Nucleic acid chemistry

• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2014, 10, 2928–2929, doi:10.3762/bjoc.10.311

• phosphordiesters or -triesters. Finally, this approach using phosphoramidites as nucleoside building blocks was significantly further developed in 1981 by Beaucage and Caruthers [4]. Since then, oligonucleotides of up to 50-mers in length have become available by an extremely efficient solid-phase methodology that

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

• group, we present here a straightforward method for direct linking of functionalized amino acids to the nucleoside base, thus equipping the nucleoside with two extra functionalities at once. As a proof of principle, we have introduced three amino acids with functional groups frequently used as key

• modification is the most common as it causes only minor disturbance in the helical structure [31]. Depending on the position of the incorporation on the nucleoside structure, the introduced functionalities can be pointed towards the major or the minor groove of the duplex. Modification of position 1’ and 2

• per nucleoside, mainly for synthetic reasons, and preferably making use of commercially available building blocks. We therefore considered the incorporation of moieties containing multiple functionalities on a nucleoside residue and present a straightforward method for the introduction of side chain

Regio- and stereoselective synthesis of new diaminocyclopentanols

• Evgeni A. Larin,
• Valeri S. Kochubei and
• Yuri M. Atroshchenko

Beilstein J. Org. Chem. 2014, 10, 2513–2520, doi:10.3762/bjoc.10.262

• those mimics may subtly influence their biological activity [11][12][13][14]. The functionalization of synthetic, unnatural aminocyclitols represents an attractive strategy towards the preparation of aminoglycoside and nucleoside mimics, and the development of common synthesis routes to various regio

Specific DNA duplex formation at an artificial lipid bilayer: fluorescence microscopy after Sybr Green I staining

• Emma Werz and
• Helmut Rosemeyer

Beilstein J. Org. Chem. 2014, 10, 2307–2321, doi:10.3762/bjoc.10.240

• Figure 17), as well as of lipid derivatives of nucleoside antimetabolites [23][24]. Moreover, studies of a transdermal application of lipo-oligonucleotides through the human Stratum corneum by iontophoresis techniques are underway. Experimental Materials 1-Palmitoyl-2-oleyl-sn-glycero-3

Reversibly locked thionucleobase pairs in DNA to study base flipping enzymes

• Christine Beuck and
• Elmar Weinhold

Beilstein J. Org. Chem. 2014, 10, 2293–2306, doi:10.3762/bjoc.10.239

• strand will need to be filled in with orthogonal 5' to 3' chemistry. A dT nucleoside analog with an exocyclic aziridine moiety has been chemically incorporated into poly-T ODN. Upon hybridization with a complementary poly-A strand, the aziridine group is attacked by the exocyclic amino group of the

• opposing adenine, resulting in ring opening and formation of an ethylene cross-linked base pair [29][30]. Other aziridine-substituted nucleobases have been incorporated enzymatically by a DNA polymerase, but elongation past the modified nucleoside has not been reported [31]. Another approach uses

• , long linkers that might interfere with protein binding are typically employed. The Verdine group has developed a cross-linking approach based on the easy postsynthetic introduction of cystamine or longer amino-alkylthiol linkers into ODN using a convertible nucleoside approach [39][40][41][42][43][44

Solution phase synthesis of short oligoribonucleotides on a precipitative tetrapodal support

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

Beilstein J. Org. Chem. 2014, 10, 2279–2285, doi:10.3762/bjoc.10.237

• '-UUGCA-5', has been prepared on a precipitative tetrapodal tetrakis(4-azidomethylphenyl)pentaerythritol support. The 3'-terminal nucleoside was coupled to the support as a 3'-O-(4-pentynoyl) derivative by Cu(I) promoted 1,3-dipolar cycloaddition. Couplings were carried out with 1.5 equiv of the building

• them has so far been applied to the synthesis of RNA. Tetrakis(4-azidomethylphenyl)pentaerythritol has recently been introduced as a practical soluble support for the synthesis of short oligodeoxyribonucleotides [16]. The 3'-terminal nucleoside is attached as a 3'-O-(4-pentynoyl) derivative to the

• immobilization of the 3'-terminal nucleoside to the azido functionalized support, 3-benzoyl-2-O-cyanoethyl-5-(1-methoxy-1-methylethyl)uridine (4a) was transformed to its 3'-O-(4-pentynoyl) derivative 6a. To accomplish this, 4-pentynoic acid was first converted to its anhydride by DCC activation in dioxane and

