Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis of O ⁶-alkylated preQ₁ derivatives.

ABSTRACT: A naturally occurring riboswitch can utilize 7-aminomethyl-O ⁶-methyl-7-deazaguanine (m⁶preQ₁) as cofactor for methyl group transfer resulting in cytosine methylation. This recently discovered riboswitch-ribozyme activity opens new avenues for the development of RNA labeling tools based on tailored O ⁶-alkylated preQ₁ derivatives. Here, we report a robust synthesis for this class of pyrrolo[2,3-d]pyrimidines starting from readily accessible N ²-pivaloyl-protected 6-chloro-7-cyano-7-deazaguanine. Substitution of the 6-chloro atom with the alcoholate of interest proceeds straightforward. The transformation of the 7-cyano substituent into the required aminomethyl group turned out to be challenging and was solved by a hydration reaction sequence on a well-soluble dimethoxytritylated precursor via in situ oxime formation. The synthetic path now provides a solid foundation to access O ⁶-alkylated 7-aminomethyl-7-deazaguanines for the development of RNA labeling tools based on the preQ₁ class-I riboswitch scaffold.

SUBMITTER: Flemmich L

PROVIDER: S-EPMC8450960 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis of O 6-alkylated preQ1 derivatives.

Flemmich Laurin L Moreno Sarah S Micura Ronald R

Beilstein journal of organic chemistry 20210902

A naturally occurring riboswitch can utilize 7-aminomethyl-O 6-methyl-7-deazaguanine (m6preQ1) as cofactor for methyl group transfer resulting in cytosine methylation. This recently discovered riboswitch-ribozyme activity opens new avenues for the development of RNA labeling tools based on tailored O 6-alkylated preQ1 derivatives. Here, we report a robust synthesis for this class of pyrrolo[2,3-d]pyrimidines starting fro ...[more]

PMID: 34621392

Similar Datasets

Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.

Project description:Inhibition of angiogenesis is a promising addition to current cancer treatment strategies. Neutralization of vascular endothelial growth factor by monoclonal antibodies is clinically effective but may cause side effects due to thrombosis. Low molecular weight angiogenesis inhibitors are currently less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S)-levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure-activity relationships with regard to inhibition of angiogenesis. N-methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S)-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with normal human dermal fibroblasts. Interestingly, the cluster morphology caused by N-methyllevamisole was different than the clusters observed for levamisole, and a third "cord-like" morphology resembling that of the known drug suramin was observed for an aniline-containing derivative. New chemotypes exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted.

| S-EPMC3443238 | biostudies-literature

Synthesis of electrophile-tethered preQ1 analogs for covalent attachment to preQ1 RNA.

Project description:The preQ1 cIass-I riboswitch aptamer can utilize 7-aminomethyl-7-deazaguanine (preQ1) ligands that are equipped with an electrophilic handle for the covalent attachment of the ligand to the RNA. The simplicity of the underlying design of irreversibly bound ligand-RNA complexes has provided a new impetus in the fields of covalent RNA labeling and RNA drugging. Here, we present short and robust synthetic routes for such reactive preQ1 and (2,6-diamino-7-aminomethyl-7-deazapurine) DPQ1 ligands. The readily accessible key intermediates of preQ0 and DPQ0 (both bearing a nitrile moiety instead of the aminomethyl group) were reduced to the corresponding 7-formyl-7-deazapurine counterparts. These readily undergo reductive amination to form the hydroxyalkyl handles, which were further converted to the haloalkyl or mesyloxyalkyl-modified target compounds. In addition, we report hydrogenation conditions for preQ0 and DPQ0 that allow for cleaner and faster access to preQ1 compared to existing routes and provide the novel compound DPQ1.

| S-EPMC11897656 | biostudies-literature

ArcS from Thermococcus kodakarensis transfers L-lysine to preQ0 nucleoside derivatives as minimum substrate RNAs.

