Recent Trends in Nucleotide Synthesis

Roy, Béatrice; Depaix, Anaïs; Philouze, Christian; Peyrottes, Suzanne

doi:10.1021/acs.chemrev.6b00174

Cited by 175 publications

(153 citation statements)

References 265 publications

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“…Given the broad applicability of these phosphate‐containing molecules, synthetic approaches for the preparation of 5′‐mono‐, 5′‐di‐, and 5′‐triphosphorylated nucleosides, as well as cyclic nucleotides and dinucleotides, dinucleoside 5′,5′‐polyphosphates, and sugar nucleotides have been reviewed …”

Section: Nucleotidesmentioning

confidence: 99%

The Role of the Phosphorus Atom in Drug Design

2019

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Although the phosphorus atom is found in a variety of oxidation states, most of the phosphorus‐containing molecules of pharmacological importance possess phosphorus in the form of phosphonate or phosphinate functional groups, or in a major oxidation state as a phosphate group. The most common occurrence of phosphorus in drugs is either in prodrugs or in compounds for which the phosphorus atom plays a role in the biological activity, such as in modified nucleotides, in metabolically stable analogues of metabolites bearing phosphate groups, and as bioisosteric analogues of carboxyl groups.

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Section: Nucleotidesmentioning

confidence: 99%

The Role of the Phosphorus Atom in Drug Design

2019

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“…trans-5-Bromo-1-((-5-(hydroxymethyl)-2methylisoxazolidin-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione (22c) White amorphous solid; IR (KBr, cm À1 ) n max : 3450, 3150, 3094, 2972, 2927, 2838, 1686, 1612, 1466, 1432, 1329, 1107; (signals of trans-22c were extracted from the spectra of an 80:20 mixture oftrans-22c and cis-21c); 1 H NMR (300 MHz, CD 3 OD) d:8.00 (s, 1H), 4.13 (dddd, 1H, J ¼ 8.1 Hz, J ¼ 7.5 Hz, J ¼ 5.4 Hz, J ¼ 4.2 Hz, H-C5), 3.89 (dd, 1H, J ¼ 13.8 Hz, J ¼ 4.8 Hz, HCHN), 3.70 (dd, 1H, J ¼ 13.8 Hz, J ¼ 8.4 Hz, HCHN), 3.66 (dd, 1H, J ¼ 12.0 Hz, J ¼ 4.2 Hz, HCHOH), 3.56 (dd, 1H, J ¼ 12.0 Hz, J ¼ 5.4 Hz, HCHOH), 3.28 (dddd, 1H, J ¼ 8.4 Hz, J ¼ 7.8 Hz, J ¼ 4.8 Hz, J ¼ 3.9 Hz, H-C3), 2.67 (s, 3H, CH 3 N), 2.32 (ddd, 1H, J ¼ 12.6 Hz, J ¼ 8.1 Hz, J ¼ 7.8 Hz, H a -C4), 2.11 (ddd, 1H, J ¼ 12.6 Hz, J ¼ 7.8 Hz, J ¼ 3.9 Hz, H b -C4); 13 C NMR (75 MHz, CD 3 OD) d: 162.1 (C]O), 152.3 (C]O), 147.6 (C]C), 96.0 (C]C), 80.6 (C5), 67.1 (C3), 65.0 (CH 2 OH), 51.1 (CH 2 N), 46.2 (CH 3 N), 34.3 (C4). trans-5-Bromo-1-((-5-(hydroxymethyl)-2methylisoxazolidin-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione (22c) White amorphous solid; IR (KBr, cm À1 ) n max : 3450, 3150, 3094, 2972, 2927, 2838, 1686, 1612, 1466, 1432, 1329, 1107; (signals of trans-22c were extracted from the spectra of an 80:20 mixture oftrans-22c and cis-21c); 1 H NMR (300 MHz, CD 3 OD) d:8.00 (s, 1H), 4.13 (dddd, 1H, J ¼ 8.1 Hz, J ¼ 7.5 Hz, J ¼ 5.4 Hz, J ¼ 4.2 Hz, H-C5), 3.89 (dd, 1H, J ¼ 13.8 Hz, J ¼ 4.8 Hz, HCHN), 3.70 (dd, 1H, J ¼ 13.8 Hz, J ¼ 8.4 Hz, HCHN), 3.66 (dd, 1H, J ¼ 12.0 Hz, J ¼ 4.2 Hz, HCHOH), 3.56 (dd, 1H, J ¼ 12.0 Hz, J ¼ 5.4 Hz, HCHOH), 3.28 (dddd, 1H, J ¼ 8.4 Hz, J ¼ 7.8 Hz, J ¼ 4.8 Hz, J ¼ 3.9 Hz, H-C3), 2.67 (s, 3H, CH 3 N), 2.32 (ddd, 1H, J ¼ 12.6 Hz, J ¼ 8.1 Hz, J ¼ 7.8 Hz, H a -C4), 2.11 (ddd, 1H, J ¼ 12.6 Hz, J ¼ 7.8 Hz, J ¼ 3.9 Hz, H b -C4); 13 C NMR (75 MHz, CD 3 OD) d: 162.1 (C]O), 152.3 (C]O), 147.6 (C]C), 96.0 (C]C), 80.6 (C5), 67.1 (C3), 65.0 (CH 2 OH), 51.1 (CH 2 N), 46.2 (CH 3 N), 34.3 (C4).…”

