Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• better hybridization properties than LNA-thymidine; however, only modification 22 gave significant increases in Tm relative to modification 19 used as control. This finding was ascribed to both the extended π-conjugation of the alkynyl-functionalized nucleobase and stabilizing electrostatic interactions

• containing 4′-C-(aminomethyl)thymidine (monomer 63) [98][99]. Later, the amine-functionalized group was expanded into the monomer 4′-C-(2-((N-(2-aminoethyl)carbamoyl)oxy)ethyl)thymidine (not shown) that was shown to display improved resistance against endo- and exonuclease cleavage relative to the DNA

• ) thymidine dinucleotide linked through the 3’-5’ oxygen atoms modified with the phthalimidomethyl phosphonate linkage [113]. Later, a halogenated phthalimide protection was employed for the synthesis of the amidoethyl phosphonate variant [114]. The desired dinucleotides were phosphitylated and incorporated

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• ′-thymin-1-yl derivatives of 2′-deoxythymidine, i.e., compounds 59 and 60 starting from 5′-O-tritylthymidine (55). The tritylated thymidine 55 first was converted to the protected azide derivative 57 in two steps, followed by its reduction in the presence of tin(II) chloride, thiophenol and triethylamine

• intermediate benzoxazole derivative 68 (Scheme 16) [12]. Herdewijn and co-workers [54] synthesized the double-headed nucleoside monomers 4′-C-((N6-benzoyladenin-9-yl)methyl)thymidine (75) and 4′-C-((thymin-1-yl)methyl)thymidine (77) starting from 3′-O-(tert-butyldimethylsilyl)-4′-(hydroxymethyl)thymidine (72

• ) which was conveniently synthesized from thymidine in five steps as reported in the literature [54][55][56]. The nucleoside 72 was then converted into the corresponding triflate derivative which was further reacted with the nucleobases adenine or thymine to afford compounds 73 and 76, respectively

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

• Yongdong Su,
• Maitsetseg Bayarjargal,
• Tracy K. Hale and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2021, 17, 749–761, doi:10.3762/bjoc.17.65

• -phase DNA or RNA synthesis, the introduction of SaRNA monomers into an RNA backbone involved a 14-step preparation of the phosphoramidite for the SaRNA-TT dinucleotide. Similarly, the incorporation of BCNS groups on a DNA backbone requires the synthesis of thymidine and 2’-OMe-uridine phosphoramidites

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

• Jonas Becher,
• Daria V. Berdnikova,
• Heiko Ihmels and
• Christopher Stremmel

Beilstein J. Org. Chem. 2020, 16, 2795–2806, doi:10.3762/bjoc.16.230

• terminated with an N-benzylamide functionality to establish the attractive hydrogen bonding and π stacking with the thymidine residues in the loops in G4-DNA, so that this ligand binds with very high selectivity to the particular quadruplex-forming oligonucleotide J19 [49]. Overall, the above-mentioned

• may allow to deduce a relationship between the chain length and the binding properties. The adenine unit was supposed to establish binding interactions with the loop region of the quadruplex, namely through Watson–Crick base pairing with the complementary thymidine residues. Herein, we describe the

• vicinity of the adenine unit thus hindering the binding of the latter to the thymidine residues in the loops. Conclusion In summary, we have synthesized five novel berberine–adenine derivatives 4a–e with different lengths of the alkyltriazole linker units, which show the characteristic properties of

Anion exchange resins in phosphate form as versatile carriers for the reactions catalyzed by nucleoside phosphorylases

• Julia N. Artsemyeva,
• Ekaterina A. Remeeva,
• Tatiana N. Buravskaya,
• Irina D. Konstantinova,
• Roman S. Esipov,
• Anatoly I. Miroshnikov,
• Natalia M. Litvinko and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2020, 16, 2607–2622, doi:10.3762/bjoc.16.212

• substrates of the phosphorolysis of uridine, thymidine, and 1-(β-ᴅ-arabinofuranosyl)uracil (Ara-U) catalyzed by recombinant E. coli uridine (UP) and thymidine (TP) phosphorylases. α-ᴅ-Pentofuranose-1-phosphates (PF-1Pis) obtained by phosphorolysis were used in the enzymatic synthesis of nucleosides. It was

