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

• bind to mRNA targets through Watson–Crick base pairing and form a RNA/DNA duplex [4]. This can result in either mRNA cleavage mediated by RNase H or mRNA translational arrest through steric blocking. Another strategy for gene inhibition involves ribozymes [5] and DNAzymes [6], which are nucleic acid

• molecules with enzymatic activity. These catalytic RNAs and DNAs trigger the cleavage of RNA substrates at a specific position. Additionally, ribozymes can catalyze the ligation of target mRNA, extending their therapeutic potential to RNA repair applications. Finally, another promising ON-based therapy

• , more potent than AONs or ribozymes for gene knockdown, is centered on the RNA interference (RNAi) mechanism, which uses two natural pathways for gene silencing. One is guided by double-stranded siRNAs of 19–23 nucleotides in length that are fully complementary to the mRNA targets, and the other is

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• bicyclic octapeptide toxin belonging to the amatoxin family, found in Amanita Phalloides (death cap mushroom), see Figure 1 [1]. Its mechanism of action consists in the inhibition of cellular transcription by an effective blocking of RNA polymerase II, which is present in the nuclei of eukaryotic cells and

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

• polystyrene support decorated with a photolabile linker and its potential use for the synthesis of siRNA duplexes under mild and neutral conditions [36]. A similar strategy was used for the synthesis of partially 2'/3'-O-acetylated RNA oligonucleotides [37]. A photo-cleavable linker would also have potential

Fluorogenic PNA probes

• Tirayut Vilaivan

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

• the principle, showcase state-of-the-art technologies and update recent developments in the areas of fluorogenic PNA probes during the past 20 years. Keywords: DNA; fluorescence; molecular beacons; molecular probes; oligonucelotides; RNA; Review Introduction The development of molecular probes that

• (aeg) backbone that can recognize its target DNA and RNA was reported [21]. Considering the enormous difference between the two backbones, it is quite surprising that PNA can still retain the ability to recognize natural oligonucleotides having a complementary sequence with high affinity and

• unique properties not observed in other classes of oligonucleotide analogues with negatively charged phosphate groups. These include the relative insensitivity of the PNA–DNA or PNA–RNA hybrids to the ionic strength of the solvent [23], and the complete stability towards nucleases as well as proteases

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• are currently used in several marketed drugs like cartazolate (1), zaleplon (2), sildenafil (3), allopurinol (4), indiplon (5), etazolate (6) etc. (Figure 1). Fused pyrazole derivatives, especially pyrazoloazines have been reported to mimic purine bases, present in DNA and RNA, due to close structural

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

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

• FBAs (see Figure 2 for chemical structures) include C8 to S8 thio-RNA analogue thA [23], the C8-naphtalene substituted adenines cnA and dnA [24], as well as our own quadracyclic qAN1 [25]. A handful of fluorescent guanine analogues has been synthesized and characterized and includes the recent turn-on

• probe BFdG, 3-MI, 2PyG, as well as the emissive RNA analogue thG [23][26][27][28]. Some notable pyrimidine analogues include our tricyclic analogues tC and tCO [29][30][31], pyrrolo-dC [32] and its derivatives [33] as well as thU, thC [23] and DMAC [34]. Apart from tC, tCO, qAN1 and thG, FBAs have not

• made it impractical to handle. Instead, KF was used in combination with 18-crown-6 in anhydrous diglyme which furnished compounds 24a–e in modest 3–24% yields after isolation (Scheme 5) [47]. Recently, our group gained interest in RNA chemistry and therefore revisited the synthesis of tCO containing a

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

• Tamara Šmidlehner,
• Ivo Piantanida and
• Gennaro Pescitelli

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

• the most commonly used method for the characterization of the helical structure of DNA and RNA and their complexes with ligands. Less common but complementary to ECD, is flow-oriented linear dichroism (LD). Other methods such as vibrational CD (VCD) and emission-based methods (FDCD, CPL), can also be

• used for suitable samples. Despite the popularity of polarization spectroscopy in biophysics, aside several highly focused reviews on the application of these methods to DNA/RNA research, there is no systematic tutorial covering all mentioned methods as a tool for the characterization of adducts

