From chemical metabolism to life: the origin of the genetic coding process

• Antoine Danchin

Beilstein J. Org. Chem. 2017, 13, 1119–1135, doi:10.3762/bjoc.13.111

• convincing way [31]. Other coenzymes, possibly generated by such a swinging-arm thioester-dependent catalysis, may have been precursors of nucleotides, the essential building blocks of nucleic acids. As a matter of fact, extant biosynthesis of nucleotides (built on purine and pyrimidine carbon–nitrogen

• , an amino acid absent from the very first steps of prebiotic metabolism), while purine biosynthesis combines glycine and aspartate, together with phosphorylated derivatives of ribose. These pathways open up a major chemical challenge. Ribose is a very unstable metabolite. Any scenario that advances

Revaluation of biomass-derived furfuryl alcohol derivatives for the synthesis of carbocyclic nucleoside phosphonate analogues

• Bemba Sidi Mohamed,
• Christian Périgaud and
• Christophe Mathé

Beilstein J. Org. Chem. 2017, 13, 251–256, doi:10.3762/bjoc.13.28

• carbocyclic nucleoside methylphosphonate analogues bearing purine bases (adenine and guanine) was accomplished using bio-sourced furfuryl alcohol derivatives. All compounds were prepared using a Mitsunobu coupling between the heterocyclic base and an appropriate carbocyclic precursor. After deprotection, the

• nucleoside methylphosphonates (Figure 1) bearing purine bases (adenine and guanine) in order to evaluate their antiviral properties. Results and Discussion Synthesis of precursors (+/−)-5 and (+/−)-7 The synthesis began with the preparation of racemic 4-O-TBDMS-2-cyclopentenone (1) which was obtained in two

Nucleophilic displacement reactions of 5′-derivatised nucleosides in a vibration ball mill

• Olga Eguaogie,
• Patrick F. Conlon,
• Francesco Ravalico,
• Jamie S. T. Sweet,
• Thomas B. Elder,
• Louis P. Conway,
• Marc E. Lennon,
• David R. W. Hodgson and
• Joseph S. Vyle

Beilstein J. Org. Chem. 2017, 13, 87–92, doi:10.3762/bjoc.13.11

• ′-tosylates in five to 60 minutes. Under these conditions, commonly-encountered nucleoside cyclisation byproducts (especially of purine nucleosides) were not observed. Liquid-assisted grinding of the same 5'-iodide and 5′-tosylate substrates with potassium selenocyanate in the presence of DMF produced the

• reactions require the use of high-boiling, dipolar aprotic solvents and anionic nucleophiles under anhydrous conditions at elevated temperatures (up to 150 °C). Competing intramolecular cyclisation reactions between both purine and pyrimidine nucleobases and (especially) the 5′-position of the (deoxy

• were observed with IdT (1d) and IdG (1e) although maximal conversion of IdG was achieved within one hour in the absence of added liquid (the reaction was inhibited in the presence of DMF). During these studies, LAG of both purine and pyrimidine substrates in the presence of ethyl acetate or hexane was

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

• reaction [37][38] using 2'-deoxyguanosine (dG) as a donor of the pentofuranose moiety in a combination with the recombinant E. coli purine nucleoside phosphorylase (PNP; product of deoD gene; EC 2.4.2.1) [36] were tested under standard reaction conditions and then individual nucleosides 1b, 3b–5b were

Facile synthesis of a 3-deazaadenosine phosphoramidite for RNA solid-phase synthesis

• Elisabeth Mairhofer,
• Elisabeth Fuchs and
• Ronald Micura

Beilstein J. Org. Chem. 2016, 12, 2556–2562, doi:10.3762/bjoc.12.250

• basicity of these purine nitrogen atoms, because N1 represents the major protonation site, followed by N7 and N3. This order is deduced from the macroscopic pKa values that were measured for adenine, 9-methyladenine, and adenosine [11]. Importantly, there is growing evidence that the pKa values of

