Celebrating the role of chemistry in the success of oligonucleotides as therapeutics
In recent years, oligonucleotides have made remarkable strides as future medicines. The potential of oligonucleotides as treatment for previous untreatable conditions has been realized by the recent regulatory approvals of antisense oligonucleotides (inotersen and golodirsen) and small interfering double stranded RNA (patisiran and givosiran). Additionally, significant progress has been made in emerging technologies such as CRISPR-Cas systems.
Chemistry has played a critical role in the success of therapeutic oligonucleotides. This year mark the approval of first, fully chemically modified small interfering double stranded RNA conjugated to a ligand (N-acetylgalactosamine) by the FDA. This special issue is intended to celebrate the success of chemists and chemistry, and we invite all the researchers in the field of nucleic acids to participate by submitting their novel research work, or sharing their knowledge of the field in the form of review articles.
- Full Research Paper
- Published 29 Mar 2021
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Figure 1: Illustration of H-bonding in a DNA duplex and a parallel triplex. A) Depiction of Watson–Crick base...
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Scheme 1: The synthesis of ONs with Ts and N+ modification using the Staudinger reaction during the solid-pha...
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Figure 2: Percentage of intact ONs after 120 min. A) N+ONs; B) Ts-ONs. Percentage of intact ONs was determine...
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Figure 3: Representative images of mouse NIH 3T3 fibroblasts incubated with either (A–C) no oligo or 20 µM of...
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Figure 4: Representative confocal microscopy section showing the FAM vesicles inside the cell. Mouse NIH 3T3 ...
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- Full Research Paper
- Published 26 Apr 2021
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Figure 1: Components of the LNPs. A) Lipid species and lipidated cell-penetrating peptides applied by postins...
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Figure 2: LNPs with T7 pass through the transwell cell barrier and are taken up by target cells. HeLa (CCR5-n...
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Figure 3: LNPs with Tat pass through the transwell cell barrier and are taken up by target cells. A) Percenta...
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Figure 4: LNPs do not stimulate secretion of proinflammatory cytokines. A) GMCSF-primed MDMs were treated wit...
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Figure 5: LNPs modestly affect cell viability in a cell-specific manner. HeLa (A) or HEK293T cells (B) were t...
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- Review
- Published 28 Apr 2021
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Figure 1: Structures of the chemically modified oligonucleotides (A) N3' → P5' phosphoramidate linkage, (B) a...
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Scheme 1: Synthesis of a N3' → P5' phosphoramidate linkage by solid-phase synthesis. (a) dichloroacetic acid;...
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Figure 2: Crystal structures of (A) N3' → P5' phosphoramidate DNA (PDB ID 363D) [71] and (B) amide (AM1) RNA in c...
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Scheme 2: Synthesis of a phosphorodithioate linkage by solid-phase synthesis. (a) detritylation; (b) tetrazol...
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Figure 3: Close-up view of a key interaction between the PS2-modified antithrombin RNA aptamer and thrombin i...
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Scheme 3: Synthesis of the (S)-GNA thymine phosphoramidite from (S)-glycidyl 4,4'-dimethoxytrityl ether. (a) ...
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Figure 4: Surface models of the crystal structures of RNA dodecamers with single (A) (S)-GNA-T (PDB ID 5V1L) [54]...
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Figure 5: Structures of 2'-O-alkyl modifications. (A) 2'-O-methoxy RNA (2'-OMe RNA), (B) 2'-O-(2-methoxyethyl...
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Scheme 4: Synthesis of the 2'-OMe uridine from 3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)uridine. (a) Benzoy...
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Scheme 5: Synthesis of the 2'-O-MOE uridine from uridine. (a) (PhO)2CO, NaHCO3, DMA, 100 °C; (b) Al(OCH2CH2OCH...
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Figure 6: Structure of 2'-O-(2-methoxyethyl)-RNA (MOE-RNA). (A) View into the minor groove of an A-form DNA d...
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Figure 7: Structures of locked nucleic acids (LNA)/bridged nucleic acids (BNA) modifications. (A) LNA/BNA, (B...