• found that phosphorolysis of uridine, thymidine, and Ara-U in the presence of Dowex® 1X8 (phosphate; Dowex-nPi) proceeded smoothly in the presence of magnesium cations in water at 20–50 °C for 54–96 h giving rise to quantitative formation of the corresponding pyrimidine bases and PF-1Pis. The resulting

• ; purine nucleoside phosphorylases; recombinant E. coli uridine; thymidine; Introduction Diverse variants of enzymatic syntheses of nucleosides using nucleoside phosphorylases as biocatalysts have been repeatedly described in original studies and discussed in a number of recent reviews (see, e.g., [1][2

Palladium-catalyzed synthesis and nucleotide pyrophosphatase inhibition of benzo[4,5]furo[3,2-b]indoles

• Hoang Huy Do,
• Saif Ullah,
• Alexander Villinger,
• Joanna Lecka,
• Jean Sévigny,
• Peter Ehlers,
• Jamshed Iqbal and
• Peter Langer

Beilstein J. Org. Chem. 2019, 15, 2830–2839, doi:10.3762/bjoc.15.276

• and NPP3. Absorbance was taken at wavelength of 405 nm as pre-read by using a microplate reader (BioTek FLx800, Instruments, Inc. USA). After pre-read the artificial substrate p-nitrophenyl 5'-thymidine monophosphate (pNP-TMP), 400 µM for NPP1 and 600 µM in case of NPP3, was added followed by a second

Tuning the stability of alkoxyisopropyl protection groups

• Zehong Liang,
• Henna Koivikko,
• Mikko Oivanen and
• Petri Heinonen

Beilstein J. Org. Chem. 2019, 15, 746–751, doi:10.3762/bjoc.15.70

• ’-acetal-protected 2’-deoxythymidines were prepared using 7 equiv of the appropriate reagent 1a–e with the suitably protected thymidine 2 or 5 (Scheme 1) in the presence of p-toluenesulfonic acid as the acid catalyst. A suitable amount of the acid catalyst is 0.5 to 1 mol %, with which the reaction takes

• (Scheme 2). Experimental data on the acidity of the 5’- and 3’-hydroxy groups of thymidine are not available, but computed NBO charges suggest that the electronic properties of both hydroxy functions are close to each other [10]. Our DFT level calculations indicated that the 3’-hydroxy function is

• of acetal synthesis. We also prepared the corresponding derivative 8b of thymidine and studied its hydrolytic stability separately. This is of some interest for discussion of mechanisms of acetal hydrolysis, since the vinyl ether intermediate 8b could probably be formed on the pathway shown in the

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• into 2'-deoxy-L-thymidine and other nucleosides [119]. Syntheses of all four enantiomers of tricholomic acid of interest as a flycidal compound as well as in receptor studies [120] were accomplished starting from enantiomeric 3-hydroxyglutamic acid, e.g., (2S,3R)-3-hydroxyglutamic acid was converted in

Synthesis, biophysical properties, and RNase H activity of 6’-difluoro[4.3.0]bicyclo-DNA

• Sibylle Frei,
• Adam K. Katolik and
• Christian J. Leumann

Beilstein J. Org. Chem. 2019, 15, 79–88, doi:10.3762/bjoc.15.9

• -DNA (6’-diF-bc4,3-DNA). The difluorinated thymidine phosphoramidite building block was synthesized starting from an already known gem-difluorinated tricyclic glycal. This tricyclic siloxydifluorocyclopropane was converted into the [4.3.0]bicyclic nucleoside via cyclopropane ring-opening through the

• structural effect of this functional unit was explored. Herein we report on the synthesis and properties of the 6’-diF-bc4,3-thymidine analog (Figure 1), and the biophysical properties of oligonucleotides containing this modification. Moreover, we investigated the substrate recognition of the 6’-diF-bc4,3-T

• steps. Synthesis of the thymidine phosphoramidite building block 9. Reagents and conditions: a) HF-pyridine, DCM/pyridine 5:1, 0 °C to rt, 2.5 h, 64%; b) DMTr-OTf, DCM/pyridine 1:2, rt, 22 h, 56%; c) CEP-Cl, DIPEA, THF, rt, 3 h, 73%. Evaluation of the reaction mechanism for the production of bicyclic