Project description:Archaeosine (G+) is an archaea-specific tRNA modification synthesized via multiple steps. In the first step, archaeosine tRNA guanine transglucosylase (ArcTGT) exchanges the G15 base in tRNA with 7-cyano-7-deazaguanine (preQ0). In Euryarchaea, preQ015 in tRNA is further modified by archaeosine synthase (ArcS). Thermococcus kodakarensis ArcS catalyzes a lysine-transfer reaction to produce preQ0-lysine (preQ0-Lys) as an intermediate. The resulting preQ0-Lys15 in tRNA is converted to G+15 by a radical S-adenosyl-L-methionine enzyme for archaeosine formation (RaSEA), which forms a complex with ArcS. Here, we focus on the substrate tRNA recognition mechanism of ArcS. Kinetic parameters of ArcS for lysine and tRNA-preQ0 were determined using a purified enzyme. RNA fragments containing preQ0 were prepared from Saccharomyces cerevisiae tRNAPhe-preQ015. ArcS transferred 14C-labeled lysine to RNA fragments. Furthermore, ArcS transferred lysine to preQ0 nucleoside and preQ0 nucleoside 5'-monophosphate. Thus, the L-shaped structure and the sequence of tRNA are not essential for the lysine-transfer reaction by ArcS. However, the presence of D-arm structure accelerates the lysine-transfer reaction. Because ArcTGT from thermophilic archaea recognizes the common D-arm structure, we expected the combination of T. kodakarensis ArcTGT and ArcS and RaSEA complex would result in the formation of preQ0-Lys15 in all tRNAs. This hypothesis was confirmed using 46 T. kodakarensis tRNA transcripts and three Haloferax volcanii tRNA transcripts. In addition, ArcTGT did not exchange the preQ0-Lys15 in tRNA with guanine or preQ0 base, showing that formation of tRNA-preQ0-Lys by ArcS plays a role in preventing the reverse reaction in G+ biosynthesis.

| S-EPMC11298593 | biostudies-literature

Synthesis of 4-O-Alkylated N-Acetylneuraminic Acid Derivatives.

Project description:The synthesis of 4-O-alkyl analogues of N-acetylneuraminic acid (Neu5Ac) and the scope of the reaction are described. Activated alkyl halides and sulfonates and primary alkyl iodides give products in useful yields. The utility of the methodology is exemplified using a thiophenyl Neu5Ac building block to synthesize a 4-O-alkyl DANA analogue. These results expand the toolbox of Neu5Ac chemistry with value in drug discovery and for the design of novel tools to study the biology of Neu5Ac lectins.

| S-EPMC8279483 | biostudies-literature

Structure and function of preQ1 riboswitches.

Project description:PreQ1 riboswitches help regulate the biosynthesis and transport of preQ1 (7-aminomethyl-7-deazaguanine), a precursor of the hypermodified guanine nucleotide queuosine (Q), in a number of Firmicutes, Proteobacteria, and Fusobacteria. Queuosine is almost universally found at the wobble position of the anticodon in asparaginyl, tyrosyl, histidyl and aspartyl tRNAs, where it contributes to translational fidelity. Two classes of preQ1 riboswitches have been identified (preQ1-I and preQ1-II), and structures of examples from both classes have been determined. Both classes form H-type pseudoknots upon preQ1 binding, each of which has distinct unusual features and modes of preQ1 recognition. These features include an unusually long loop 2 in preQ1-I pseudoknots and an embedded hairpin in loop 3 in preQ1-II pseudoknots. PreQ1-I riboswitches are also notable for their unusually small aptamer domain, which has been extensively investigated by NMR, X-ray crystallography, FRET, and other biophysical methods. Here we review the discovery, structural biology, ligand specificity, cation interactions, folding, dynamics, and applications to biotechnology of preQ1 riboswitches. This article is part of a Special Issue entitled: Riboswitches.

| S-EPMC4177978 | biostudies-literature

Efficient synthesis of 1,3-naphtoxazine derivatives using reusable magnetic catalyst (GO-Fe3O4-Ti(IV)): anticonvulsant evaluation and computational studies.

Project description:A series of 2-aryl/alkyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines (S1-S11) were synthesized with an eco-friendly and recoverable nanocatalyst (GO-Fe3O4-Ti(IV)) as an efficient magnetic composite. The new nanocatalyst was characterized by FT-IR, XRD and, EDS analysis. A conformable procedure, easy to work up and having a short reaction time with high yields are some advantages of this method. The new catalyst is also thermal-stable, reusable and, environment-friendly. The chemical structures of the synthesized 1,3-oxazine compounds were confirmed by comparing their melting points with those reported in literature. Then, the anticonvulsant activity of these compounds was assessed by the intraperitoneal pentylenetetrazole test (ipPTZ). Compounds S10 and S11 displayed considerable activity against chemically-induced seizure tests. The molecular simulation was also done to achieve their binding affinities as γ-aminobutyric acid A (GABA-A) receptor agonists as an assumptive mechanism of their anticonvulsant action. The result of molecular studies represented strongly matched with biological activity. Molecular docking simulation of the potent compound (S10) and diazepam as the positive control was performed and some critical residues like Thr262, Asn265, Met286, Phe289, and Val290 were identified. Based on the anticonvulsant results and also in silico ADME predictions, S11 can be to become a potential drug candidate as an anticonvulsant agent.

| S-EPMC9188075 | biostudies-literature

Observation of preQ1-II riboswitch dynamics using single-molecule FRET.