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Scheme 6: Synthesis of the uridine LNA phosphoramidite. (a) i) NaH, BnBr, DMF, ii) acetic anhydride, pyridine...
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Scheme 7: Synthesis of the 2'-fluoroarabinothymidine. (a) 30% HBr in acetic acid; (b) 2,4-bis-O-(trimethylsil...
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Figure 8: Sugar puckers of arabinose (ANA) and arabinofluoro (FANA) nucleic acids compared with the puckers o...
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Figure 9: Structures of C4'-modified nucleic acids. (A) 4'-methoxy, (B) 4'-(2-methoxyethoxy), (C) 2',4'-diflu...
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Scheme 8: Synthesis of the 4'-F-rU phosphoramidite. (a) AgF, I2, dichloromethane, tetrahydrofuran; (b) NH3, m...
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Scheme 9: Synthesis of the thymine FHNA phosphoramidite. (a) thymine, 1,8-diazabicyclo[5.4.0]undec-7-ene, ace...
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Scheme 10: Synthesis of the thymine Ara-FHNA phosphoramidite. (a) i) trifluoromethanesulfonic anhydride, pyrid...
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Figure 10: Crystal structures of (A) FHNA and (B) Ara-FHNA in modified A-form DNA decamers (PDB IDs 3Q61 and 3...
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- Full Research Paper
- Published 01 Jun 2021
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Figure 1: Analysis of the VLP-dsRNAvp28 assembly by electrophoresis mobility shift assay (EMSA) in a 1% nativ...
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Figure 2: TEM micrographs of different stages of the assemblies of CCMV CP with dsRNAvp28. In section A, the ...
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Figure 3: P. vannamei survival when exposed to WSSV and treatments. (A) IM inoculum activation in two consecu...
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Figure 4: Cumulative survival curves of P. vannamei infected with WSSV and provided with VLPs antiviral treat...
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- Review
- Published 08 Jun 2021
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Figure 1: Double-headed nucleosides. B1 and B2 = nucleobases or heterocyclic/carbocyclic moieties; L = linker....
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Scheme 1: Synthesis of 2′-(pyrimidin-1-yl)methyl- or 2′-(purin-9-yl)methyl-substituted double-headed nucleosi...
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Scheme 2: Synthesis of double-headed nucleoside 7 having two cytosine moieties.
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Scheme 3: Synthesis of double-headed nucleoside 2′-deoxy-2′-C-(2-(thymine-1-yl)ethyl)-uridine (11).
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Scheme 4: Double-headed nucleosides 14 and 15 obtained by click reaction.
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Scheme 5: Synthesis of the double-headed nucleoside 19.
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Scheme 6: Synthesis of the double-headed nucleosides 24 and 25.
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Scheme 7: Synthesis of double-headed nucleosides 28 and 29.
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Scheme 8: Synthesis of double-headed nucleoside 33.
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Scheme 9: Synthesis of double-headed nucleoside 37.
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Scheme 10: Synthesis of the double-headed nucleoside 1-(5′-O-(4,4′-dimethoxytrityl)-2′-C-((4-(pyren-1-yl)-1,2,...
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Scheme 11: Synthesis of triazole-containing double-headed ribonucleosides 46a–c and 50a–e.
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Scheme 12: Synthesis of double-headed nucleosides 54a–g.
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Scheme 13: Synthesis of double-headed nucleosides 59 and 60.
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Scheme 14: Synthesis of the double-headed nucleosides 63 and 64.
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Scheme 15: Synthesis of double-headed nucleosides 66a–c.
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Scheme 16: Synthesis of benzoxazole-containing double-headed nucleosides 69 and 71 from 5′-amino-5′-deoxynucle...
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Scheme 17: Synthesis of 4′-C-((N6-benzoyladenin-9-yl)methyl)thymidine (75) and 4′-C-((thymin-1-yl)methyl)thymi...