6’-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations

• Sibylle Frei,
• Andrei Istrate and
• Christian J. Leumann

Beilstein J. Org. Chem. 2018, 14, 3088–3097, doi:10.3762/bjoc.14.288

• -diisopropylchlorophosphoramidite (CEP-Cl) furnishing thymidine phosphoramidite 10. Since significant amounts of the alcohols 5α/β were obtained, it was decided to redirect our initial synthetic plan for the cytidine phosphoramidite. Hence, the sugars 5α/β were first acetylated yielding the intermediate 11α/β (Scheme 3), which is

• thymidine or cytidine building blocks 10 and 16 were synthesized to study the pairing properties of the new modification with complementary DNA and RNA. At the beginning, the synthesis of the oligonucleotides was conducted using standard automated phosphoramidite chemistry (for details see the experimental

• thymidine unit exhibited a duplex destabilization when paired to DNA (ΔTm/mod = −1.5 to −3.7 °C). The Tm depression was more pronounced for multiple (ΔTm/mod ≈ −3.5 °C) than for single (ΔTm/mod ≈ −2.0 °C) inclusions. When the same four oligonucleotides were hybridized to RNA the duplex stability further

Oligonucleotide analogues with cationic backbone linkages

• Melissa Meng and
• Christian Ducho

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

• oligonucleotide analogues was performed on solid support using H-phosphonate chemistry (Scheme 1). Thus, solid phase-linked thymidine 12 was coupled with 5'-dimethoxytrityl-(DMTr)-protected thymidine 3'-H-phosphonate 13 to give dimeric H-phosphonate 14, which was then acidically DMTr-deprotected to furnish 15

• . After the desired number of such coupling-deprotection cycles, the phosphite-linked oligo-thymidine 16 was transformed in an oxidative amidation reaction [42] in the presence of iodine and N,N,N'-trimethylethylenediamine (17) to yield, after basic cleavage from the solid support, the envisioned

• an oligo-deoxyadenosyl DNG in complex with a native oligo-thymidylate DNA [53]. Overall, the obtained results suggest that adenosine- and thymidine-derived DNG oligomers support the formation of triplex structures, but that the DNG-DNA ratio within the complex is determined by the respective

Mechanochemistry of nucleosides, nucleotides and related materials

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

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

• Reactions of nucleoside sugar and nucleobase moieties An early example of the application of mechanochemistry for nucleoside derivatisation was reported by Khalafi-Nezhad and Mokhtari who effected regioselective 5′-protection of ribonucleosides and thymidine using a mortar and pestle with trityl

• presence of excess nucleoside (1.1 equiv), the corresponding 5′-trityl ethers of uridine, adenosine or thymidine were isolated in yields up to 86%. Reactions of guanosine or cytidine under these conditions gave rise to mixtures of products from which the corresponding tritylated products could not be

• adenosine or thymidine derivatives (Scheme 8). No reaction of 5′-chloro-5′-deoxyadenosine was observed. Under these conditions, cyclisation of 5′-tosyladenosine was inferred although rapid and clean reaction of 5′-iodo-5′-deoxyguanosine was apparent in the absence of added solvent – the product from this

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

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

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

• the modified ONs in addition to an increase in their nuclease resistance. Thus, two Japanese groups have proposed prodrug-type phosphotriester ONs responsive to GSH (Scheme 1) [13][14]. Ono presented a preliminary study on a model of a thymidine dimer with differently substituted benzyl groups at the

• within a robust cyclic disulfide moiety [14]. Several modified ONs containing the cyclic disulfide trans-5-benzyl-1,2-dithiane-4-yl moiety have been synthesized using the corresponding thymidine phosphoramidite. Although they exhibited strong stability in serum and penetrated cells more efficiently

• a hypoxia-labile modification either in the phosphate backbone to mask the negative charge and provide better tumor selectivity [25][26] or at the nucleobase to modulate the hybridization properties with the target [27]. In all cases, a nitro-derivative-modified thymidine phosphoramidite was

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

• Ruth Suchsland,
• Bettina Appel and
• Sabine Müller

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

• well suited to it. Also the solution-phase synthesis of protected trinucleotide building blocks has been described in the literature [21][22][23]. In an initial attempt, thymidine as a start nucleoside was tethered to a precipitative tetrapodal soluble support via a disulfide-linker [21] (Table 1

• support [23]. The support was attached via the benzyloxycarbonyl (Cbz) group to the 3'-OH of the starting nucleoside being adenosine, cytidine, guanosine or thymidine, and trimers were assembled by phosphoramidite chemistry (Table 1, entry 3). The support was found to disperse homogenously in the reaction