Project description:PreQ1 riboswitches regulate the synthesis of the hypermodified tRNA base queuosine by sensing the pyrrolopyrimidine metabolite preQ1. Here, we use single-molecule FRET to interrogate the structural dynamics of apo and preQ1-bound states of the preQ1-II riboswitch from Lactobacillus rhamnosus. We find that the apo-form of the riboswitch spontaneously samples multiple conformations. Magnesium ions and preQ1 stabilize conformations that sequester the ribosome-binding site of the mRNA within the pseudoknotted structure, thus inhibiting translation initiation. Our results reveal that folding of the preQ1-II riboswitch is complex and provide evidence favoring a conformational selection model of effector binding by riboswitches of this class.

| S-EPMC6693549 | biostudies-literature

Novel Ionic Liquid-Functionalized Chitosan [DSIM][AlCl3] x -@CS: Synthesis, Characterization, and Catalytic Application for Preparation of Substituted Pyrazine Derivatives.

Project description:Pyrazines are renowned heterocyclic compounds that have played an important role in drug design and are part of many polycyclic compounds of biological and industrial significance. In this article, a novel chitosan-immobilized ionic liquid, [DSIM][AlCl3] x -@CS, has been synthesized easily at ambient temperature and used for catalyzing the synthesis of a series of biologically relevant pyrazine derivatives. The catalyst is well characterized by various techniques such as Fourier transform infrared spectroscopy, Raman spectroscopy, solid-state 13C MAS nuclear magnetic resonance, scanning electron microscopy/energy-dispersive X-ray, elemental mapping, transmission electron microscopy, powder X-ray diffraction, and thermal gravimetric analyses. The advantageous features of the present energy-sustainable methodology include high yield of product (>99%), shorter reaction time periods, and recyclability of the catalyst.

| S-EPMC6648620 | biostudies-literature

Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection.

Project description:We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) derivative 7 (CM-10-18) with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC(50) against DENV in BHK cells of 6.5 ?M, which limited its use in in vivo. Compound 7 presented structural opportunities for activity relationship analysis, which we exploited and report here. These structure-activity relationship studies led to analogues 2h, 2l, 3j, 3l, 3v, and 4b-4c with nanomolar antiviral activity (EC(50) = 0.3-0.5 ?M) against DENV infection, while maintaining low cytotoxicity (CC(50) > 500 ?M, SI > 1000). In male Sprague-Dawley rats, compound 3l was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 ± 4%).

| S-EPMC3395807 | biostudies-literature

Synthesis of Disubstituted Carboxonium Derivatives of Closo-Decaborate Anion [2,6-B10H8O2CC6H5]-: Theoretical and Experimental Study.

Project description:A comprehensive study focused on the preparation of disubstituted carboxonium derivatives of closo-decaborate anion [2,6-B10H8O2CC6H5]- was carried out. The proposed synthesis of the target product was based on the interaction between the anion [B10H11]- and benzoic acid C6H5COOH. It was shown that the formation of this product proceeds stepwise through the formation of a mono-substituted product [B10H9OC(OH)C6H5]-. In addition, an alternative one-step approach for obtaining the target derivative is postulated. The structure of tetrabutylammonium salts of carboxonium derivative ((C4H9)4N)[2,6-B10H8O2CC6H5] was established with the help of X-ray structure analysis. The reaction pathway for the formation of [2,6-B10H8O2CC6H5]- was investigated with the help of density functional theory (DFT) calculations. This process has an electrophile induced nucleophilic substitution (EINS) mechanism, and intermediate anionic species play a key role. Such intermediates have a structure in which one boron atom coordinates two hydrogen atoms. The regioselectivity for the process of formation for the 2,6-isomer was also proved by theoretical calculations. Generally, in the experimental part, the simple and available approach for producing disubstituted carboxonium derivative was introduced, and the mechanism of this process was investigated with the help of theoretical calculations. The proposed approach can be applicable for the preparation of a wide range of disubstituted derivatives of closo-borate anions.

| S-EPMC9966448 | biostudies-literature