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confidence: 99%

Novel isoxazolidine analogues of homonucleosides and homonucleotides

et al. 2016

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a b s t r a c tIsoxazolidine analogues of homonucleos(t)ides were synthesized from nucleobase-derived nitrones 20a-20e (uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine) employing 1,3-dipolar cycloadditions with allyl alcohol as well as with alkenylphosphonates (allyl-, allyloxymethyl-and vinyloxymethyl-and vinylphosphonate). Besides reactions with vinylphosphonate the additions proceeded regioselectively to produce mixtures of major cis and minor trans 3,5-disubstituted isoxazolidines (d.e. 28e82%). From vinylphosphonate up to 10% of 3,4-disubstituted isoxazolidines was additionally produced. Vicinal couplings, shielding effects and 2D NOE correlations were employed in configurational assignments as well as in conformational analysis to find out preferred conformations for several isoxazolidines and to observe anomeric effects (pseudoaxial orientation of phosphonylmethoxy groups) for those obtained from vinyloxymethylphosphonate. None of the tested compounds were endowed in vitro with antiviral activity against a variety of DNA and RNA viruses at subtoxic concentrations (up to 250 mM) nor exhibited antiproliferative activity towards L1210, CEM, and HeLa cells (IC 50 ¼ !100 mM).

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“…Selective functionalization at the N 3 -position can be achieved with weak bases, such as potassium carbonate, given the p K a differences between alcohols (p K a ≈ 16–17) and the N 3 -proton (p K a ≈ 9.5). 20 In contrast, strong bases, such as sodium hydride, have the capability to deprotonate the 3′-OH, 5′-OH, and N 3 -protons, with functionalization occurring preferentially at the 3′-OH and 5′-OH positions, due to the increased nucleophilicity of alkoxides over imide anions. The standard retrosynthetic analysis for the target monomer, 5 , a strained 3′,5′-cyclic structure, is given in Figure 1b.…”

Section: Resultsmentioning

confidence: 99%

Synthetic, Functional Thymidine-Derived Polydeoxyribonucleotide Analogues from a Six-Membered Cyclic Phosphoester

Tsao

Wooley

2017

J. Am. Chem. Soc.

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A grand challenge that crosses synthetic chemistry and biology is the scalable production of functional analogues of biomacromolecules. We have focused our attention on the use of deoxynucleoside building blocks bearing non-natural bases to develop a synthetic methodology that allows for the construction of high molecular weight deoxynucleotide polymers. Our six-membered cyclic phosphoester ring-opening polymerization strategy is demonstrated, herein, by an initial preparation of novel polyphosphoesters, comprised of butenyl-functionalized deoxyribonucleoside repeat units, connected via 3′,5′-backbone linkages. A thymidine-derived bicyclic monomer, 3′,5′-cyclic 3-(3-butenyl) thymidine ethylphosphate, was synthesized in two steps directly from thymidine, via butenylation and diastereoselective cyclization promoted by N,N-dimethyl-4-aminopyridine. Computational modeling of the six-membered 3′,5′-cyclic phosphoester ring derived from deoxyribose indicated strain energies at least 5.4 kcal/mol higher than those of the six-membered monocyclic phosphoester, 2-ethoxy-1,3,2-dioxaphosphinane 2-oxide. These calculations supported the hypothesis that the strained 3′,5′-cyclic monomer can promote ring-opening polymerization to afford the resulting poly(3′,5′-cyclic 3-(3-butenyl) thymidine ethylphosphate)s with low dispersities (Đ < 1.10). This advanced design combines the merits of natural product-derived materials and functional, degradable polymers to provide a new platform for functional, synthetically derived polydeoxyribonucleotide-analogue materials.

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Recent Trends in Nucleotide Synthesis

Cited by 175 publications

References 265 publications

The Role of the Phosphorus Atom in Drug Design

The Role of the Phosphorus Atom in Drug Design

Novel isoxazolidine analogues of homonucleosides and homonucleotides

Synthetic, Functional Thymidine-Derived Polydeoxyribonucleotide Analogues from a Six-Membered Cyclic Phosphoester

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