Enzymatic separation of epimeric 4-C-hydroxymethylated furanosugars: Synthesis of bicyclic nucleosides

• Neha Rana,
• Manish Kumar,
• Vinod Khatri,
• Jyotirmoy Maity and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2017, 13, 2078–2086, doi:10.3762/bjoc.13.205

• hydroxy groups present in different sugars and sugar moieties of synthetic or naturally occurring glycosides, nucleosides, etc. Gotor et al. [11] have reported a lipase-mediated acylation of an equimolecular mixture of D/L-thymidine with acetonoxime levulinate as acylating agent and Pseudomonas cepacia

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

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

• was then precipitated with the EtOAc/Et2O mixture. The product was, however, still partly tritylated, and the detritylation had therefore to be repeated. The longest oligomer synthesized was a thymidine tetramer. The yield of the support-bound tetramer was 87%, but no isolated yield was reported

Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases

• Vladimir A. Stepchenko,
• Anatoly I. Miroshnikov,
• Frank Seela and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2016, 12, 2588–2601, doi:10.3762/bjoc.12.254

• , 6-azathymine and 6-aza-2-thiothymine was studied using dG and E. coli purine nucleoside phosphorylase (PNP) for the in situ generation of 2-deoxy-α-D-ribofuranose-1-phosphate (dRib-1P) followed by its coupling with the bases catalyzed by either E. coli thymidine (TP) or uridine (UP) phosphorylases

• ; recombinant E. coli uridine, thymidine and purine nucleoside phosphorylases; substrate properties; 4(2)-thioxo- and 6(5)-aza-uacil and -thymine; Introduction Nucleosides of 4- and 2-thioxopyrimidines and 6-azapyrimidines attract much attention from the time of pioneering works in the early 1950s on the

• publications are available on the enzymatic synthesis of these nucleosides. W. H. Prusoff reported on the first efficient transformation of 6-azathymine into its 2'-deoxy-D-riboside in phosphate buffer (50 mM, pH 8.0; 37 °C) in the presence of thymidine as a pentofuranose donor and washed cells or cell-free

From supramolecular chemistry to the nucleosome: studies in biomolecular recognition

• Marcey L. Waters

Beilstein J. Org. Chem. 2016, 12, 1863–1869, doi:10.3762/bjoc.12.175

• -Sanders Model for π–π stacking from 1990 [4]. (d) Kool’s nonpolar isostere of thymidine from 1995 [5].(e) Gellman’s model for π–π stacking in aqueous solution [6]. (a) Model β-hairpin for investigation of aromatic interactions. (b) Examples of noncovalent interactions studied, from weakest to strongest

Nucleic acids through condensation of nucleosides and phosphorous acid in the presence of sulfur

• Tuomas Lönnberg

Beilstein J. Org. Chem. 2016, 12, 670–673, doi:10.3762/bjoc.12.67

• Tuomas Lonnberg Department of Chemistry, University of Turku, Vatselankatu 2, FIN-20014 Turku, Finland 10.3762/bjoc.12.67 Abstract Short phosphorothioate oligonucleotides have been prepared by refluxing an equimolar mixture of thymidine and triethylammonium phosphite in toluene in the presence of

• polymerization. Proposed oxidants for prebiotic phosphite chemistry include H2O2 and Fe(III). The present paper describes the polymerization of thymidine and triethylammonium phosphite, with elemental sulfur acting as the oxidant. Up to pentameric oligonucleotides with internucleosidic phosphorothioate linkages

• , solubilization by micelles [14][15] or a prebiotic oil slick [16] appears a more plausible scenario [17]. Results and Discussion Preparation of phosphorothioate oligonucleotides Equimolar amounts of thymidine and aq triethylammonium phosphite and a fourfold excess of S8 were suspended in toluene. The mixture was

Interactions between 4-thiothymidine and water-soluble cyclodextrins: Evidence for supramolecular structures in aqueous solutions

• Vito Rizzi,
• Sergio Matera,
• Paola Semeraro,
• Paola Fini and
• Pinalysa Cosma

Beilstein J. Org. Chem. 2016, 12, 549–563, doi:10.3762/bjoc.12.54

• degradative ROS-mediated oxidation process [26]. Recently, in our papers [26], we have shown the pH-related features and the photoactivity of S4TdR in aqueous solution while simultaneously elucidating the nature of products induced by light-stimulated oxidative stress. Evidence for the generation of thymidine

