group configuration, the elimination towards dideoxy- or dideoxy-dydehydro-nucleosides, the substitution/functionalization by various groups, or cleavage of the sugar ring leading to acyclic nucleosides. Other deeper structural modifications include the replacement of the oxygen atom by a methylene group, sulfur or nitrogen atom or the additional insertion of a second heteroatom in the sugar moiety. Nucleoside analogues endowed with the unnatural L-configuration have also been shown to possess interesting antiviral properties.

The second alternative takes into account structural modifications concerning the purine or pyrimidine nucleobases. Many nucleosides of natural origin, containing modified heterocyclic bases with respect to “normal” nucleobases, have been found to be bioactive. Furthermore, many unnatural bases have been synthesized and many of them are good substrates for DNA and RNA polymerases. In this context, great interest has been addressed towards C-nucleosides, for their higher stability toward the cleavage of the nucleoside bond due to the replacement of C-N by the non hydrolyzable C-C bond.

The research of new synthetic procedures towards nucleoside analogs is a field continuously explored as a consequence of the urgent demand for new therapeutic agents in which an improved biological activity is assisted by a low toxicity towards the host cell. This Special Issue covers all aspects related to the synthesis and molecular actions in organisms of new derivatives. Specific interests include the design of nanostructured materials for a controlled release of bioactive nucleotides. The efforts in this field, in concert with improved synthetic advances, will provide strong impetus for the next wave of design and development of nucleoside therapeutics.

Prof. Roberto Romeo
Guest Editor

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Keywords

Base-modified nucleosides
Sugar ring-modified nucleosides
Acyclic nucleosides
C-nucleosides
Delivery systems

Published Papers (3 papers)

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Research

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12 pages, 2011 KiB

Open AccessArticle

Promutagenicity of 8-Chloroguanine, A Major Inflammation-Induced Halogenated DNA Lesion

by Yi Kou, Myong-Chul Koag and Seongmin Lee

Molecules 2019, 24(19), 3507; https://doi.org/10.3390/molecules24193507 - 27 Sep 2019

Cited by 17 | Viewed by 2953

Abstract

Chronic inflammation is closely associated with cancer development. One possible mechanism for inflammation-induced carcinogenesis is DNA damage caused by reactive halogen species, such as hypochlorous acid, which is released by myeloperoxidase to kill pathogens. Hypochlorous acid can attack genomic DNA to produce 8-chloro-2′-deoxyguanosine (ClG) as a major lesion. It has been postulated that ClG promotes mutagenic replication using its syn conformer; yet, the structural basis for ClG-induced mutagenesis is unknown. We obtained crystal structures and kinetics data for nucleotide incorporation past a templating ClG using human DNA polymerase β (polβ) as a model enzyme for high-fidelity DNA polymerases. The structures showed that ClG formed base pairs with incoming dCTP and dGTP using its anti and syn conformers, respectively. Kinetic studies showed that polβ incorporated dGTP only 15-fold less efficiently than dCTP, suggesting that replication across ClG is promutagenic. Two hydrogen bonds between syn-ClG and anti-dGTP and a water-mediated hydrogen bond appeared to facilitate mutagenic replication opposite the major halogenated guanine lesion. These results suggest that ClG in DNA promotes G to C transversion mutations by forming Hoogsteen base pairing between syn-ClG and anti-G during DNA synthesis. Full article

(This article belongs to the Special Issue Nucleotide Analogues: Modifications, Biological Activities and Applications)

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14 pages, 2387 KiB

Open AccessFeature PaperArticle

Pyrimidine 2,4-Diones in the Design of New HIV RT Inhibitors

by Roberto Romeo, Daniela Iannazzo, Lucia Veltri, Bartolo Gabriele, Beatrice Macchi, Caterina Frezza, Francesca Marino-Merlo and Salvatore V. Giofrè

Molecules 2019, 24(9), 1718; https://doi.org/10.3390/molecules24091718 - 2 May 2019

Cited by 32 | Viewed by 3214

Abstract

The pyrimidine nucleus is a versatile core in the development of antiretroviral agents. On this basis, a series of pyrimidine-2,4-diones linked to an isoxazolidine nucleus have been synthesized and tested as nucleoside analogs, endowed with potential anti-HIV (human immunodeficiency virus) activity. Compounds 6a–c, characterized by the presence of an ethereal group at C-3, show HIV reverse transcriptase (RT) inhibitor activity in the nanomolar range as well as HIV-infection inhibitor activity in the low micromolar with no toxicity. In the same context, compound 7b shows only a negligible inhibition of RT HIV. Full article

(This article belongs to the Special Issue Nucleotide Analogues: Modifications, Biological Activities and Applications)

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Review

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25 pages, 5965 KiB

Open AccessReview

Current Aspects of siRNA Bioconjugate for In Vitro and In Vivo Delivery

by Wanyi Tai

Molecules 2019, 24(12), 2211; https://doi.org/10.3390/molecules24122211 - 13 Jun 2019

Cited by 59 | Viewed by 10590

Abstract

Studies on siRNA delivery have seen intense growth in the past decades since siRNA has emerged as a new class of gene therapeutics for the treatment of various diseases. siRNA bioconjugate, as one of the major delivery strategies, offers the potential to enhance and broaden pharmacological properties of siRNA, while minimizing the heterogeneity and stability-correlated toxicology. This review summarizes the recent developments of siRNA bioconjugate, including the conjugation with antibody, peptide, aptamer, small chemical, lipidoid, cell-penetrating peptide polymer, and nanoparticle. These siRNA bioconjugate, either administrated alone or formulated with other agents, could significantly improve pharmacokinetic behavior, enhance the biological half-life, and increase the targetability while maintaining sufficient gene silencing activity, with a concomitant improvement of the therapeutic outcomes and diminishment of adverse effects. This review emphasizes the delivery application of these siRNA bioconjugates, especially the conjugation strategy that control the integrity, stability and release of siRNA bioconjugates. The limitations conferred by these conjugation strategies have also been covered. Full article

(This article belongs to the Special Issue Nucleotide Analogues: Modifications, Biological Activities and Applications)

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