• of these methods are found in structural studies of biomacromolecules [3]. For instance electronic circular dichroism (ECD), the most commonly used method, is indispensable in the structural studies of proteins and also intensively used in the characterization of the helical structure of DNA and RNA

Halogen-containing thiazole orange analogues – new fluorogenic DNA stains

• Aleksey A. Vasilev,
• Meglena I. Kandinska,
• Stanimir S. Stoyanov,
• Stanislava B. Yordanova,
• David Sucunza,
• Juan J. Vaquero,
• Obis D. Castaño,
• Stanislav Baluschev and
• Silvia E. Angelova

Beilstein J. Org. Chem. 2017, 13, 2902–2914, doi:10.3762/bjoc.13.283

• properties as a fluorogenic noncovalent DNA or RNA binder, many representatives of this class of dyes have been developed [3][4][5][6][7]. Thiazole orange does not fluoresce in the free state in solution. Fluorescence appears when the rotation about the monomethine bridge between the two heterocyclic

• ]. Hybridization-sensitive fluorescent probes in which TO is tethered to a nucleic acid: DNA [22][23][33][34][35][36], RNA [20][36] or PNA [18][19][21][31]) strands have been constructed by several research groups (the Krull, Kubista, Seitz and Wagenknecht groups). The continued scientific and commercial interest

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

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

• with its 5′-cap is of central importance for the cell. Many studies involving mRNA require reliable preparation and modification of 5′-capped RNAs. Depending on the length of the desired capped RNA, chemical or enzymatic preparation – or a combination of both – can be advantageous. We review state-of

• ; enzymatic capping; methyltransferase; RNA; Introduction The 5′-cap is a hallmark of eukaryotic mRNA and involved in numerous interactions required for cellular functions. Chemically, the 5′-cap consists of an inverted 7-methylguanosine connected to the rest of the eukaryotic mRNA via a 5′–5′ triphosphate

• binding complex (CBC) [9][10] in the nucleus required for nuclear export and the eukaryotic translation initiation factor 4E (eIF4E) [11] in the cytoplasm which is indispensable for cap-dependent translation. Additionally, capped RNA serves as a marker for the innate immune system to distinguish

Binding abilities of polyaminocyclodextrins: polarimetric investigations and biological assays

• Marco Russo,
• Daniele La Corte,
• Annalisa Pisciotta,
• Serena Riela,
• Rosa Alduina and
• Paolo Lo Meo

Beilstein J. Org. Chem. 2017, 13, 2751–2763, doi:10.3762/bjoc.13.271

• , different forms may be detected, i.e., the circular, linear and supercoiled topoisomers (Figure 8; in some preparations of pDNA, even after RNAse treatment, RNA can be present). Two sets of experiments were carried out: the first one (Figure 8a) with the same N/P ratios for each AmCD, and the second one

• the linear one at 38.5. Both, CD2 and CD3 bound the supercoiled conformation of pDNA almost completely at N/P 49.5, the linear one at 38.5 and 27.5, respectively. The lack of RNA migration occurred at N/P 16.5, 27.5 and 16.5 for CD1, CD2 and CD3, respectively. The minimum N/P ratios for complete

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• measurements can be used to study ligand–protein [12] and protein–protein interactions [13]; membrane proteins [14][15][16] and membrane-associated peptides [17][18]; equilibria among conformations of RNA [19], DNA [20], and peptide nucleic acids (PNA) [21]; and many others. Particularly recent is the

Superstructures with cyclodextrins: Chemistry and applications IV

• Gerhard Wenz

Beilstein J. Org. Chem. 2017, 13, 2157–2159, doi:10.3762/bjoc.13.215

• ]. The group of Ravoo also conjugated arylazopyrazoles to amphiphilic cyclodextrin derivatives that form vesicles triggered by light [17]. A star-shaped polycationic CD derivative with many breakable, intrinsic, disulfide linkages forms nanoparticles with messenger RNA and drugs and is particularly

β-Cyclodextrin- and adamantyl-substituted poly(acrylate) self-assembling aqueous networks designed for controlled complexation and release of small molecules

• Liang Yan,
• Duc-Truc Pham,
• Philip Clements,
• Stephen F. Lincoln,
• Jie Wang,
• Xuhong Guo and
• Christopher J. Easton