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Scheme 18: Synthesis of double-headed nucleosides 5′-(adenine-9-yl)-5′-deoxythymidine (79) and 5′-(adenine-9-y...
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Scheme 19: Synthesis of double-headed nucleosides 85–87 via reversed nucleosides methodology.
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Scheme 20: Double-headed nucleosides 91 and 92 derived from ω-terminal-acetylenic sugar derivatives 90a,b.
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Scheme 21: Synthesis of double-headed nucleosides 96a–g.
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Scheme 22: Synthesis of double-headed nucleosides 100 and 103.
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Scheme 23: Double-headed nucleosides 104 and 105 with a triazole motif.
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Scheme 24: Synthesis of the double-headed nucleosides 107 and 108.
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Scheme 25: Synthesis of double-headed nucleoside 110 with additional nucleobase in 5′-(S)-C-position joined th...
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Scheme 26: Synthesis of double-headed nucleosides 111–113 with additional nucleobases in the 5′-(S)-C-position...
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Scheme 27: Synthesis of double-headed nucleoside 114 by click reaction.
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Scheme 28: Synthesis of double-headed nucleosides 118 with an additional nucleobase at the 5′-(S)-C-position.
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Scheme 29: Synthesis of bicyclic double-headed nucleoside 122.
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Scheme 30: Synthesis of double-headed nucleosides 125a–c derived from 2′-amino-LNA.
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Scheme 31: Double-headed nucleoside 127 obtained by click reaction.
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Scheme 32: Synthesis of double-headed nucleoside 130.
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Scheme 33: Double-headed nucleosides 132a–d and 134a–d synthesized by Sonogashira cross coupling reaction.
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Scheme 34: Synthesis of double-headed nucleosides 137 and 138 via Suzuki coupling.
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Scheme 35: Synthesis of double-headed nucleosides 140 and 141 via Sonogashira cross coupling reaction.
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Scheme 36: Synthesis of double-headed nucleoside 143.
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Scheme 37: Synthesis of the double-headed nucleoside 146.
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Scheme 38: Synthesis of 5-C-alkynyl-functionalized double-headed nucleosides 151a–d.
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Scheme 39: Synthesis of 5-C-triazolyl-functionalized double-headed nucleosides 154a, b.
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Scheme 40: Synthesis of double-headed nucleosides 157a–c.
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Scheme 41: Synthesis of double-headed nucleoside 159, phosphoramidite 160 and the corresponding nucleotide mon...
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Scheme 42: Synthesis of double-headed nucleoside 163, phosphoramidite 164 and the corresponding nucleotide mon...
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Scheme 43: Synthesis of double-headed nucleoside 167, phosphoramidite 168, and the corresponding nucleotide mo...
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Scheme 44: Synthesis of double-headed nucleoside 171, phosphoramidite 172, and the corresponding nucleotide mo...
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Scheme 45: Synthesis of double-headed nucleoside 175, phosphoramidite 176, and the corresponding nucleotide mo...
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Scheme 46: Synthesis of double-headed nucleoside 178.
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Scheme 47: Synthesis of the double-headed nucleosides 181 and 183.
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Scheme 48: Alternative synthesis of the double-headed nucleoside 183.
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Scheme 49: Synthesis of double-headed nucleoside 188 through thermal [2 + 3] sydnone–alkyne cycloaddition reac...
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Scheme 50: Synthesis of the double-headed nucleosides 190 and 191.
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Scheme 51: Synthesis of 1-((5S)-2,3,4-tri-O-acetyl-5-(2,6-dichloropurin-9-yl)-β-ᴅ-xylopyranosyl)uracil (195).
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Scheme 52: Synthesis of hexopyranosyl double-headed pyrimidine homonucleosides 200a–c.
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Figure 2: 3′-C-Ethynyl-β-ᴅ-allopyranonucleoside derivatives 201a–f.
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Scheme 53: Synthesis of 3′-C-(1,4-disubstituted-1,2,3-triazolyl)-double-headed pyranonucleosides 203–207.
