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Recent Development of Nucleic Acid Analogs
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Recent Development of Nucleic Acid Analogs

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

Deadline for manuscript submissions: closed (30 January 2020) | Viewed by 18946

Special Issue Editor

Prof. Dr. Yoshiyuki Hari

E-Mail Website
Guest Editor
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Nishihama, Yamashiro-cho, Tokushima 770-8514, Japan
Interests: nucleic acid chemistry; bioorganic chemistry; organic synthesis; medicinal chemistry

Special Issue Information

Dear Colleagues,

Nucleic acid analogs that provide improved properties and/or new functions to DNA or RNA molecules including oligonucleotides are extensively used for investigating the life phenomenon, developing nucleic acid medicines, and creating biotechnologies, etc. For example, fluorescent nucleobases can be used for microenvironmental monitoring and studying dynamic structures of nucleic acids. Nucleobase analogs, forming metal-mediated base pairs or unnatural base pairs, can also be applied to genetic code expansion technology. Besides, cross-linkable nucleic acids, external stimuli-responsive nucleic acids, function-switchable nucleic acids, and RNA mimics including bridged nucleic acids, etc., are also promising materials. Therefore, also because synthetic methodology and the technology of modified DNA/RNA molecules have been making progress, the development of nucleic acid analogs possessing attractive properties will become continuously and increasingly active.

Thus, the aim of this Special Issue is to provide recent attractive and exciting findings concerning nucleic acid analogs. A wide research area ranging from the synthesis to the application of nucleic acid analogs will be covered in this Special Issue. I would like to cordially invite everyone to submit research articles and comprehensive reviews dealing with this research area.

Prof. Dr. Yoshiyuki Hari
Guest Editor

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Keywords

  • functional nucleic acids
  • functional oligonucleotides
  • nucleic acid analogs
  • nucleobase analogs
  • nucleoside analogs
  • nucleotide analogs

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Published Papers (4 papers)

