Nucleic acid chemistry II

Editor: Prof. Hans-Achim Wagenknecht
Karlsruhe Institute of Technology

The organic chemistry and synthesis of nucleic acids allows introducing natural and artificial functional groups as well as probes, markers or other biologically active molecules into these types of biopolymers and their synthetic analogs. Thus, nucleic acid chemistry is of fundamental importance for the actual and future research in chemical biology. Moreover, besides its biological functions, DNA and RNA are considered as an increasingly important architecture and scaffold for two- and three-dimensional objects in material sciences and photochemistry. These are enough reasons to summarize and highlight the different aspects of nucleic acid chemistry by focused reviews that are written by leading experts in this research field.

Synthesis of oligonucleotides on a soluble support

Harri Lönnberg

Review
Published 12 Jul 2017

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1. Graphical Abstract
2. Figure 1: General principle of oligonucleotide synthesis.
  
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3. Scheme 1: Alternative coupling methods used in the synthesis of oligonucleotides.
  
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4. Scheme 2: Synthesis of ODNs on a precipitative PEG-support by phosphotriester chemistry using MSNT/NMI activa...
  
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5. Scheme 3: Synthesis of ODNs on a precipitative tetrapodal support by phosphotriester chemistry using 1-hydrox...
  
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6. Scheme 4: Synthesis of ODNs on a precipitative PEG-support by conventional phosphoramidite chemistry [51].
  
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7. Scheme 5: Synthesis of ODNs on a precipitative tetrapodal support by conventional phosphoramidite chemistry [43].
  
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8. Scheme 6: Synthesis of ODNs by an extractive strategy on an adamant-1-ylacetyl support [57].
  
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9. Scheme 7: Synthesis of ODNs by a combination of extractive and precipitative strategy [58].
  
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10. Scheme 8: Synthesis of ODNs by phosphoramidite chemistry on a N¹,N³,N⁵-tris(2-aminoethyl)benzene-1,3,5-tricar...
  
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11. Scheme 9: Synthesis of ORNs by phosphoramidite chemistry on a hydrophobic support [61].
  
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12. Scheme 10: Synthesis of ORNs by the phosphoramidite chemistry on a precipitative tetrapodal support using 2´-O...
  
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13. Scheme 11: Synthesis of ORNs by phosphoramidite chemistry on a precipitative tetrapodal support from commercia...
  
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14. Scheme 12: Synthesis of ODNs on a precipitative PEG-support by H-phosphonate chemistry [65].
  
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15. Scheme 13: Synthesis of 2´-O-methyl ORN phosphorothioates by phosphoramidite chemistry by making use of nanofi...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

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Metal-mediated base pairs in parallel-stranded DNA

Jens Müller

Review
Published 13 Dec 2017

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1. Graphical Abstract
2. Figure 1: Structure of a B-DNA duplex comprising a central C–Ag(I)–C base pair. This figure was created based...
  
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3. Scheme 1: Hydrogen-bonding patterns of various reversed Watson–Crick base pairs. a) A:T; b) G:C (steric clash...
  
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4. Scheme 2: Various hydrogen-bonding patterns. a) T:A:T and CH⁺:G:C base triples indicating how T:A and CH⁺:G H...
  
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5. Scheme 3: Representation of a β-dA:α-dT base pair.
  
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6. Scheme 4: Representation of mononuclear metal-mediated base pairs involving canonical pyrimidine nucleobases....
  
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7. Scheme 5: Proposed base pairing patterns of FP–Ag(I)–FP, involving a) the Watson–Crick edge (antiparallel-str...
  
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8. Scheme 6: Reaction pathway towards a parallel-stranded DNA duplex bearing a G–Pt(II)–G base pair. Adapted fro...
  
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9. Scheme 7: Possible base pairing patterns of dinuclear Ag(I)-mediated base pairs. Base pairs within an antipar...
  
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10. Scheme 8: Base pairing patterns of the dinuclear Ag(I)-mediated homo base pair of 1,N⁶-ethenoadenine (εA) wit...
  
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11. Scheme 9: Additional metal-mediated base pairs involving 1,N⁶-ethenoadenine (εA). Base pairs within an antipa...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2017, 13, 2671–2681, doi:10.3762/bjoc.13.265

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Synthetic mRNA capping

Fabian Muttach,
Nils Muthmann and
Andrea Rentmeister

Review
Published 20 Dec 2017

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1. Graphical Abstract
2. Figure 1: Schematic representation of enzymatic 5′-cap formation in eukaryotic mRNA. The 5′-triphosphate-end ...
  