DNA functionalization by dynamic chemistry

• Zeynep Kanlidere,
• Oleg Jochim,
• Marta Cal and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2016, 12, 2136–2144, doi:10.3762/bjoc.12.203

• template strand (TC). The Watson–Crick base-pairing with three hydrogen bonds together with a high-stacking contribution of purine nucleobases seems to be beneficial. The selectivity for the incorporation of the other aldehydes is significantly lower (20–40%). Especially for CCHO with the complementary

• energetically favorable, while other purine–purine (like A·A, G·G) mismatches are less frequent than T·G and C·A ones. These results indicate that the selectivity of base pairing is not only driven by the number and strength of hydrogen bonds formed between two bases, but also by the backbone plasticity

Synthesis of the C8’-epimeric thymine pyranosyl amino acid core of amipurimycin

• Pramod R. Markad,
• Navanath Kumbhar and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2016, 12, 1765–1771, doi:10.3762/bjoc.12.165

•  1) that involves (a) a unique pyranosyl amino acid ring skeleton with a hydroxy group and a branched 1,2-dihydroxyethyl side chain at C3’, (b) a glycosidic β-linked purine nucleobase, and (c) a five-membered cis-pentacin framework coupled to C6’ via the N-terminus of an amino acid [5]. The absolute

• ester 15. Acetylation of 15 with acetic anhydride in pyridine gave acetate derivative 16 in 95% yield. Having fully functionalized intermediate 16 in hand, we thought to incorporate the purine nucleobase using Vorbrüggen conditions. Thus, reaction of glycosyl donor 16 with bis(trimethylsilyl)-2-(N

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

• Tai Nguyen Van,
• Audrey Hospital,
• Corinne Lionne,
• Lars P. Jordheim,
• Charles Dumontet,
• Christian Périgaud,
• Laurent Chaloin and
• Suzanne Peyrottes

Beilstein J. Org. Chem. 2016, 12, 1476–1486, doi:10.3762/bjoc.12.144

• (cN-II), an enzyme involved in the regulation of purine nucleotide pools. NMR and molecular modelling studies showed that a few derivatives adopted similar structural features to IMP or GMP. Five derivatives were identified as modest inhibitors with 53 to 64% of cN-II inhibition at 1 mM. Keywords

• : cancer; cN-II inhibitors; nucleotide; phosphonate; triazole; Introduction Nucleotidases are an important family of enzymes involved in the metabolism of nucleotides [1]. In particular, human cytosolic 5’-nucleotidase II (cN-II) catalyses the dephosphorylation of purine 5’-monophosphate derivatives to

• hydrophilic pocket (Ser251 and Lys215) where the hydroxy groups of the sugar interact and a phosphonate binding site close to the magnesium ion located in the substrate binding site. Thus, as few cytosine-containing analogues were equipotent in terms of cN-II inhibition to their purine counterparts (Figure 1

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• amide carbonyl by ATP (Figure 3B, pathway b), which is analogous to a reaction catalysed by PurM family enzymes (aminoimidazole ribonucleotide synthetases) in the biosynthesis of aminoimidazole ribonucleotide as part of the purine biosynthetic pathway [39] (Figure 3, inset). This activated amide would

The role of alkyl substituents in deazaadenine-based diarylethene photoswitches

• Christopher Sarter,
• Michael Heimes and
• Andres Jäschke

Beilstein J. Org. Chem. 2016, 12, 1103–1110, doi:10.3762/bjoc.12.106

• in which a purine nucleobase represented one of the aryl rings of the photoswitch (Figure 1B). Importantly and different from most other approaches towards photoswitchable nucleic acids, the nucleobase constituted an active part of the photoswitch (rather than an appendage), changing its bonding and

• are compared. Therefore, we set out to clarify this matter. If pyrimidine-based diarylethenes with one methyl group are good photoswitches, purine derivatives might work as well with just one methyl group. If this hypothesis was true, the synthesis of such photoswitches would be much simplified

• diarylethenes by direct comparison, and ii) we wanted to test whether our prior successful violation of this “rule” with photochromic pyrimidine nucleosides could be expanded to purine nucleosides. Our analysis reveals that – depending on the substituents – the one-methyl 7-deaza-2’-deoxyadenosine compounds can