Second generation silver(I)-mediated imidazole base pairs

• Susanne Hensel,
• Nicole Megger,
• Kristina Schweizer and
• Jens Müller

Beilstein J. Org. Chem. 2014, 10, 2139–2144, doi:10.3762/bjoc.10.221

• obtained using synthetic procedures established previously for the non-methylated imidazole analogue (Scheme 3) [34][38]. Methylimidazole, deprotonated in situ via the addition of sodium hydride, has been reacted with Hoffer’s chloro sugar to give the p-toluoyl-protected nucleoside (1a, 1b). In the case of

• 2-methylimidazole, only one product (2-methylimidazole nucleoside, 1a) was formed due to the symmetry of the deprotonated starting compound. When performing this reaction with 4-methylimidazole, two product isomers were obtained as a result of the asymmetric substitution of the deprotonated starting

• compound, namely 4-methylimidazole nucleoside (1b) and 5-methylimidazole nucleoside. The latter isomer was obtained in very low yield only (isomer ratio of ~15:1). It was not further investigated, because its methyl group is oriented in a direction that is not expected to lead to an increased shielding of

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

• successful approach in developing antiviral therapeutics. Our long-term interest in the synthesis and evaluation of biological properties of phosphonate azanucleotides has yielded several potent inhibitors of nucleoside/nucleotide metabolizing enzymes: thymine derivatives 4 and 11 (Figure 1 and Figure 2

• ) – 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

• nucleoside, nucleotide and oligonucleotide spatial structure. The conformation predefines, for example, the stability of DNA:RNA duplexes – complexes between oligodeoxyribonucleotide and a complementary RNA strain [7] or an overall shape of oligonucleotide. It is also well known that the structure of DNA may

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

• , and other chemical experiments, phosphonium and tosylate derivatives of alcohols seem to be intermediates. These then react with BtO− and AtO− produced in situ. In order to demonstrate broader utility, this novel reaction has been used to prepare a series of acyclic nucleoside-like compounds. Because

• demonstrated the isolation and synthetic utility of a nucleoside phosphonium salt [28]. Thus, to us the reaction of oximes with BOP was an intriguing result, leading us to query whether a benzotriazolyl intermediate, rather than a phosphonium ion, was formed en route to the cyanide. This line of reasoning

• nucleobase, we first considered synthesis of nucleoside-like entities (Scheme 5). In this context, N-alkylbenzotriazolyl derivatives and ribonucleoside analogues containing a benzotriazole as a nucleobase surrogate have shown interesting activities towards NTPase/helicase of Flaviviridae viruses [1][2

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

• pathway of the hypermodified tRNA nucleoside queuosine (Que). The core structure of preQ1 is represented by 7-(aminomethyl)-7-deazaguanine (preQ1 base). Here, we report the synthesis of three preQ1 base derivatives with complementary 15N-labeling patterns, utilizing [15N]-KCN, [15N]-phthalimide, and [15N3

• biosynthetic pathway of the hypermodified tRNA nucleoside queuosine [3]. Recently, preQ1 base has attracted considerable attention because this nucleobase specifically binds to bacterial mRNA domains and regulates genes that are required for queuosine biosynthesis, by a so-called riboswitch mechanism [4][5][6

• , see UV spectroscopic data and extinction coefficients of 7-deazaguanine, N9-methyl-7-deazaguanine and preQ1 nucleoside in references [19][20][21]. Comparison of 1H NMR spectra of the preQ1 bases 1, 2 and 3 with complementary 15N labeling patterns. Conditions: cpreQ1 base = 1 mM; DMSO-d6, 298 K. The

Synthesis of a bifunctional cytidine derivative and its conjugation to RNA for in vitro selection of a cytidine deaminase ribozyme

• Nico Rublack and
• Sabine Müller

Beilstein J. Org. Chem. 2014, 10, 1906–1913, doi:10.3762/bjoc.10.198

• derivative suitable for conjugation to RNA and linkage of the conjugated library to a streptavidine-coated surface. Successful conjugation of the cytidine derivative to the 3'-terminus of a model RNA is demonstrated. Keywords: cytidine deaminase; modified nucleoside; nucleic acids; ribozyme; RNA world

• -position of 3 in order to attach a biotin unit to the modified nucleoside. Linker 4 was synthesized from 2,2’-(ethylenedioxy)diethylamine (8) with di-tert-butyl dicarbonate (Boc2O) in dioxane [35] (Figure 3). The mono protected diamino linker 4 was purified by chromatography on silica gel and subsequently