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3. Figure 2: Nucleotide analogues 1–11 were converted by Paramecium bursaria Chlorella virus-1 capping enzyme in...
  
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4. Figure 3: Schematic representation of co-transcriptional capping with different cap analogues. A DNA-dependen...
  
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5. Figure 4: (A) Structures of commercially available mRNA cap analogues. (B) Synthetic route to cap analogues a...
  
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6. Figure 5: Enzymatic modification of cap analogues at their N²- or N7-position or a combination of both. (A) F...
  
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7. Figure 6: Synthesis of cap-containing RNA by solid-phase synthesis. (A) A TMG-capped mRNA was synthesized sta...
  
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8. Figure 7: Click chemistry for the preparation of capped RNA and cap analogues. (A) Preparation of capped RNA ...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

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Polarization spectroscopy methods in the determination of interactions of small molecules with nucleic acids – tutorial

Tamara Šmidlehner,
Ivo Piantanida and
Gennaro Pescitelli

Review
Published 08 Jan 2018

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1. Graphical Abstract
2. Figure 1: Plane polarized light (PP, cyan) as the sum of the left and right circularly polarized light (L-CP,...
  
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3. Figure 2: Schematic representation of ligand binding modes to DNA or RNA (left to right: DNA minor groove bin...
  
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4. Scheme 1: Principal electronic transitions of nucleobases (uracil is similar to thymine, Thy). The arrows dep...
  
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5. Figure 3: Exciton coupling mechanism in its degenerate (top) and non-degenerate version (bottom). a) Chiralit...
  
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6. Figure 4: ECD and UV (inset) spectra of poly(dG-dC)–poly(dG-dC) in the B and Z-form, obtained in 59% and 67% ...
  
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7. Figure 5: Schematic illustration of an ECD instrument. Legend: S, source; M, monochromator (wavelength select...
  
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8. Figure 6: Exciton coupling in the G-quadruplex [d(TG₄T)]₄. For this sequence, the quadruplex is formed by fou...
  
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9. Figure 7: Empirical analysis of ECD and flow LD spectra to establish the preferred orientation of a ligand bo...
  
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10. Figure 8: CD titration of poly rA-poly rU (left) and poly rU (right) (c(polynucleotide) = 2.0 × 10⁻⁵ mol dm⁻³...
  
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11. Figure 9: a) Schematic diagram of a flow LD instrument. b) Definition of the optical factor relating the dire...
  
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12. Figure 10: LD spectrum of calf thymus (ct) DNA (c = 2 × 10⁻⁴ M), pH 7, sodium cacodylate buffer, I = 0.05 M.
  
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13. Figure 11: Schematic illustration of an FDCD a) and a CPL b) instrument. Legend: S, source; M, monochromator (...
  
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14. Figure 12: Minimal model to be considered to simulate the ICD spectrum of an intercalated ligand. ICD will be ...
  
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15. Figure 13: Schematic representation of the main steps for calculating the ICD spectrum of a ligand bound to a ...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2018, 14, 84–105, doi:10.3762/bjoc.14.5

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Fluorescent nucleobase analogues for base–base FRET in nucleic acids: synthesis, photophysics and applications

Mattias Bood,
Sangamesh Sarangamath,
Moa S. Wranne,
Morten Grøtli and
L. Marcus Wilhelmsson

Review
Published 10 Jan 2018

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1. Graphical Abstract
2. Figure 1: a) Angles and unit vectors used to define the relative orientations of the donor and acceptor trans...
  
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3. Figure 2: Notable recent examples of fluorescent base analogues. For ^cnA and ^dnA the attachment point to the ...
  
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4. Scheme 1: Synthesis of the tricyclic cytosine aromatic core [39]. (a) Ethylene glycol, K₂CO₃, 120 °C, 1 h, 40%; (...
  
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5. Scheme 2: Synthesis of protected tC and tC^O deoxyribose phosphonates [41]. (a) Ac₂O, pyridine, rt; (b) 2-mesityle...
  
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6. Scheme 3: Synthesis of protected tC_nitro deoxyribose phosphoramidite [14]. a) aq NaOH, 24 h, reflux; b) EtOH, HCl...
  
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7. Scheme 4: Improved synthesis of tC and tC derivatives, where R = H, 7-MeO or 8-MeO [47]. a) H₂NNH₂ followed by H₂O...
  