• glance, regardless of the structural similarity with thymidine, S4TdR (Figure 1) shows a different ultraviolet absorption spectrum. The UV–vis absorption spectrum of 1 × 10−5 M aqueous solution of S4TdR, was acquired and is reported in Figure 2 (black lines). Subsequently, a comparison in presence of CDs

• was performed in accordance with similar works reported in literature [32][33] (see dark grey lines in Figure 2). As reported in Figure 2 (black line), the main absorption band of S4TdR shifts from 270 nm (already observed for thymidine) to 337 nm (UVA) [26][34]. The nature of this band was already

Lewis acid-promoted hydrofluorination of alkynyl sulfides to generate α-fluorovinyl thioethers

• Davide Bello and
• David O'Hagan

Beilstein J. Org. Chem. 2015, 11, 1902–1909, doi:10.3762/bjoc.11.205

• example as illustrated in Figure 1, CF2-phosphonates became popular mimetics of the phosphate group [3][4], and vinyl fluorides were developed as analogues of the amide bond [5]. Difluorotoluene has proved to be a good spacial mimetic of the thymine base in thymidine, and has been shown to act as a

Preparation of a disulfide-linked precipitative soluble support for solution-phase synthesis of trimeric oligodeoxyribonucleotide 3´-(2-chlorophenylphosphate) building blocks

• Amit M. Jabgunde,
• Alejandro Gimenez Molina,
• Pasi Virta and
• Harri Lönnberg

Beilstein J. Org. Chem. 2015, 11, 1553–1560, doi:10.3762/bjoc.11.171

• tetrapodal soluble support 3. Previously [11] described phosphorylation with bis(benzotriazol-1-yl) 2-chlorophenyl phosphate in 1,4-dioxane was applied to convert commercial thymidine, N4-benzoyl-2’-deoxycytidine and N2-isobutyryl-2’-deoxyguanosine into their 3’-(benzotriazol-1-yl 2-chlorophenyl phosphates

• essentially as described previously [8]. Accordingly, the dried support was treated under nitrogen with the thymidine derived building block 4 (2 equiv per support-bound OH), in dioxane in the presence of 1-methylimidazole. The coupling was completed in 12 h, and the excess of 4 and the coupling reagents were

• the coupling of 1-hydroxybenzotriazole-activated phosphotriester building blocks: The coupling cycle was analogous to that described previously [8]. 5’-O-(4,4’-Dimethoxytrityl)thymidine (0.30 g, 0.54 mmol) was dried by co-evaporation with anhydrous pyridine (3 × 5 mL) and concentrated to a small

Terminal lipophilization of a unique DNA dodecamer by various nucleolipid headgroups: Their incorporation into artificial lipid bilayers and hydrodynamic properties

• Emma Werz and
• Helmut Rosemeyer

Beilstein J. Org. Chem. 2015, 11, 913–929, doi:10.3762/bjoc.11.103

• lipid bilayer against perfusion. Figure 7 presents the bilayer brightness as a function of the perfusion/incubation events for the oligomer 12. This oligomer is 5’-terminated with a nucleolipid head group which carries a double-chained lipid with a clickable group at N(3) of thymidine (6a). Among all

• with a cyclic O-2’,3’-ketal, which was washed out completely from the bilayer after only three perfusion steps (Figure 11). LON 12 represents an oligomer with a long double-tailed lipid moiety at the N(3) position of thymidine. Interestingly, this LON is incorporated into the bilayer at a relatively

DNA display of glycoconjugates to emulate oligomeric interactions of glycans

• Alexandre Novoa and
• Nicolas Winssinger

Beilstein J. Org. Chem. 2015, 11, 707–719, doi:10.3762/bjoc.11.81

• alkyne by oxidative amidation using carbon tetrachloride with propargylamine. The microwave-assisted click-conjugation was performed on a solid phase upon completion of the DNA synthesis (Scheme 4). Lönnberg and co-workers prepared a thymidine modified at the 4’-position with an azidomethyl group to

• achieve conjugation during solid-phase DNA synthesis or in solution post DNA cleavage [28]. Subsequently, the same group reported a method to introduce two different glycans sequentially on the DNA strand at the 2’-position using an azido and a bromo-modified thymidine 6 and 7 (Scheme 5) [29]. Krauss and