• . Two linker moieties of different lengths and functionality were attached to the nucleobase and to the sugar residue of cytidine, thus enabling for one coupling of the nucleoside to periodate-oxidized RNAs, and for second linking the functionalized library to a surface. The 5'-O-coupled linker carrying

Structure/affinity studies in the bicyclo-DNA series: Synthesis and properties of oligonucleotides containing bc^en-T and iso-tricyclo-T nucleosides

• Branislav Dugovic,
• Michael Wagner and
• Christian J. Leumann

Beilstein J. Org. Chem. 2014, 10, 1840–1847, doi:10.3762/bjoc.10.194

• tertiary hydroxy group in 4 as TMS ether, however, was unsuccessful and yielded only the corresponding α-nucleoside in yields below 25%. We reasoned that the exclusive formation of α-nucleosides is due to the steric bulk of the TBS group, further suppressing the intrinsically disfavored β-(endo)-face

• structure/nucleic acid affinity profile of this modification we also became interested in nucleoside 11β, containing a double bond instead of the cyclopropane ring. In the context of oligonucleotides this derivative seemed appropriate to investigate the direct steric influence of the cyclopropyl/methylene

• ,β in a ratio of β:α = 1.2:1. After standard tritylation of 11α,β the anomeric mixture 12α,β became separable by flash chromatography and the corresponding β-nucleoside 12β could be smoothly converted into the phosphoramidite 13 by standard methods. Structural properties of nucleosides To get an

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

• the synthesis of novel nucleoside analogs. The reported approaches were employed for modifications of the parent nucleoside core or for de novo construction of a nucleoside scaffold from non-nucleoside substrates. The cited references are grouped according to the usually recognized types of the MCRs

• . Biochemical properties of the novel nucleoside analogs are also presented (if provided by the authors). Keywords: multicomponent reaction; nucleoside analog; nucleoside antibiotics; nucleoside construction; nucleoside modification; Introduction Chemical modifications of natural ribose or 2'-deoxyribose

• nucleosides resulted in the development of a group of compounds referred to as nucleoside analogs (Figure 1). The essential role of nucleoside analogs in medicine is reflected by the fact that currently thirty-six compounds from this class are used throughout the world in the therapy of viral or cancer

Concise total synthesis of two marine natural nucleosides: trachycladines A and B

• Haixin Ding,
• Wei Li,
• Zhizhong Ruan,
• Ruchun Yang,
• Zhijie Mao,
• Qiang Xiao and
• Jun Wu

Beilstein J. Org. Chem. 2014, 10, 1681–1685, doi:10.3762/bjoc.10.176

• ), nucleoside 3 could be synthesized by using 1,2,3,5-tetra-O-benzoyl-2-C-methyl-D-ribofuranose (5) as a carbohydrate acceptor by a Vorbrüggen glycosylation with the corresponding silylated nucleobases and a Lewis acid as a catalyst. As the key intermediate for the preparation of the anti-HCV nucleoside

• with 40% yield. To further improve the yield and add to the molecular diversity, N6-benzoyladenine 17 was used as a base to give nucleoside 14 in 87% yield (Scheme 2). All benzoyl protecting groups were removed simultaneously by using ammonia saturated methanol in a sealed press tube to give 15 in 96

• yield. The reaction is a novel instance of the broad substrate tolerance of AMPDA and extends its usage in nucleoside chemistry. Therefore, trachycladine B was synthesized in 35.0% overall yield from 5-deoxy-1,2,3-tri-O-acetyl-β-D-ribofuranose (6). Next, the coupling of carbohydrate 4 with 2,6

The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases

• Ilja V. Fateev,
• Konstantin V. Antonov,
• Irina D. Konstantinova,
• Tatyana I. Muravyova,
• Frank Seela,
• Roman S. Esipov,
• Anatoly I. Miroshnikov and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2014, 10, 1657–1669, doi:10.3762/bjoc.10.173

• -arabinofuranose (9) into the phosphate 12a without isolation of intermediary products. Condensation of 12a with 2-chloroadenine catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP) resulted in the formation of clofarabine in 67% yield. The reaction was also studied with a number of purine

• ab initio calculations in terms of the electronic structure (natural purines vs analogues) and stereochemical features (2FAra-1P vs Ara-1P) of the studied compounds to determine the substrate recognition by E. coli nucleoside phosphorylases. The second approach starts with the cascade one-pot