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8. Scheme 5: Improved synthesis of tC^O derivatives [47]. a) Ac₂O, pyridine, 16 h, rt, 85%; b) PPh₃, CCl₄, DCM, 5 h, ...
  
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9. Scheme 6: Synthesis of protected tC^O ribose phosphoramidite [50]. a) MesSO₂Cl, DIPEA, MeCN, 4 h, rt; b) 2-aminoph...
  
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10. Scheme 7: Synthesis of protected deoxyribose qA [51]. a) N-(tert-Butoxycarbonyl)-2-(trimethylstannyl)aniline, (Ph₃...
  
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11. Scheme 8: Synthesis of protected deoxyribose qA for DNA SPS [53]. a) AcCl, MeOH, rt, 40 min; b) p-toluoyl chlorid...
  
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12. Scheme 9: Synthesis of qA derivatives. a) EtI, Cs₂CO₃, DMF, 4 h, rt, 90%; b) HBPin, Pd(PPh₃)₄, Et₃N, 1,4-diox...
  
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13. Scheme 10: Synthesis of quadracyclic adenine base–base FRET pair. a) HCHO, NaOH, MeCN, H₂O, 50 °C, 1 h; b) TBD...
  
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14. Figure 3: Absorption and emission of tC (dashed line) and tC^O (solid line) in dsDNA. The absorption below 300...
  
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15. Figure 4: Spectral overlap between the emission of qAN1 (cyan) and the absorption of qA_nitro (black) in dsDNA...
  
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16. Figure 5: Example of typical FRET efficiency as a function of number of base pairs separating the donor and a...
  
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17. Figure 6: FRET efficiency as a function of number of base pairs separating the donor (qAN1) and acceptor (qA_n...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2018, 14, 114–129, doi:10.3762/bjoc.14.7

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Fluorogenic PNA probes

Tirayut Vilaivan

Review
Published 29 Jan 2018

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1. Graphical Abstract
2. Figure 1: The design of classical DNA molecular beacons.
  
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3. Figure 2: Structures of DNA and selected PNA systems.
  
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4. Figure 3: Various binding modes of PNA to double stranded DNA including triplex formation, triplex invasion, ...
  
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5. Figure 4: The design and working principle of the PNA beacons according to (A) Ortiz et al. [41] and (B) Armitage...
  
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6. Figure 5: The design of "stemless" PNA beacons.
  
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7. Figure 6: The applications of PNA openers to facilitate the binding of PNA beacons to double stranded DNA [40,47].
  
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8. Figure 7: The working principle of snap-to-it probes that employed metal chelation to bring the dyes in close...
  
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9. Figure 8: Examples of pre-formed dye-labeled PNA monomers and functionalizable PNA monomers.
  
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10. Figure 9: Dual-labeled PNA beacons with end-stacking or intercalating quencher.
  
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11. Figure 10: The working principle of hybrid PNA-peptide beacons for detection of (A) proteins [80] and (B) protease...
  
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12. Figure 11: The working principle of binary probes.
  
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13. Figure 12: The working principle of nucleic acid templated fluorogenic reactions leading to a (A) ligated prod...
  
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14. Figure 13: Catalytic cycles in fluorogenic nucleic acid templated reactions [90].
  
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15. Figure 14: The working principle of strand displacement probes.
  
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16. Figure 15: (A) Examples of CPP successfully used with labeled PNA probes. (B) The use of single-labeled PNA pr...
  
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17. Figure 16: The concept of PNA–GO platform for DNA/RNA sensing.
  
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18. Figure 17: Single-labeled fluorogenic PNA probes.
  
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19. Figure 18: Examples of environment sensitive fluorescent labels that have been incorporated into PNA probes as...
  
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20. Figure 19: The mechanism of fluorescence change in TO dye.
  
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21. Figure 20: Fluorescent nucleobases capable of hydrogen bonding that have been incorporated into PNA probes.
  
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22. Figure 21: Comparison of the designs of the (A) light-up PNA probe and (B) FIT PNA probe.
  
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23. Figure 22: The structures of TO and its analogues that have successfully been used in FIT PNA probes.
  
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24. Figure 23: The working principle of dual-labeled FIT PNA probes [222,223].
  
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Graphical Abstract

Beilstein J. Org. Chem. 2018, 14, 253–281, doi:10.3762/bjoc.14.17

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Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries

Ruth Suchsland,
Bettina Appel and
Sabine Müller

Review
Published 13 Feb 2018

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1. Graphical Abstract
2. Figure 1: Preparation of fully protected trinucleotides in solution (A), on solid phase (B) and on soluble po...
  