Beilstein J. Org. Chem. 2017, 13, 1879–1892, doi:10.3762/bjoc.13.183

• , fluconazole [40] and curcumin [37], along with larger species exemplified by RNA and DNA segments [26][32][33][36][39][47]. Some systems are designed to target specific tissues [26][35]. We are particularly interested in the extent to which small molecule guest complexation and release characteristics may be

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• ) histopathological examination [64]. Alternatively, serological testing has been proposed and promising results were obtained in a case control study in Ghana [65]. More recently, the detection of mycolactone from patient biopsy samples via LC–MS [66] and RNA aptamer binding [67] has been suggested, but the

• nor did the silencing of (N)-WASP by RNA interference alter the suppression of secretory and membrane protein production by mycolactone. The angiotensin pathway was identified as a third target of mycolactones by Brodin and co-workers in 2014 [104]. It has been known for some time that mycolactone is

• course of mycolactone-mediated apoptosis. Silencing Bim and Fas by RNA interference proved that Bim is the key driver of mycolactone-mediated apoptosis while Fas upregulation may represent a passive bystander effect. Based on these results and considering the remote similarity of mycolactones with

Chemical systems, chemical contiguity and the emergence of life

• Terrence P. Kee and
• Pierre-Alain Monnard

Beilstein J. Org. Chem. 2017, 13, 1551–1563, doi:10.3762/bjoc.13.155

• ], and RNA-worlds [7], or designated by a general concept such as the metabolism- and gene-first scenarios [8]. This multi-faceted approach (Figure 2), whilst suffering somewhat from a lack of effective integration or cohesion, has nonetheless permitted the accumulation of essential insights in the

• characteristics of various biomolecules, e.g., the catalytic activity of RNAs and their evolution potential [9][10][11], as well as processes that were essential for their syntheses, such as Fischer–Tropsch-like reactions [12], non-enzymatic RNA [13] or peptide polymerization [14]. Moreover, it has also allowed

• life to emerge [29], distinct geochemical environments could have not only produced specific chemicals, but could also have contributed to their evolution at different stages. For instance, the idea of RNA polymers as information components, precursors of a genetic system, can be partially realized

Framing major prebiotic transitions as stages of protocell development: three challenges for origins-of-life research

• Ben Shirt-Ediss,
• Sara Murillo-Sánchez and
• Kepa Ruiz-Mirazo

Beilstein J. Org. Chem. 2017, 13, 1388–1395, doi:10.3762/bjoc.13.135

• will defend the view that in order to reconstruct this process a strict ‘bottom-up’ approach should be pursued, starting with chemical precursors of biomolecules, rather than with fully functional biomolecules. Whereas the encapsulation of biopolymers (DNA, RNA, proteins) or cell extracts in self

• macromolecular structures, like proteins or nucleic acids, took control of metabolic dynamics. In fact, although the mainstream way to experimentally investigate protocells and their evolutionary capacity has been to take a ‘semi-synthetic’ approach (encapsulating populations of RNA or DNA polymers inside lipid

• devoted to control division processes. Challenge 3: characterizing the evolutionary dynamics of pre-Darwinian protocells. Rather than focusing on the reaction kinetics and evolutionary dynamics of populations of naked nucleic acid molecules (the core idea underlying the ‘RNA world’ hypothesis), or even

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

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

• . Several of protocols developed for the soluble-supported synthesis allow the preparation of both DNA and RNA oligomers of limited length in gram scale without any special equipment, being evidently of interest for research groups that need oligonucleotides in large amounts for research purposes. However

• , none of them has really tested at such a scale that the feasibility of their industrial use could be critically judged. Keywords: DNA; oligonucleotides; RNA; soluble support; synthesis; Introduction The synthesis of oligonucleotides (ONs) consists of linking nucleosides to each other in a specified

• used to assemble a 21-mer RNA sequence in gram scale [61] (Scheme 9). First, the DMTr group was removed with DCA in DCM and the detritylated support was precipitated from MeOH. A base-moiety-protected (APac, GiPac, CAc) 5´-O-DMTr-2´-O-TBDMS-nucleoside 3´-(2-cyanoethyl-N,N-diisopropylphosphoramidite