• 2-chloro-9-(β-D-arabinofuranosyl)adenine (6) in 45 min, the formation of 2-chloro-9-(β-D-xylofuranosyl)adenine (7) proceeded very slowly attaining ca. 8% yield in 48 h. Keywords: chemoenzymatic synthesis; clofarabine; nucleoside phosphorylases; phosphopentomutase; recombinant E. coli ribokinase

Glycosystems in nanotechnology: Gold glyconanoparticles as carrier for anti-HIV prodrugs

• Fabrizio Chiodo,
• Marco Marradi,
• Javier Calvo,
• Eloisa Yuste and
• Soledad Penadés

Beilstein J. Org. Chem. 2014, 10, 1339–1346, doi:10.3762/bjoc.10.136

• prodrug candidates. The nucleoside reverse transcriptase inhibitors abacavir and lamivudine have been converted to the corresponding thiol-ending ester derivatives and then conjugated to ~3 nm glucose-coated gold nanoparticles by means of “thiol-for-thiol” ligand place exchange reactions. The drugs

• on ~3 nm glucose-coated gold nanoparticles as a potential drug-delivery system. As antiviral drugs, the nucleoside analog reverse transcriptase inhibitors (NRTIs) abacavir (ABC) and lamivudine (3TC) were selected. NRTIs are drugs that compete in the cytoplasm as triphosphates with endogenous

• nucleoside substrates acting as chain terminators in the DNA polymerisation reaction catalyzed by HIV-1 RT [3]. Both drugs were transformed in ester derivatives to prepare the GNPs. The pH-mediated release of the drugs from the GNPs surface was evaluated and cellular experiments demonstrated that abacavir

Stereoselective synthesis of carbocyclic analogues of the nucleoside Q precursor (PreQ₀)

• Sabin Llona-Minguez and
• Simon P. Mackay

Beilstein J. Org. Chem. 2014, 10, 1333–1338, doi:10.3762/bjoc.10.135

• & Biophysics, Karolinska Institutet, Stockholm, S-171 21, Sweden 10.3762/bjoc.10.135 Abstract A convergent and stereoselective synthesis of chiral cyclopentyl- and cyclohexylamine derivatives of nucleoside Q precursor (PreQ0) has been accomplished. This synthetic route allows for an efficient preparation of 4

• -substituted analogues with interesting three-dimensional character, including chiral cyclopentane-1,2-diol and -1,2,3-triol derivatives. This unusual substitution pattern provides a useful starting point for the discovery of novel bioactive molecules. Keywords: diol synthesis; nucleoside; PreQ0

• pharmacological profiles including antibacterial, antiviral and anticancer properties [2][3][4]. Nucleoside Q precursor (PreQ0) 1 is a common precursor in the biosynthesis of queuosine (Q, 2) and archaeosine (G+, 3), two hyper-modified nucleosides present in the tRNA of prokaryote/eukaryote and euryarchaeota

Synthesis, characterization and DNA interaction studies of new triptycene derivatives

• Sourav Chakraborty,
• Snehasish Mondal,
• Rina Kumari,
• Sourav Bhowmick,
• Prolay Das and
• Neeladri Das

Beilstein J. Org. Chem. 2014, 10, 1290–1298, doi:10.3762/bjoc.10.130

• that selected triptycene derivatives show anticancer activities by virtue of inhibition of topoisomerase [29][30], obstruction of macromolecule synthesis [31], blocking of nucleoside transport [32], induction of caspase activities [33] and poly(ADP)-ribose polymerase-1 (PARP) cleavage [34], and at the

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

Solid-phase-supported synthesis of morpholinoglycine oligonucleotide mimics

• Tatyana V. Abramova,
• Sergey S. Belov,
• Yulia V. Tarasenko and
• Vladimir N. Silnikov

Beilstein J. Org. Chem. 2014, 10, 1151–1158, doi:10.3762/bjoc.10.115

• efficient solid-phase-supported peptide synthesis (SPPS) of morpholinoglycine oligonucleotide (MorGly) mimics has been developed. The proposed strategy includes a novel specially designed labile linker group containing the oxalyl residue and the 2-aminomethylmorpholino nucleoside analogues as first subunits

• compounds 3a,d was published earlier [8]. Thymine containing morpholino nucleoside 3e was obtained similarly to 3d starting from the 5-methyluridine. See Supporting Information File 1 for the synthetic schemes, procedures and physicochemical data for intermediates in the synthesis of monomer 3e. Our next