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3. Figure 2: Strategies for trinucleotide synthesis using different pairs of orthogonal groups for protection of...
  
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4. Figure 3: Strategy for the synthesis of nucleotide dimers and extension to the trimer in either 5'- or 3'-dir...
  
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5. Figure 4: Removal of the 3'-O-protecting group under conditions that leave all other protecting groups at 5'-...
  
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6. Figure 5: Release of trinucleotide blocks from the solid support by cleavage of an oxalyl anchor (A) and by a...
  
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7. Figure 6: Release of the trinucleotide from the support under reductive conditions.
  
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8. Figure 7: Phosphitylation of trimers. Reaction conditions, in particular the choice of the phosphitylation re...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2018, 14, 397–406, doi:10.3762/bjoc.14.28

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Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

Françoise Debart,
Christelle Dupouy and
Jean-Jacques Vasseur

Review
Published 19 Feb 2018

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1. Graphical Abstract
2. Scheme 1: Demasking under reducing agents of ON prodrugs modified as phosphotriesters with A) benzyl groups [13] ...
  
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3. Scheme 2: A) Synthesis via phosphoramidite chemistry and B) demasking under the reducing environment of 2’-O-...
  
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4. Scheme 3: Synthesis via phosphoramidite chemistry of various 2’-O-alkyldithiomethyl (RSSM)-modified RNAs bear...
  
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5. Scheme 4: A) siRNA conjugates to cholesterol [19] and B) PNA conjugates to a triphenylphosphonium [20] through a disu...
  
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6. Scheme 5: Synthesis via phosphoramidite chemistry and deprotection mediated by nitroreductase/NADH of hypoxia...
  
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7. Scheme 6: Synthesis via phosphoramidite chemistry and conversion mediated by nitroreductase/NADH of hypoxia-a...
  
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8. Scheme 7: Incorporation of O⁶-(4-nitrobenzyl)-2’-deoxyguanosine into an ON prone to form a G-quadruplex struc...
  
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9. Scheme 8: Synthesis and mechanism for the demasking of ON prodrugs from A) S-acylthioethyl phosphotriester [29] a...
  
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10. Figure 1: Oligothymidylates bearing A) 2,2-bis(ethoxycarbonyl)-3-(pivaloyloxy)propyl- and B) 2-cyano-2(2-phen...
  
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11. Figure 2: Oligothymidylates containing esterase and thermo-labile (4-acetylthio-2,2-dimethyl-3-oxobutyl) phos...
  
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12. Scheme 9: Phosphoramidites and the corresponding RNA prodrugs protected as A) t-Bu-SATE, B) OH-SATE and C) A-...
  
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13. Scheme 10: Mechanism of the hydrolysis of 2’-O-acyloxymethyl ONs mediated by carboxyesterases [46]. The hydrolysis...
  
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14. Scheme 11: Synthesis of partially 2’-O-PivOM-modified RNAs [49] and 2’-O-PiBuOM-modified RNAs [53] using their corresp...
  
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15. Figure 3: A) 2’-O-amino and guanidino-containing acetal ester phosphoramidites and B) 2’-O-(amino acid) aceta...
  
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16. Scheme 12: Prodrugs of tricyclo-ONs functionalized with A) ethyl (tc^ee-T) and B) hexadecyl (tc^hd-T) ester func...
  
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17. Scheme 13: Demasking mechanism of fma thiophosphate triesters in CpG ODN upon heat action [58].
  
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18. Scheme 14: Thermolytic cleavage of the hydroxy-alkylated thiophosphate and phosphato-/thiophosphato-alkylated ...
  
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19. Scheme 15: Synthesis via phosphoramidite chemistry and thermolytic cleavage of alkylated (diisopropyl, diethyl...
  
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20. Scheme 16: Synthesis of thermosensitive prodrugs of ODNs containing fma thiophosphate triesters combined to po...
  
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21. Scheme 17: Caging of deoxycytidine in methylphosphonate ONs by using the thermolabile phenylsulfonylcarbamoyl ...
  
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22. Figure 4: Biotinylated 1-(5-(aminomethyl)-2-nitrophenyl)ethyl phosphoramidite used to cage the 5’-end of a si...
  
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23. Scheme 18: Introduction and cleavage of 1-(4,5-dimethoxy-2-nitrophenyl)ethyl (DMNPE) [74] and cyclododecyl-DMNPE (...
  