Synthesis of cyclic N¹-pentylinosine phosphate, a new structurally reduced cADPR analogue with calcium-mobilizing activity on PC12 cells

• Ahmed Mahal,
• Stefano D’Errico,
• Nicola Borbone,
• Brunella Pinto,
• Agnese Secondo,
• Valeria Costantino,
• Valentina Tedeschi,
• Giorgia Oliviero,
• Vincenzo Piccialli and
• Gennaro Piccialli

Beilstein J. Org. Chem. 2015, 11, 2689–2695, doi:10.3762/bjoc.11.289

• reason, to obtain new cADPR derivatives the exploitation of chemical synthetic strategies is still necessary. A lot of modifications regarding the northern and southern ribose as well as the purine base of cADPR have been proposed so far [22][23]. Matsuda and co-workers were the first who synthesized new

• diluted conditions. In our opinion, the target intramolecular cyclizations failed because of the poor mobility of the 5’-OH ribose function, as well as because of the unfavourable anti conformation of the N-glycosidic bond induced by the presence at the N1 position of the purine base of the bulky ω

• results indicate that 3 and 4 possess almost the same activity, thus indicating that the role of the pyrophosphate bridge is not stringent and that the introduction of an alkyl chain in the N1 position of the purine base improves the permeation of the cell membrane by passive diffusion or through an

Versatile synthesis and biological evaluation of novel 3’-fluorinated purine nucleosides

• Hang Ren,
• Haoyun An,
• Paul J. Hatala,
• William C. Stevens Jr,
• Jingchao Tao and
• Baicheng He

Beilstein J. Org. Chem. 2015, 11, 2509–2520, doi:10.3762/bjoc.11.272

• University of Chicago Medical Center, Chicago, Illinois 60637, USA 10.3762/bjoc.11.272 Abstract A unified synthetic strategy accessing novel 3'-fluorinated purine nucleoside derivatives and their biological evaluation were achieved. Novel 3’-fluorinated analogues were constructed from a common 3’-deoxy-3

• ’-fluororibofuranose intermediate. Employing Suzuki and Stille cross-coupling reactions, fifteen 3’-fluororibose purine nucleosides 1–15 and eight 3’-fluororibose 2-chloro/2-aminopurine nucleosides 16–23 with various substituents at position 6 of the purine ring were efficiently synthesized. Furthermore, 3’-fluorine

• analogs of natural products nebularine and 6-methylpurine riboside were constructed via our convergent synthetic strategy. Synthesized nucleosides were tested against HT116 (colon cancer) and 143B (osteosarcoma cancer) tumor cell lines. We have demonstrated 3’-fluorine purine nucleoside analogues display

Syntheses of 2-substituted 1-amino-4-bromoanthraquinones (bromaminic acid analogues) – precursors for dyes and drugs

• Enas M. Malik,
• Younis Baqi and
• Christa E. Müller

Beilstein J. Org. Chem. 2015, 11, 2326–2333, doi:10.3762/bjoc.11.253

• proposed the compound to interact with ATP-binding sites [33], and it was subsequently used as a pharmacological tool for studying ATP and other nucleotide receptors. RB-2 has played a crucial role in identifying different purine receptor subtypes, since it was found to selectively block only certain

• members of the nucleotide-activated purine P2 receptor family [34][35][36][37][38][39][40]. However, it should be mentioned that ever since the commercially available dye has been used as a tool compound in P2 receptor research, there has been some doubt about its identity and purity, both of which are

• prerequisites for reliable receptor characterization and subdifferentiation [41]. Our laboratory has a long-standing interest in the development of potent and selective purine receptor antagonists and ectonucleotidase inhibitors as pharmacological tool compounds to study the proteins’ functions and their

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• enantioselectivities of the 1,4-addition products (Scheme 38). As shown in Scheme 38, two 1,4-addition products were isolated because purine exists as a tautomeric mixture (N-7H and N-9H). Under the optimal reaction conditions, the N-9 regioisomer was produced preferentially. 2.4.3 Asymmetric 1,4-addition of