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Scheme 54: Synthesis of 3′-C-(1,4-disubstituted-1,2,3-triazolyl)-double-headed pyranonucleosides 208 and 209.
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Scheme 55: Synthesis of 3′-C-(1,4-disubstituted-1,2,3-triazolyl)-double-headed pyranonucleoside 210.
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Scheme 56: Synthesis of double-headed acyclic nucleosides (2S,3R)-1,4-bis(thymine-1-yl)butane-2,3-diol (213a) ...
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Scheme 57: Synthesis of double-headed acyclic nucleosides (2R,3S)-1,4-bis(thymine-1-yl)butane-2,3-diol (213c) ...
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Scheme 58: Synthesis of double-headed acetylated 1,3,4-oxadiazino[6,5-b]indolium-substituted C-nucleosides 218b...
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Scheme 59: Synthesis of double-headed acyclic nucleoside 222.
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Scheme 60: Synthesis of functionalized 1,2-bis(1,2,4-triazol-3-yl)ethane-1,2-diols 223a–f.
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Scheme 61: Synthesis of acyclic double-headed 1,2,4-triazino[5,6-b]indole C-nucleosides 226–231.
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Scheme 62: Synthesis of double-headed 1,3,4-thiadiazoline, 1,3,4-oxadiazoline, and 1,2,4-triazoline acyclo C-n...
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Scheme 63: Synthesis of double-headed acyclo C-nucleosides 240–242.
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Scheme 64: Synthesis of double-headed acyclo C-nucleoside 246.
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Scheme 65: Synthesis of acyclo double-headed nucleoside 250.
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Scheme 66: Synthesis of acyclo double-headed nucleoside 253.
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Scheme 67: Synthesis of acyclo double-headed nucleosides 259a–d.
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Scheme 68: Synthesis of acyclo double-headed nucleoside 261.
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- Review
- Published 19 Jul 2021
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Figure 1: Structure of DNA and PNA.
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Figure 2: PNA binding modes: (A) PNA–dsDNA 1:1 triplex; (B) PNA–DNA–PNA strand-invasion triplex; (C) the Hoog...
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Figure 3: Structure of P-form PNA–DNA–PNA triplex from reference [41]. (A) view in the major groove and (B) view ...
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Figure 4: Structures of backbone-modified PNA.
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Figure 5: Structures of PNA having α- and γ-substituted backbones.
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Figure 6: Structures of modified nucleobases in PNA to improve Hoogsteen hydrogen bonding to guanine and aden...
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Figure 7: Proposed hydrogen bonding schemes for modified PNA nucleobases designed to recognize pyrimidines or...
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Figure 8: Modified nucleobases to modulate Watson–Crick base pairing and chemically reactive crosslinking PNA...
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Figure 9: Examples of triplets formed by Janus-wedge PNA nucleobases (blue). R1 denotes DNA, RNA, or PNA back...
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Figure 10: Examples of fluorescent PNA nucleobases. R1 denotes DNA, RNA, or PNA backbones.
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Figure 11: Endosomal entrapment and escape pathways of PNA and PNA conjugates.
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Figure 12: (A) representative cell-penetrating peptides (CPPs), (B) conjugation designs and linker chemistries....
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Figure 13: Proposed delivery mode by pHLIP-PNA conjugates (A) the transmembrane section of pHLIP interacting w...
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Figure 14: Structures of modified penetratin CPP conjugates with PNA linked through either disulfide (for stud...
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Figure 15: Chemical structure of C9–PNA, a stable amphipathic (cyclic-peptide)–PNA conjugate.
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Figure 16: Structures of PNA conjugates with a lipophilic triphenylphosphonium cation (TPP–PNA) through (A) th...
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Figure 17: Structures of (A) chloesteryl–PNA, (B) cholate–PNA and (C) cholate–PNA(cholate)3.
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Figure 18: Structures of PNA–GalNAc conjugates (A) (GalNAc)2K, (B) triantennary (GalNAc)3, and (C) trivalent (...
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Figure 19: Vitamin B12–PNA conjugates with different linkages.
