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A New 1,5-Disubstituted Triazole DNA Backbone Mimic with Enhanced Polymerase Compatibility.

ABSTRACT: Triazole linkages (TLs) are mimics of the phosphodiester bond in oligonucleotides with applications in synthetic biology and biotechnology. Here we report the RuAAC-catalyzed synthesis of a novel 1,5-disubstituted triazole (TL2) dinucleoside phosphoramidite as well as its incorporation into oligonucleotides and compare its DNA polymerase replication competency with other TL analogues. We demonstrate that TL2 has superior replication kinetics to these analogues and is accurately replicated by polymerases. Derived structure-biocompatibility relationships show that linker length and the orientation of a hydrogen bond acceptor are critical and provide further guidance for the rational design of artificial biocompatible nucleic acid backbones.

SUBMITTER: Epple S

PROVIDER: S-EPMC8499026 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Regioselective Synthesis and Molecular Docking Studies of 1,5-Disubstituted 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases.

Project description:1,2,3-triazoles are versatile building blocks with growing interest in medicinal chemistry. For this reason, organic chemistry focuses on the development of new synthetic pathways to obtain 1,2,3-triazole derivatives, especially with pyridine moieties. In this work, a novel series of 1,5-disubstituted-1,2,3-triazoles functionalized with pyrimidine nucleobases were prepared via 1,3-dipolar cycloaddition reaction in a regioselective manner for the first time. The N1-propargyl nucleobases, used as an alkyne intermediate, were obtained in high yields (87-92%) with a new two-step procedure that selectively led to the monoalkylated compounds. Then, FeCl3 was employed as an efficient Lewis acid catalyst for 1,3-dipolar cycloaddition between different aryl and benzyl azides and the N1-propargyl nucleobases previously synthesized. This new protocol allows the synthesis of a series of new 1,2,3-triazole derivatives with good to excellent yields (82-92%). The ADME (Absorption, Distribution, Metabolism, and Excretion) analysis showed good pharmacokinetic properties and no violations of Lipinsky's rules, suggesting an appropriate drug likeness for these new compounds. Molecular docking simulations, conducted on different targets, revealed that two of these new hybrids could be potential ligands for viral and bacterial protein receptors such as human norovirus capsid protein, SARS-CoV-2 NSP13 helicase, and metallo-β-lactamase.

| S-EPMC9735522 | biostudies-literature

Synthesis, Structure and In Vitro Cytotoxic Activity of Novel Cinchona-Chalcone Hybrids with 1,4-Disubstituted- and 1,5-Disubstituted 1,2,3-Triazole Linkers.

Project description:By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine- and quinidine-derived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted- and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines (PANC-1, COLO-205, A2058 and EBC-1). In most cases, the cyclization reactions were accompanied by the transition-metal-catalyzed epimerization of the C9-stereogenic centre in the cinchona fragment. The results of the in vitro assays disclosed that all the prepared hybrids exhibit marked cytotoxicity in concentrations of low micromolar range, while the C9-epimerized model comprising quinidine- and (E)-1-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl) fragments, connected by 1,5-disubstituted 1,2,3-triazole linker, and can be regarded as the most potent lead of which activity is probably associated with a limited conformational space allowing for the adoption of a relatively rigid well-defined conformation identified by DFT modelling. The mechanism of action of this hybrid along with that of a model with markedly decreased activity were approached by comparative cell-cycle analyses in PANC-1 cells. These studies disclosed that the hybrid of enhanced antiproliferative activity exerts significantly more extensive inhibitory effects in subG1, S and G2/M phases than does the less cytotoxic counterpart.

| S-EPMC6891474 | biostudies-literature

Synthesis of Dense 1,2,3-Triazole Oligomers Consisting Preferentially of 1,5-Disubstituted Units via Ruthenium(II)-Catalyzed Azide-Alkyne Cycloaddition.

Project description:Ruthenium(II)-catalyzed azide-alkyne cycloaddition (RuAAC) polymerization of t-butyl 4-azido-5-hexynoate (tBuAH), i.e., a heterobifunctional monomer carrying azide and alkyne moieties, was investigated in this study. RuAAC of the monofunctional precursors of tBuAH yielded a dimer possessing a 1,5-disubstituted 1,2,3-triazole moiety. 1H NMR data showed that the dimer was a mixture of diastereomers. Polymerization of tBuAH using ruthenium(II) (Ru(II)) catalysts produced oligomers of Mw ≈ (2.7-3.6) × 103 consisting of 1,5-disubstituted 1,2,3-triazole units (1,5-units) as well as 1,4-disubstituted 1,2,3-triazole units (1,4-units). The fractions of 1,5-unit (f1,5) were roughly estimated to be ca. 0.8 by comparison of signals of the methine and triazole protons in 1H NMR spectra, indicating that RuAAC proceeded preferentially and thermal Huisgen cycloaddition (HC) somehow took place during the polymerization. The oligomer samples obtained were also characterized by solubility test, size exclusion chromatography (SEC), ultraviolet-visible (UV-Vis) absorption spectroscopy, and thermogravimetric analysis (TGA). The UV-Vis and TGA data indicated that the oligomer samples contained a substantial amount of Ru(II) catalysts. To the best of our knowledge, this is the first report on dense 1,2,3-triazole oligomers consisting of 1,5-units linked via a carbon atom.

| S-EPMC10180885 | biostudies-literature

Synthesis of symmetrical 1,5-disubstituted granatanines.