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24. Scheme 19: Post-synthetic introduction of a thioether-enol phosphodiester (TEEP) linkage into a DNAzyme by the...
  
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25. Scheme 20: A) NPP dT and dG phosphoramidites [91,92] and B) NPOM U and G phosphoramidites [83] used to introduce photocag...
  
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26. Scheme 21: Introduction of the photocaged 3-NPOM nucleobase into phosphorothioate antisense and morpholino ant...
  
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27. Scheme 22: Control of the activity of an antisense ODN using a photocaged hairpin [82]. Formation of the hairpin s...
  
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28. Scheme 23: Control of alternative splicing using phosphorothioate (PS) 2’-OMe-photocaged ONs resulting from th...
  
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29. Scheme 24: A) Light activation of a photocaged DNAzyme incorporating 3-NPOM thymidine in its catalytic site [87]; ...
  
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30. Scheme 25: Incorporation of 3-(6-nitropiperonyloxymethyl) (NPOM) thymidine and 4-nitropiperonylethyl (NPE) deo...
  
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31. Scheme 26: Synthesis of a photocaged DNA decoy from a 3-NPOM thymidine phosphoramidite and release of the NPOM...
  
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32. Scheme 27: Synthesis of a caged DNA decoy hairpin containing a 7-nitroindole nucleotide and release of the mod...
  
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33. Figure 5: Caged-2’-adenosines used by MacMillan et al [93,94] (X = O) and Piccirilli et al [95] (X = S) to study RNA mec...
  
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34. Scheme 28: Synthesis of circular ODNs containing a photolabile linker as described by Tang et al. [101,104].
  
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35. Scheme 29: Control of RNA digestion with RNase H using light activation of a photocaged hairpin [97].
  
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36. Scheme 30: Photocontrol of RNA degradation using caged circular antisense ODNs containing a photoresponsive li...
  
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37. Scheme 31: Control of RNA translation using an “RNA bandage” consisting of two short 2’-OMe ONs linked togethe...
  
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38. Scheme 32: Control of alternative splicing using photocaged ONs resulting from the incorporation of an o-nitro...
  
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39. Scheme 33: A) Light deactivation of a photocaged DNAzyme incorporating one photocleavable spacer in its cataly...
  
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40. Scheme 34: Solid-phase synthesis of a caged vit E-siRNA conjugate and its release upon UV irradiation [106].
  
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41. Scheme 35: Synthesis of a siRNA conjugated to a nanoparticle (NP) via a cyclooctene heterolinker from a siRNA-...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

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Enzyme-free genetic copying of DNA and RNA sequences

Marilyne Sosson and
Clemens Richert

Review
Published 12 Mar 2018

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1. Graphical Abstract
2. Figure 1: Enzyme-free template-directed extension of an RNA primer by one nucleotide. B = nucleobase, LG = le...
  
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3. Figure 2: Oligomerization of the 2-methylimidazolide of guanosine-5'-monophosphate on a poly(C) template.
  
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4. Figure 3: Structures of backbone linkages produced in enzyme-free primer extension reactions: the phosphorami...
  
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5. Figure 4: System used for studying the template effect with all 64 possible triplets at the extension site (B...
  
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6. Figure 5: Interactions attracting the incoming nucleotide to the extension site. Besides base pairing via hyd...
  
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7. Figure 6: Three possible fates of activated nucleotides in aqueous buffer that result from hydrolysis, primer...
  
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8. Figure 7: Steps and equilibria considered in our quantitative model of chemical primer extension [34]. The model ...
  
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9. Figure 8: Binding equilibrium between mononucleotides and hairpins representing primer–template duplexes, as ...
  
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10. Figure 9: Template-directed primer extension on an RNA template performed with OAt-GMP at 1.8 mM (orange), 3....
  
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11. Figure 10: Copying of four nucleotides on an immobilized RNA duplex, as reported by Deck et al. [32].
  
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12. Figure 11: Extension cycle of aminoterminal primer with N-protected nucleotides on solid support, as described...
  
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13. Figure 12: Formation of a highly reactive methylimidazolium bisphosphate from methylimidazolides of nucleotide...
  
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14. Figure 13: ³¹P NMR spectrum (161.9 MHz) of crude MeIm-GMP in D₂O. The resonance of the imidazolium bisphosphat...
  
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15. Figure 14: Imidazolium bisphosphate as intermediate in the primer extension reaction, as described by Szostak ...
  