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Figure 20: Structures of (A) neomycin B, (B) PNA–neamine conjugate, and (C) PNA–neosamine conjugate.
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Figure 21: PNA clamp (red) binding to target DNA containing a mixture of sequences (A) PNA binds with higher a...
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Figure 22: Rolling circle amplification using PNA openers (red) to invade a dsDNA target forming a P-loop. A p...
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Figure 23: Molecular beacons containing generic fluorophores (Fl) and quenchers (Q) recognizing a complementar...
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Figure 24: (A) Light-up fluorophores such as thiazole orange display fluorescence enhancement upon binding to ...
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Figure 25: Templated fluorogenic detection of oligonucleotides using two PNAs. (A) Templated FRET depends on h...
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Figure 26: Lateral flow devices use a streptavidin labeled strip on nitrocellulose paper to anchor a capture P...
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- Review
- Published 04 Nov 2021
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Figure 1: Representative modified 1,3-oxathiolane nucleoside analogues.
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Figure 2: Mechanism of antiviral action of 1,3-oxathiolane nucleosides, 3TC (1) and FTC (2), as chain termina...
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Figure 3: Synthetic strategies for the construction of the 1,3-oxathiolane sugar ring.
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Scheme 1: Synthesis of 4 from benzoyloxyacetaldehyde (3a) and 2-mercapto-substituted dimethyl acetal 3na.
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Scheme 2: Synthesis of 8 from protected glycolic aldehyde 3b and 2-mercaptoacetic acid (3o).
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Scheme 3: Synthesis of 20 from ᴅ-mannose (3c).
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Scheme 4: Synthesis of 20 from 1,6-thioanhydro-ᴅ-galactose (3d).
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Scheme 5: Synthesis of 8 from 2-(tert-butyldiphenylsilyloxy)methyl-5-oxo-1,2-oxathiolane (3m).
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Scheme 6: Synthesis of 20a from ʟ-gulose derivative 3f.
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Scheme 7: Synthesis of 31 from (+)-thiolactic acid 3p and 2-benzoyloxyacetaldehyde (3a).
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Scheme 8: Synthesis of 35a from 1,4-dithiane-2,5-diol (3q) and glyoxylic acid (3g) hydrate.
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Scheme 9: Synthetic routes toward 41 through Pummerer reaction from methyl 2-mercaptoacetate (3j) and bromoac...
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Scheme 10: Strategy for the synthesis of 2,5-substituted 1,3-oxathiolane 41a using 4-nitrobenzyl glyoxylate an...
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Scheme 11: Synthesis of 44 by a resolution method using Mucor miehei lipase.
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Scheme 12: Synthesis of 45 from benzoyloxyacetaldehyde (3a) and 2-mercaptoacetaldehyde bis(2-methoxyethyl) ace...
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Scheme 13: Synthesis of 46 from 2-mercaptoacetaldehyde bis(2-methoxyethyl) acetal (3nc) and diethyl 3-phosphon...
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Scheme 14: Synthesis of 48 from 1,3-dihydroxyacetone dimer 3l.
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Scheme 15: Approach toward 52 from protected alkene 3rb and lactic acid derivative 51 developed by Snead et al....
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Scheme 16: Recent approach toward 56a developed by Kashinath et al.
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Scheme 17: Synthesis of 56a from ʟ-menthyl glyoxylate (3h) hydrate by DKR.
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Scheme 18: Possible mechanism with catalytic TEA for rapid interconversion of isomers.
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Scheme 19: Synthesis of 35a by a classical resolution method through norephedrine salt 58 formation.
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Scheme 20: Synthesis of 63 via [1,2]-Brook rearrangement from silyl glyoxylate 61 and thiol 3nb.
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Scheme 21: Combined use of STS and CAL-B as catalysts to synthesize an enantiopure oxathiolane precursor 65.
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Scheme 22: Synthesis of 1 and 1a from glycolaldehyde dimer 64 and 1,4-dithiane-2,5-diol (3q) using STS and CAL...