Sequence-specific RNA cleavage by PNA conjugates of the metal-free artificial ribonuclease tris(2-aminobenzimidazole)

• Friederike Danneberg,
• Alice Ghidini,
• Plamena Dogandzhiyski,
• Elisabeth Kalden,
• Roger Strömberg and
• Michael W. Göbel

Beilstein J. Org. Chem. 2015, 11, 493–498, doi:10.3762/bjoc.11.55

• have only pyrimidine bases, while RNA 15 and 17 have mainly purine bases in the corresponding regions. If the tris(2-aminobenzimidazole) cleaver interacts with the purine bases (e.g., by stacking) it is not impossible that this could also be related to the apparent lower rate and lower selectivity in

C-5’-Triazolyl-2’-oxa-3’-aza-4’a-carbanucleosides: Synthesis and biological evaluation

• Roberto Romeo,
• Caterina Carnovale,
• Salvatore V. Giofrè,
• Maria A. Chiacchio,
• Adriana Garozzo,
• Emanuele Amata,
• Giovanni Romeo and
• Ugo Chiacchio

Beilstein J. Org. Chem. 2015, 11, 328–334, doi:10.3762/bjoc.11.38

• ][11][12]. Many structural variations of the natural nucleosides have been exploited. In general, the performed modifications included the replacement of the furanose moiety by other carbon or heterocyclic systems [13][14] or even acyclic fragments [15][16], the substitution of pyrimidine or purine

TEMPO-derived spin labels linked to the nucleobases adenine and cytosine for probing local structural perturbations in DNA by EPR spectroscopy

• Dnyaneshwar B. Gophane and
• Snorri Th. Sigurdsson

Beilstein J. Org. Chem. 2015, 11, 219–227, doi:10.3762/bjoc.11.24

• surroundings of a nucleic acid groove can be detected with spin labels by EPR spectroscopy. Here, we describe the use of an analogous derivative of A, namely TA, in which a TEMPO moiety is conjugated to the exocyclic amino group of 2´-deoxyadenosine (Figure 1B), to study local perturbations for a purine base

• space-demanding purine–purine pairs [81], where the spin-label mobility would be less affected by the local surroundings. The mobility of TA•C at pH 7, as judged by its EPR spectrum (Figure 2A), was between that of TA•T and TA•G. Previous NMR studies of the TA•C mismatch at pH 8.5 [47] and 8.9 [82

NAA-modified DNA oligonucleotides with zwitterionic backbones: stereoselective synthesis of A–T phosphoramidite building blocks

• Boris Schmidtgall,
• Claudia Höbartner and
• Christian Ducho

Beilstein J. Org. Chem. 2015, 11, 50–60, doi:10.3762/bjoc.11.8

• phosphoramidites with X representing pyrimidine or purine nucleobases appears to be feasible. This will enable the preparation of NAA-modified oligonucleotides with significant variations in the base sequence. We are currently finishing the synthesis of a comprehensive set of corresponding X–T phosphoramidites

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• (Table 2) show that the phenanthridine/phenanthridinium cation interacts with purine ss-sequences with affinity approximately one–two orders of magnitude lower in comparison to ds-DNA or ds-RNA, while interaction with pyrimidine ss-polynucleotides is even one order of magnitude lower. This agrees well

Versatile synthesis of amino acid functionalized nucleosides via a domino carboxamidation reaction

• Vicky Gheerardijn,
• Jos Van den Begin and
• Annemieke Madder

Beilstein J. Org. Chem. 2014, 10, 2566–2572, doi:10.3762/bjoc.10.268

• lysine derivatives onto nucleosides via a straightforward and easy domino carboxamidation reaction. Previously the groups of Gait and Eaton [41][42][43] have used this reaction to couple histamine or simple amine derivatives to both 5-iodo-2’-deoxyuridine and purine nucleosides. Although a large number