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Research

15 pages, 1692 KiB  
Article
Synthesis and Evaluation of Artificial Nucleic Acid Bearing an Oxanorbornane Scaffold
by Hibiki Komine, Shohei Mori, Kunihiko Morihiro, Kenta Ishida, Takumi Okuda, Yuuya Kasahara, Hiroshi Aoyama, Takao Yamaguchi and Satoshi Obika
Molecules 2020, 25(7), 1732; https://doi.org/10.3390/molecules25071732 - 9 Apr 2020
Cited by 6 | Viewed by 3825
Abstract
Natural oligonucleotides have many rotatable single bonds, and thus their structures are inherently flexible. Structural flexibility leads to an entropic loss when unwound oligonucleotides form a duplex with single-stranded DNA or RNA. An effective approach to reduce such entropic loss in the duplex-formation [...] Read more.
Natural oligonucleotides have many rotatable single bonds, and thus their structures are inherently flexible. Structural flexibility leads to an entropic loss when unwound oligonucleotides form a duplex with single-stranded DNA or RNA. An effective approach to reduce such entropic loss in the duplex-formation is the conformational restriction of the flexible phosphodiester linkage and/or sugar moiety. We here report the synthesis and biophysical properties of a novel artificial nucleic acid bearing an oxanorbornane scaffold (OxNorNA), where the adamant oxanorbornane was expected to rigidify the structures of both the linkage and sugar parts of nucleic acid. OxNorNA phosphoramidite with a uracil (U) nucleobase was successfully synthesized over 15 steps from a known sugar-derived cyclopentene. Thereafter, the given phosphoramidite was incorporated into the designed oligonucleotides. Thermal denaturation experiments revealed that oligonucleotides modified with the conformationally restricted OxNorNA-U properly form a duplex with the complementally DNA or RNA strands, although the Tm values of OxNorNA-U-modified oligonucleotides were lower than those of the corresponding natural oligonucleotides. As we had designed, entropic loss during the duplex-formation was reduced by the OxNorNA modification. Moreover, the OxNorNA-U-modified oligonucleotide was confirmed to have extremely high stability against 3′-exonuclease activity, and its stability was even higher than those of the phosphorothioate-modified counterparts (Sp and Rp). With the overall biophysical properties of OxNorNA-U, we expect that OxNorNA could be used for specialized applications, such as conformational fixation and/or bio-stability enhancement of therapeutic oligonucleotides (e.g., aptamers). Full article
(This article belongs to the Special Issue Recent Development of Nucleic Acid Analogs)
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11 pages, 1402 KiB  
Article
Efficient Biocatalytic Synthesis of Dihalogenated Purine Nucleoside Analogues Applying Thermodynamic Calculations
by Heba Yehia, Sarah Westarp, Viola Röhrs, Felix Kaspar, Robert T. Giessmann, Hendrik F.T. Klare, Katharina Paulick, Peter Neubauer, Jens Kurreck and Anke Wagner
Molecules 2020, 25(4), 934; https://doi.org/10.3390/molecules25040934 - 19 Feb 2020
Cited by 17 | Viewed by 4355
Abstract
The enzymatic synthesis of nucleoside analogues has been shown to be a sustainable and efficient alternative to chemical synthesis routes. In this study, dihalogenated nucleoside analogues were produced by thermostable nucleoside phosphorylases in transglycosylation reactions using uridine or thymidine as sugar donors. Prior [...] Read more.
The enzymatic synthesis of nucleoside analogues has been shown to be a sustainable and efficient alternative to chemical synthesis routes. In this study, dihalogenated nucleoside analogues were produced by thermostable nucleoside phosphorylases in transglycosylation reactions using uridine or thymidine as sugar donors. Prior to the enzymatic process, ideal maximum product yields were calculated after the determination of equilibrium constants through monitoring the equilibrium conversion in analytical-scale reactions. Equilibrium constants for dihalogenated nucleosides were comparable to known purine nucleosides, ranging between 0.071 and 0.081. To achieve 90% product yield in the enzymatic process, an approximately five-fold excess of sugar donor was needed. Nucleoside analogues were purified by semi-preparative HPLC, and yields of purified product were approximately 50% for all target compounds. To evaluate the impact of halogen atoms in positions 2 and 6 on the antiproliferative activity in leukemic cell lines, the cytotoxic potential of dihalogenated nucleoside analogues was studied in the leukemic cell line HL-60. Interestingly, the inhibition of HL-60 cells with dihalogenated nucleoside analogues was substantially lower than with monohalogenated cladribine, which is known to show high antiproliferative activity. Taken together, we demonstrate that thermodynamic calculations and small-scale experiments can be used to produce nucleoside analogues with high yields and purity on larger scales. The procedure can be used for the generation of new libraries of nucleoside analogues for screening experiments or to replace the chemical synthesis routes of marketed nucleoside drugs by enzymatic processes. Full article
(This article belongs to the Special Issue Recent Development of Nucleic Acid Analogs)
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10 pages, 1557 KiB  
Article
Synthesis of Oligonucleotides Containing 2′-N-alkylaminocarbonyl-2′-amino-LNA (2′-urea-LNA) Moieties Using Post-Synthetic Modification Strategy
by Shoko Yamashita, Kodai Nishida, Takashi Osawa, Ayumi Nakanishi, Yuta Ito and Yoshiyuki Hari
Molecules 2020, 25(2), 346; https://doi.org/10.3390/molecules25020346 - 15 Jan 2020
Cited by 6 | Viewed by 3452
Abstract
The post-synthetic modification of an oligonucleotide is a powerful strategy for the synthesis of various analogs of the oligonucleotide, aiming to achieve the desired functions. In this study, we synthesized the thymidine phosphoramidite of 2′-N-pentafluorophenoxycarbonyl-2′-amino-LNA, which was introduced into oligonucleotides. Oligonucleotides [...] Read more.
The post-synthetic modification of an oligonucleotide is a powerful strategy for the synthesis of various analogs of the oligonucleotide, aiming to achieve the desired functions. In this study, we synthesized the thymidine phosphoramidite of 2′-N-pentafluorophenoxycarbonyl-2′-amino-LNA, which was introduced into oligonucleotides. Oligonucleotides containing a 2′-N-pentafluorophenoxycarbonyl-2′-amino-LNA unit could be isolated under ultra-mild deprotection conditions (50 mM K2CO3 in MeOH at room temperature for 4 h). Moreover, by treatment with various amines as a post-synthetic modification, the oligonucleotides were successfully converted into the corresponding 2′-N-alkylaminocarbonyl-2′-amino-LNA (2′-urea-LNA) derivatives. The duplex- and triplex-forming abilities of the synthesized oligonucleotides were evaluated by UV-melting experiments, which showed that 2′-urea-LNAs could stabilize the nucleic acid complexes, similar to the proto-type, 2′-amino-LNA. Thus, 2′-urea-LNAs could be promising units for the modification of oligonucleotides; the design of a substituent on urea may aid the formation of useful oligonucleotides. In addition, pentafluorophenoxycarbonyl, an amino moiety, acted as a precursor of the substituted urea, which may be applicable to the synthesis of oligonucleotide conjugates. Full article
(This article belongs to the Special Issue Recent Development of Nucleic Acid Analogs)
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14 pages, 10525 KiB  
Article
Novel Convenient Approach to the Solid-Phase Synthesis of Oligonucleotide Conjugates
by Mariya I. Meschaninova, Darya S. Novopashina, Olga A. Semikolenova, Vladimir N. Silnikov and Alya G. Venyaminova
Molecules 2019, 24(23), 4266; https://doi.org/10.3390/molecules24234266 - 22 Nov 2019
Cited by 23 | Viewed by 6625
Abstract
A novel and convenient approach for the solid-phase 5′-functionalization of oligonucleotides is proposed in this article. The approach is based on the activation of free 5′-hydroxyl of polymer support-bound protected oligonucleotides by N,N′-disuccinimidyl carbonate followed by interaction with amino-containing ligands. [...] Read more.
A novel and convenient approach for the solid-phase 5′-functionalization of oligonucleotides is proposed in this article. The approach is based on the activation of free 5′-hydroxyl of polymer support-bound protected oligonucleotides by N,N′-disuccinimidyl carbonate followed by interaction with amino-containing ligands. Novel amino-containing derivatives of closo-dodecaborate, estrone, cholesterol, and α-tocopherol were specially prepared. A wide range of oligonucleotide conjugates bearing closo-dodecaborate, short peptide, pyrene, lipophilic residues (cholesterol, α-tocopherol, folate, estrone), aliphatic diamines, and propargylamine were synthesized and characterized to demonstrate the versatility of the approach. The developed method is suitable for the conjugate synthesis of oligonucleotides of different types (ribo-, deoxyribo-, 2′-O-methylribo-, and others). Full article
(This article belongs to the Special Issue Recent Development of Nucleic Acid Analogs)
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