Project description:A general entry into symmetrical 1,5-disubstituted granatanines that involves an alkylative ring-closure on a 2,6-bis enolate piperidine intermediate is described.

| S-EPMC3652803 | biostudies-literature

Backbone Flexibility Influences Nucleotide Incorporation by Human Translesion DNA Polymerase ? opposite Intrastrand Cross-Linked DNA.

Project description:Intrastrand cross-links (IaCL) connecting two purine nucleobases in DNA pose a challenge to high-fidelity replication in the cell. Various repair pathways or polymerase bypass can cope with these lesions. The influence of the phosphodiester linkage between two neighboring 2'-deoxyguanosine (dG) residues attached through the O(6) atoms by an alkylene linker on bypass with human DNA polymerase ? (hPol ?) was explored in vitro. Steady-state kinetics and mass spectrometric analysis of products from nucleotide incorporation revealed that although hPol ? is capable of bypassing the 3'-dG in a mostly error-free fashion, significant misinsertion was observed for the 5'-dG of the IaCL containing a butylene or heptylene linker. The lack of the phosphodiester linkage triggered an important increase in frameshift adduct formation across the 5'-dG by hPol ?, in comparison to the 5'-dG of IaCL DNA containing the phosphodiester group.

| S-EPMC4889123 | biostudies-literature

Discovery of 1,5-disubstituted pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor.

Project description:A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.

| S-EPMC3368638 | biostudies-other

Protein prosthesis: 1,5-disubstituted[1,2,3]triazoles as cis-peptide bond surrogates.

Project description: Not available

| S-EPMC2531141 | biostudies-literature

Synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives from amino acids.

Project description:A versatile method for the synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives starting from easily accessible naturally occurring D-or L-amino acids as chiral synthons is described. The amino acids were converted into azido alcohols, followed by copper catalyzed [3+2] cycloaddition reactions between the azido alcohols and methyl propiolate and subsequent ester aminolysis with primary and secondary amines furnished the target compounds, which were obtained in excellent yields with no racemization. Docking of selected target compounds shows that the chiral 1,4-disubstituted-1,2,3-triazoles derivatives has the potential of mimicking the binding mode of known purine analogues.

| S-EPMC6255254 | biostudies-literature

1,4-Disubstituted 1<i>H</i>-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties.

Project description:Peptidotriazolamers are hybrid foldamers with features of peptides and triazolamers, containing alternation of amide bonds and 1,4-disubstituted 1H-1,2,3-triazoles with conservation of the amino acid side chains. We report on the synthesis of a new class of peptidomimetics, containing 1,4-disubstituted 1H-1,2,3-triazoles in alternation with amide bonds and the elucidation of their conformational properties in solution. Based on enantiomerically pure propargylamines bearing the stereogenic center in the propargylic position and α-azido esters, building blocks were obtained by copper-catalyzed azide-alkyne cycloaddition. With these building blocks the peptidotriazolamers were readily available by solution phase synthesis. A panel of homo- and heterochiral tetramers, hexamers, and heptamers was synthesized and the heptamer Boc-Ala-Val-Ψ[4Tz]Phe-LeuΨ[4Tz]Phe-LeuΨ[4Tz]Val-OAll as well as an heterochiral and a Gly-containing equivalent were structurally characterized by NMR-based molecular dynamics simulations using a specifically tailored force field to determine their conformational and solvation properties. All three variants adopt a compact folded conformation in DMSO as well as in water. In addition to the heptamers we predicted the conformational behavior of similar longer oligomers i.e., Boc-Ala-(AlaΨ[4Tz]Ala)6-OAll as well as Boc-Ala-(d-AlaΨ[4Tz]Ala)6-OAll and Boc-Ala-(GlyΨ[4Tz]Ala)6-OAll. Our calculations predict a clear secondary structure of the first two molecules in DMSO that collapses in water due to the hydrophobic character of the side chains. The homochiral compound folds into a regular helical structure and the heterochiral one shows a twisted "S"-shape, while the Gly variant exhibits no clear secondary structure.

| S-EPMC6443886 | biostudies-literature

1,5-Disubstituted benzimidazoles that direct cardiomyocyte differentiation from mouse embryonic stem cells.

Project description:Cardiomyopathy is the leading cause of death worldwide. Despite progress in medical treatments, heart transplantation is one of the only current options for those with infarcted heart muscle. Stem cell differentiation technology may afford cell-based therapeutics that may lead to the generation of new, healthy heart muscle cells from undifferentiated stem cells. Our approach is to use small molecules to stimulate stem cell differentiation. Herein, we describe a novel class of 1,5-disubstituted benzimidazoles that induce differentiation of stem cells into cardiac cells. We report on the evaluation in vitro for cardiomyocyte differentiation and describe structure-activity relationship results that led to molecules with drug-like properties. The results of this study show the promise of small molecules to direct stem cell lineage commitment, to probe signaling pathways and to develop compounds for the stimulation of stem cells to repair damaged heart tissue.

| S-EPMC4766108 | biostudies-literature

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