• plates (Merck, Germany) in the proper solvent systems (see below) and visualized by UV irradiation, ninhydrin (amine groups) or cystein/aqueous sulfuric acid (nucleoside and trityl groups). Preparative silica gel column chromatography, RPC, and cation exchange chromatography were performed using silica

Amino acid motifs in natural products: synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

• Oliver Ries,
• Martin Büschleb,
• Markus Granitzka,
• Dietmar Stalke and
• Christian Ducho

Beilstein J. Org. Chem. 2014, 10, 1135–1142, doi:10.3762/bjoc.10.113

• . Within the context of our work regarding the total synthesis of muraymycin nucleoside antibiotics, we have developed a synthetic approach towards (2S,3S)-3-hydroxyleucine building blocks. Application of different protecting group patterns led to building blocks suitable for C- or N-terminal

• ], as monosulfuric acid ester [6] or as potential acylation site for fatty acid side chains such as in A- and B-series muraymycin nucleoside antibiotics (Figure 1) [7][8][9]. In the case of these muraymycin congeners, acylation of the 3-hydroxy position with fatty acid side chains, which are ω

• , followed by concomitant acidic cleavage of the N,O- and O,O-acetal protecting groups leading to building block 22 in 89% yield (Scheme 3). Aldehyde 22 can be used for the connection of the (2S,3S)-3-hydroxyleucine motif of C-series muraymycins (such as muraymycin C1 (1c), Figure 1) to the nucleoside moiety

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• inexpensive phosphites (P(OR)3) have only been applied as phosphine substitutes in one single example: Beal [46] utilized tri-isopropylphosphite in a Mitsunobu condensation of a guanine-derived nucleoside analog with benzylic alcohols providing simplified byproduct separation through improved water solubility

Synthesis of nucleotide–amino acid conjugates designed for photo-CIDNP experiments by a phosphotriester approach

• Tatyana V. Abramova,
• Olga B. Morozova,
• Vladimir N. Silnikov and
• Alexandra V. Yurkovskaya

Beilstein J. Org. Chem. 2013, 9, 2898–2909, doi:10.3762/bjoc.9.326

• model compound conjugates of the amino acid, nucleotide, and dye residues, where key participants (dye, amino acid, and nucleoside) have to be drawn together mimicking the biologically important DNA repair processes. To fulfill the requirements of the photo-induced TR CIDNP experiments, a synthetic

• detection of elusive radicals in biomolecules using model compounds, where key participants of the reaction (dye, amino acid, and nucleoside) are spatially drawn together mimicking the biologically important DNA repair processes. Guanosine is the most easily oxidized nucleoside [12] in photoreactions of

• photoinitiating agents for electron transfer from nucleotides and amino acids [15][16][17][18]. Based on the above mentioned reasons, we have chosen 4-benzoylbenzoic acid, 2’-deoxyguanosine, and L-tryptophan [7][9][13][14][15][16][17][18][19][20] as the dye, nucleoside, and amino acid building blocks

Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine

• Ashley R. Longstreet,
• Suzanne M. Opalka,
• Brian S. Campbell,
• B. Frank Gupton and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2013, 9, 2570–2578, doi:10.3762/bjoc.9.292

• ; nicotinonitriles; Introduction Nevirapine (3) was the first commercially available non-nucleoside reverse transcriptase inhibitor (NNRTI), and has remained an important medicine in the management of human immunodeficiency virus (HIV) [1][2]. Nevirapine combined with lamivudine (3TC) and azidothymidine (AZT) or

Biosynthesis of rare hexoses using microorganisms and related enzymes

• Zijie Li,
• Yahui Gao,
• Hideki Nakanishi,
• Xiaodong Gao and
• Li Cai

Beilstein J. Org. Chem. 2013, 9, 2434–2445, doi:10.3762/bjoc.9.281

• pharmaceutical and nutrition industry [4]. In recent years, the interest in rare carbohydrates and the nucleosides (e.g. L-nucleoside analogues) derived from them has substantially increased in medicine because these molecules are potential candidates of anticancer and antiviral drugs [4][5][6]. Unfortunately

• oxygen. L-Talose and D-gulose The aldohexoses L-talose and D-gulose (C-3 epimer of D-galactose) are both very expensive owing to their scarcity in nature. L-Talofuranosyladenine, an adenine nucleoside derivative of L-talose, was found to be a slow-reacting substrate for calf intestinal adenosine