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16. Figure 15: Proposed steps of enzyme-free primer extension with in situ activation, using the "general condensa...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

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Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

Kartik Temburnikar and
Katherine L. Seley-Radtke

Review
Published 05 Apr 2018

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1. Graphical Abstract
2. Figure 1: Structural components of nucleic acids. Shown is the monomeric building block of nucleic acids. Cha...
  
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3. Figure 2: Formation of oxocarbenium ion during glycosidic bond cleavage in nucleosides [31]. The extent of leavin...
  
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4. Figure 3: Structural modifications to nucleobase-sugar connectivity. The O–C–N bond between nucleobase and su...
  
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5. Figure 4: Examples of natural and synthetic C-nucleosides. Pseudouridine and formcycin are among several natu...
  
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6. Figure 5: Synthetic approaches to C-nucleosides. A. Two common strategies for C-nucleoside synthesis involve ...
  
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7. Figure 6: Steroselective C-nucleoside synthesis using D-ribonolactone. A. Nucleophilic substitution of D-ribo...
  
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8. Figure 7: Synthesis of C1'-substituted 4-aza-7,9-dideazaadenine C-nucleosides [63-65,69,70]. A. Reaction of D-ribonolacton...
  
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9. Figure 8: Pyrrolo- and imidazo[2,1-f][1,2,4]triazine C-nucleosides. A series of sugar- and nucleobase-substit...
  
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10. Figure 9: Synthesis of 1',2'-cyclopentyl C-nucleoside [73]. Functional groups at C1' and C2' were installed and e...
  
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11. Figure 10: Anti-influenza C-nucleosides mimicking favipiravir riboside [74]. A. Structure of favipiravir and its r...
  
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12. Figure 11: Alternative method for synthesis of 2'-substituted C-nucleosides [75]. A. Synthesis of C2'-substituted ...
  
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13. Figure 12: Synthesis of carbocyclic C-nucleosides using cyclopentanone [53]. A. Nucleophlic substitution on cyclop...
  
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14. Figure 13: Synthesis of carbocyclic C-nucleosides via Suzuki coupling [53]. A. Synthesis of OTf-cyclopentene that ...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

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Phosphodiester models for cleavage of nucleic acids

Satu Mikkola,
Tuomas Lönnberg and
Harri Lönnberg

Review
Published 10 Apr 2018

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1. Graphical Abstract
2. Figure 1: Enzymatic cleavage of phosphodiester linkages of DNA and RNA.
  
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3. Figure 2: Energy profiles for a concerted A_ND_N (A) and stepwise mechanisms (A_N + D_N) with rate-limiting break...
  
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4. Figure 3: Pseudorotation of a trigonal bipyramidal phosphorane intermediate by Berry pseudorotation [20].
  
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5. Figure 4: Protolytic equilibria of phosphorane intermediate of RNA transesterification.
  
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6. Figure 5: Structures of acyclic analogs of ribonucleosides.
  
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7. Figure 6: First-order rate constants for buffer-independent partial reactions of uridyl-3´,5´-uridine at pH 5...
  
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8. Scheme 1: pH- and buffer-independent cleavage and isomerization of RNA phosphodiester linkages. Observed firs...
  
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9. Scheme 2: Mechanism for the pH- and buffer-independent cleavage of RNA phosphodiester linkages.
  
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10. Scheme 3: Hydroxide-ion-catalyzed cleavage of RNA phosphodiester linkages.
  
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11. Scheme 4: Anslyn's and Breslow's mechanism for the buffer-catalyzed cleavage and isomerization of RNA phospho...
  
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12. Scheme 5: General base-catalyzed cleavage of RNA phosphodiester bonds.
  
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13. Scheme 6: Kirby´s mechanism for the buffer-catalyzed cleavage of RNA phosphodiester bonds [65].
  
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14. Figure 7: Guanidinium-group-based cleaving agents of RNA.
  
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15. Scheme 7: Tautomers of triazine-based cleaving agents and cleavage of RNA phosphodiester bonds by these agent...
  
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16. Figure 8: Bifunctional guanidine/guanidinium group-based cleaving agents of RNA.
  
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17. Scheme 8: Cleavage of HPNP by 1,3-distal calix[4]arene bearing two guanidine groups [80].
  
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18. Figure 9: Cyclic amine-based cleaving agents of RNA.
  
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19. Scheme 9: Mechanism for the pH-independent cleavage and isomerization of model compound 12a in the pH-range 7...
  