• of imidazole modified pyrimidine and purine derivatives for solid phase synthesis have been described to date [41][44][45][46][47], we believe that the reactions described here serve as an ideal model system, which can be extended to other commercially available amino acid derivatives and nucleosides

Photo, thermal and chemical degradation of riboflavin

• Muhammad Ali Sheraz,
• Sadia Hafeez Kazi,
• Sofia Ahmed,
• Zubair Anwar and
• Iqbal Ahmad

Beilstein J. Org. Chem. 2014, 10, 1999–2012, doi:10.3762/bjoc.10.208

• iodide [81][129], purine derivatives such as uric acid, xanthine, hypoxanthine [130], α-, β-, γ- and δ-tocopherols [128], vitamin B6 family [131], xanthone derivatives [132], and 1,4-diazabicyclo[2,2,2]octane and 2,5-dimethylfuran [133]. Effect of formulation characteristics Many considerations are given

Pyrrolidine nucleotide analogs with a tunable conformation

• Lenka Poštová Slavětínská,
• Dominik Rejman and
• Radek Pohl

Beilstein J. Org. Chem. 2014, 10, 1967–1980, doi:10.3762/bjoc.10.205

• ) – inhibitors of thymidine phosphorylase isolated from spontaneous lymphoma of SD rats (IC50 = 15 and 11 nM, respectively) [4], guanine derivative 5 – a potent inhibitor of human purine nucleoside phosphorylase PNP (Ki = 10 nM) [5], and finally guanine derivative 6 – exhibiting inhibitory activity against 6

• analogs [12]. In this publication, we present a conformational analysis of pyrrolidine azanucleotide analogs 7–14 containing thymine and adenine as examples of pyrimidine and purine nucleobases, respectively (Figure 2), and show how the conformation is affected by the mode of the phosphonate moiety

Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications

• Mahesh K. Lakshman,
• Manish K. Singh,
• Mukesh Kumar,
• Raghu Ram Chamala,
• Vijayender R. Yedulla,
• Domenick Wagner,
• Evan Leung,
• Lijia Yang,
• Asha Matin and
• Sadia Ahmad

Beilstein J. Org. Chem. 2014, 10, 1919–1932, doi:10.3762/bjoc.10.200

• appeared implausible on the basis of prior observations, where no reaction of BOP with the free hydroxy groups of nucleosides was observed [23][25]. Our recent work on a two-step one-pot etherification of purine nucleosides, quinazoline, and pyrimidines, had led some interesting preliminary observations

Syntheses of ¹⁵N-labeled pre-queuosine nucleobase derivatives

• Jasmin Levic and
• Ronald Micura

Beilstein J. Org. Chem. 2014, 10, 1914–1918, doi:10.3762/bjoc.10.199

• hypermodified nucleoside queuosine (Q) and the synthetic targets of preQ1 bases 1 to 3 with complementary 15N labeling patterns for potential NMR spectroscopic applications. Purine and systematic numbering as indicated. Synthesis of [15N1,15N3,H215N(C2)]-preQ1 base (1). a) CH3ONa (10 equiv) CH3OH, reflux, 10 h

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• 19b (DADMe-Immucilin-G) were reported to be potent transition state analog inhibitors of human purine nucleoside phosphorylase (PNP). Ulodesine 19a has completed two phase II clinical trials in 2013 [68][69]. Using the fluorinated pyrrolidine (3S,4S)-22 (Scheme 9), Mason et al. obtained azanucleoside

• presence sodium acetate in dioxane at 100 °C. The compound was prepared on the 10 mg scale in 67% yield. In contrast to its (3R,4R)-enantiomer (not shown), compound (3S,4S)-23 showed inhibitory activity toward human purine nucleoside phosphorylase (PNP) with a slow-onset binding constant Ki* = 0.032 nM. In

• purine nucleoside (i.e., adenosine) was modified (Scheme 25). Tungstophosphoric acid (H3PW12O40) was employed as a catalyst (2 mol %). Hybrids 71 originated from the pseudo-four component cascade employing two equivalents of barbituric acid. The authors demonstrated that the method was applicable with