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

Towards open-ended evolution in self-replicating molecular systems

• Herman Duim and
• Sijbren Otto

Beilstein J. Org. Chem. 2017, 13, 1189–1203, doi:10.3762/bjoc.13.118

• described by Darwin in his famous work On the Origin of Species, but are still not understood in full detail [2]. It was only in the 1960’s that Spiegelman extended the scope of Darwinian evolution to chemical systems by studying the evolution of RNA-complexes [3]. In these experiments RNA was replicated

• using enzymes “borrowed” from contemporary biology. The outcome of the selection experiments was the shortening of the RNA sequence, as shorter sequences could be replicated faster. It was soon realized that a better understanding about how evolution acts on the molecular level would not only provide

• recently reported in an in vitro evolution experiment with replicating RNA species [11]. There is of course a constraint on the number of mutations that can occur without losing too much hereditary information from the parent molecules. In the same work, Eigen showed that unless mutation rates were

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

• summary, the most likely compounds that make the very first metabolic pathways are charged compounds with one to three carbon atoms, amino acids and a variety of peptides or related compounds, certainly not RNA [25]. Phosphates, with their remarkable metastable state in water were selected as surface

• nucleotides (and even more RNA) at the origin of life should be able to account for a steady synthesis of this molecule. In passing, this also argues fairly strongly against an origin involving hot temperatures, because heat considerably increases ribose instability [32]. Another argument for a late

• requirement would be that some catalysis allowed for a redox reaction (this is a general requirement of cell metabolism, involved in many metabolic steps, that is difficult, if not impossible, to fulfil using only RNA). As a consequence, primitive metabolic pathways would subsequently synthesise general

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks

• Sushil K. Maurya and
• Rohit Rana

Beilstein J. Org. Chem. 2017, 13, 1106–1118, doi:10.3762/bjoc.13.110

• rings and have shown important biological properties [5][6][7][8][9][10][11][12]. For example, macrocyclic aminoglycoside analogues have shown binding with the trans-activating region (TAR) RNA of the human immunodeficiency virus (HIV); an attractive target for RNA-based drug discovery [13]. Further

Glyco-gold nanoparticles: synthesis and applications

• Federica Compostella,
• Olimpia Pitirollo,
• Alessandro Silvestri and
• Laura Polito

Beilstein J. Org. Chem. 2017, 13, 1008–1021, doi:10.3762/bjoc.13.100

• diameter range can be obtained [4]. Moreover, this synthetic procedure allows to introduce different types of carbohydrates and other ligands (i.e., polyethylene chains, lipids, peptides, DNA, RNA or fluorescent dyes) in controlled ratios [4]. A modification of this technique consists in the application of

First total synthesis of kipukasin A

• Chuang Li,
• Haixin Ding,
• Zhizhong Ruan,
• Yirong Zhou and
• Qiang Xiao

Beilstein J. Org. Chem. 2017, 13, 855–862, doi:10.3762/bjoc.13.86

• ; Introduction Endogenous nucleosides are involved in DNA and RNA synthesis, cell signalling, enzyme regulation and metabolism etc. [1][2]. Therefore, the synthesis of novel nucleosides to mimic their physiological counterparts has potential therapeutic significance, which has led to the development of a large

How and why kinetics, thermodynamics, and chemistry induce the logic of biological evolution

• Addy Pross and
• Robert Pascal

Beilstein J. Org. Chem. 2017, 13, 665–674, doi:10.3762/bjoc.13.66

• developments [13][14] have supported a kinetically based view. Taking that kinetic approach, the concept of natural selection was able to be extended beyond biology so as to be applicable at the molecular level. Both views progressed separately in a context dominated by the RNA world hypothesis, though that

Conjecture and hypothesis: The importance of reality checks

• David Deamer

Beilstein J. Org. Chem. 2017, 13, 620–624, doi:10.3762/bjoc.13.60

• polymerization is obvious and was first proposed years ago [19]. Lahav and White [20] adopted the approach and demonstrated that peptide bonds could be produced using clay as a catalyst. The approach was largely abandoned with the advent of the RNA World scenario that suggested a way for life to begin in