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20. Scheme 10: Mechanism for the pH-independent cleavage of guanylyl-3´,3´-(2´-amino-2´-deoxyuridine) at pH 6-8 [89].
  
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21. Scheme 11: Cleavage of uridine 3´-dimethyl phosphate by A) intermolecular attack of methoxide ion and B) intra...
  
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22. Scheme 12: Transesterification of group I introns and hydrolysis of phosphotriester models proceed through a s...
  
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23. Scheme 13: Cleavage of trinucleoside 3´,3´,5´-monophosphates by A) P–O3´ and B) P–O5´ bond fission.
  
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24. Figure 10: Model compounds (23–25) and metal ion binding ligands used in kinetic studies of metal-ion-promoted...
  
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25. Figure 11: Zn²⁺-ion-based mono- and di-nuclear cleaving agents of nucleic acids.
  
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26. Figure 12: Miscellaneous complexes and ligands used in kinetic studies of metal-ion-promoted cleavage of nucle...
  
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27. Figure 13: Azacrown ligands 34 and 35 and dinuclear Zn²⁺ complex 36 used in kinetic studies of metal-ion-promo...
  
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28. Figure 14: Metal ion complexes used for determination of β_lg values of metal-ion-promoted cleavage of RNA mode...
  
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29. Figure 15: Metal ion complexes used in kinetic studies of medium effects on the cleavage of RNA model compound...
  
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30. Scheme 14: Alternative mechanisms for metal-ion-promoted cleavage of phosphodiesters.
  
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31. Figure 16: Nucleic acid cleaving agents where the attacking oxyanion is not coordinated to metal ion.
  
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Graphical Abstract

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

Full Text

Mechanochemistry of nucleosides, nucleotides and related materials

Olga Eguaogie,
Joseph S. Vyle,
Patrick F. Conlon,
Manuela A. Gîlea and
Yipei Liang

Review
Published 27 Apr 2018

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Album
1. Graphical Abstract
2. Figure 1: Examples of equipment used to perform mechanochemistry on nucleoside and nucleotide substrates (not...
  
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3. Figure 2: Ganciclovir.
  
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4. Scheme 1: Nucleoside tritylation effected by hand grinding in a heated mortar and pestle.
  
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5. Scheme 2: Persilylation of ribonucleoside hydroxy groups (and in situ acylation of cytidine) in a MBM.
  
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6. Scheme 3: Nucleoside amine and carboxylic acid Boc protection using an improvised attritor-type mill.
  
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7. Scheme 4: Nucleobase Boc protection via transient silylation using an improvised attritor-type mill.
  
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8. Scheme 5: Chemoselective N-acylation of an aminonucleoside using LAG in a MBM.
  
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9. Scheme 6: Azide–alkyne cycloaddition reactions performed in a copper vessel in a MBM.
  
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10. Figure 3: a) Custom-machined copper vessel and zirconia balls used to perform CuAAC reactions (showing: upper...
  
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11. Scheme 7: Thiolate displacement reactions of nucleoside derivatives in a MBM.
  
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12. Scheme 8: Selenocyanate displacement reactions of nucleoside derivatives in a MBM.
  
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13. Scheme 9: Nucleobase glycosidation reactions and subsequent deacetylation performed in a MBM.
  
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14. Scheme 10: Regioselective phosphorylation of nicotinamide riboside in a MBM.
  
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15. Scheme 11: Preparation of nucleoside phosphoramidites in a MBM using ionic liquid-stabilised chlorophosphorami...
  
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16. Scheme 12: Preparation of a nucleoside phosphite triester using LAG in a MBM.
  
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17. Scheme 13: Internucleoside phosphate coupling linkages in a MBM.
  
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18. Scheme 14: Preparation of ADPR analogues using in a MBM.
  
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19. Scheme 15: Synthesis of pyrophosphorothiolate-linked dinucleoside cap analogues in a MBM to effect hydrolytic ...
  
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20. Figure 4: Early low temperature mechanised ball mill as described by Mudd et al. – adapted from reference [78].
  
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21. Scheme 16: Co-crystal grinding of alkylated nucleobases in an amalgam mill (N.B. no frequency was recorded in ...
  
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22. Figure 5: Materials used to prepare a smectic phase.
  
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23. Figure 6: Structures of 5-fluorouracil (5FU) and nucleoside analogue prodrugs subject to mechanochemical co-c...
  
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24. Scheme 17: Preparation of DNA-SWNT complex in a MBM.
  