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Scheme 23: Synthesis of 68 by using Klebsiella oxytoca.
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Scheme 24: Synthesis of 71 and 72 using Trichosporon taibachii lipase and kinetic resolution.
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Scheme 25: Synthesis of 1,3-oxathiolan-5-ones 77 and 78 via dynamic covalent kinetic resolution.
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Figure 4: Pathway for glycosidic bond formation.
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Scheme 26: First synthesis of (±)-BCH-189 (1c) by Belleau et al.
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Scheme 27: Enantioselective synthesis of 3TC (1).
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Scheme 28: Synthesis of cis-diastereomer 3TC (1) from oxathiolane propionate 44.
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Scheme 29: Synthesis of (±)-BCH-189 (1c) via SnCl4-mediated N-glycosylation of 8.
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Scheme 30: Synthesis of (+)-BCH-189 (1a) via TMSOTf-mediated N-glycosylation of 20.
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Scheme 31: Synthesis of 3TC (1) from oxathiolane precursor 20a.
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Scheme 32: Synthesis of 83 via N-glycosylation of 20 with pyrimidine bases.
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Scheme 33: Synthesis of 85 via N-glycosylation of 20 with purine bases.
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Scheme 34: Synthesis of 86 and 87 via N-glycosylation using TMSOTf and pyrimidines.
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Scheme 35: Synthesis of 90 and 91 via N-glycosylation using TMSOTf and purines.
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Scheme 36: Synthesis of 3TC (1) via TMSI-mediated N-glycosylation.
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Scheme 37: Stereoselective N-glycosylation for the synthesis of 1 by anchimeric assistance of a chiral auxilia...
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Scheme 38: Whitehead and co-workers’ approach for the synthesis of 1 via direct N-glycosylation without an act...
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Scheme 39: ZrCl4-mediated stereoselective N-glycosylation.
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Scheme 40: Plausible reaction mechanism for stereoselective N-glycosylation using ZrCl4.
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Scheme 41: Synthesis of enantiomerically pure oxathiolane nucleosides 1 and 2.
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Scheme 42: Synthesis of tetrazole analogues of 1,3-oxathiolane nucleosides 97.
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Scheme 43: Synthetic approach toward 99 from 1,3-oxathiolane 45 by Camplo et al.
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Scheme 44: Synthesis of 100 from oxathiolane phosphonate analogue 46.
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Scheme 45: Synthetic approach toward 102 and the corresponding cyclic thianucleoside monophosphate 102a by Cha...
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Scheme 46: Synthesis of emtricitabine (2) from 1,4-dithiane-2,5-diol (3q) and glyoxylic acid (3g).
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Scheme 47: Synthesis of 1 and 2, respectively, from 56a–d using iodine-mediated N-glycosylation.
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Scheme 48: Plausible mechanism for silane- and I2-mediated N-glycosylation.
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Scheme 49: Pyridinium triflate-mediated N-glycosylation of 35a.
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Scheme 50: Possible pathway for stereoselective N-glycosylation via in situ chelation with a metal ligand.
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Scheme 51: Synthesis of novel 1,3-oxathiolane nucleoside 108 from oxathiolane precursor 8 and 3-benzyloxy-2-me...
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Scheme 52: Synthesis of 110 using T-705 as a nucleobase and 1,3-oxathiolane derivative 8 via N-glycosylation.
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Scheme 53: Synthesis of 1 using an asymmetric leaving group and N-glycosylation with bromine and mesitylene.
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Scheme 54: Cytidine deaminase for enzymatic separation of 1c.
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Scheme 55: Enzymatic resolution of the monophosphate derivative 116 for the synthesis of (−)-BCH-189 (1) and (...
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Scheme 56: Enantioselective resolution by PLE-mediated hydrolysis to obtain FTC (2).
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Scheme 57: (+)-Menthyl chloroformate as a resolving agent to separate a racemic mixture 120.
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Scheme 58: Separation of racemic mixture 1c by cocrystal 123 formation with (S)-(−)-BINOL.
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