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Graphical Abstract

Beilstein J. Org. Chem. 2018, 14, 955–970, doi:10.3762/bjoc.14.81

Full Text

An overview of recent advances in duplex DNA recognition by small molecules

Sayantan Bhaduri,
Nihar Ranjan and
Dev P. Arya

Review
Published 16 May 2018

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1. Graphical Abstract
2. Figure 1: A figure showing the hydrogen bonding patterns observed in (a) duplex (b) triplex and (c) quadruple...
  
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3. Figure 2: (a) Portions of MATα1–MATα2 are shown contacting the minor groove of the DNA substrate. Key arginin...
  
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4. Figure 3: Chemical structures of naturally occurring and synthetic hybrid minor groove binders.
  
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5. Figure 4: Synthetic structural analogs of distamycin A by replacing one or more pyrrole rings with other hete...
  
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6. Figure 5: Pictorial representation of the binding model of pyrrole–imidazole (Py/Im) polyamides based on the ...
  
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7. Figure 6: Chemical structures of synthetic “hairpin” pyrrole–imidazole (Py/Im) conjugates.
  
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8. Figure 7: (a) Minor groove complex formation between DNA duplex and 8-ring cyclic Py/Im polyamide (conjugate ...
  
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9. Figure 8: Telomere-targeting tandem hairpin Py/Im polyamides 23 and 24 capable of recognizing >10 base pairs; ...
  
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10. Figure 9: Representative examples of recently developed DNA minor groove binders.
  
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11. Figure 10: Chemical structures of bisbenzamidazoles Hoechst 33258 and 33342 and their synthetic structural ana...
  
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12. Figure 11: Chemical structures of bisamidines such as diminazene, DAPI, pentamidine and their synthetic struct...
  
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13. Figure 12: Representative examples of recently developed bisamidine derivatives.
  
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14. Figure 13: Chemical structures of chromomycin, mithramycin and their synthetic structural analogs 91 and 92.
  
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15. Figure 14: Chemical structures of well-known naturally occurring DNA binding intercalators.
  
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16. Figure 15: Naturally occurring indolocarbazole rebeccamycin and its synthetic analogs.
  
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17. Figure 16: Representative examples of naturally occurring and synthetic derivatives of DNA intercalating agent...
  
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18. Figure 17: Several recent synthetic varieties of DNA intercalators.
  
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19. Figure 18: Aminoglycoside (neomycin)–Hoechst 33258/intercalator conjugates.
  
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20. Figure 19: Chemical structures of triazole linked neomycin dimers and neomycin–bisbenzimidazole conjugates.
  
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21. Figure 20: Representative examples of naturally occurring and synthetic analogs of DNA binding alkylating agen...
  
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22. Figure 21: Chemical structures of naturally occurring and synthetic analogs of pyrrolobenzodiazepines.
  
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Graphical Abstract

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

Full Text

Oligonucleotide analogues with cationic backbone linkages

Melissa Meng and
Christian Ducho

Review
Published 04 Jun 2018

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Album
1. Graphical Abstract
2. Figure 1: Biological action of single-stranded oligonucleotides (ON): antigene and antisense pathways.
  
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3. Figure 2: Selected examples 1–6 of nucleic acid modifications based on additionally attached positively charg...
  
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4. Figure 3: Oligonucleotide analogues with artificial cationic backbone linkages discussed in this review: amin...
  
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5. Scheme 1: Structure of Letsinger's modified deoxyadenosyl dinucleotide 11 and synthesis of cationic oligonucl...
  
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6. Figure 4: Artificial cationic backbone linkages 19 and 20 which are structurally related to aminoalkylated ph...
  
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7. Scheme 2: Bruice's synthesis of guanidinium-linked DNG oligomer 29 in the 5'→3' direction (Troc = 2,2,2-trich...
  
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8. Scheme 3: Bruice's synthesis of purine-containing guanidinium-linked DNG oligomer 36 in the 3'→5' direction (...
  
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9. Scheme 4: Bruice's synthesis of S-methylthiourea-linked DNmt oligomer 43.
  
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10. Figure 5: Structure of the natural product muraymycin A1 (44) and design concept of nucleosyl amino acid (NAA...
  
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11. Scheme 5: Retrosynthetic summary of Ducho's synthesis of partially zwitterionic NAA-modified oligonucleotides ...
  
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12. Scheme 6: Retrosynthetic summary of Ducho's and Grossmann's synthesis of fully cationic NAA-modified oligonuc...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2018, 14, 1293–1308, doi:10.3762/bjoc.14.111

Full Text

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