Research

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13 pages, 1236 KiB

Open AccessArticle

Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics

by Brian M. Cawrse, Nia’mani M. Robinson, Nina C. Lee, Gerald M. Wilson and Katherine L. Seley-Radtke

Molecules 2019, 24(14), 2656; https://doi.org/10.3390/molecules24142656 - 23 Jul 2019

Cited by 9 | Viewed by 3151

Abstract

Pyrrolo[3,2-d]pyrimidines have been studied for many years as potential lead compounds for the development of antiproliferative agents. Much of the focus has been on modifications to the pyrimidine ring, with enzymatic recognition often modulated by C2 and C4 substituents. In contrast, [...] Read more.

Pyrrolo[3,2-d]pyrimidines have been studied for many years as potential lead compounds for the development of antiproliferative agents. Much of the focus has been on modifications to the pyrimidine ring, with enzymatic recognition often modulated by C2 and C4 substituents. In contrast, this work focuses on the N5 of the pyrrole ring by means of a series of novel N5-substituted pyrrolo[3,2-d]pyrimidines. The compounds were screened against the NCI-60 Human Tumor Cell Line panel, and the results were analyzed using the COMPARE algorithm to elucidate potential mechanisms of action. COMPARE analysis returned strong correlation to known DNA alkylators and groove binders, corroborating the hypothesis that these pyrrolo[3,2-d]pyrimidines act as DNA or RNA alkylators. In addition, N5 substitution reduced the EC₅₀ against CCRF-CEM leukemia cells by up to 7-fold, indicating that this position is of interest in the development of antiproliferative lead compounds based on the pyrrolo[3,2-d]pyrimidine scaffold. Full article

(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)

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16 pages, 2217 KiB

Open AccessArticle

Propargylated Purine Deoxynucleosides: New Tools for Fluorescence Imaging Strategies

by Akkaladevi Venkatesham, Sambasiva Rao Pillalamarri, Flore De Wit, Eveline Lescrinier, Zeger Debyser and Arthur Van Aerschot

Molecules 2019, 24(3), 468; https://doi.org/10.3390/molecules24030468 - 28 Jan 2019

Cited by 6 | Viewed by 3336

Abstract

In vivo imaging of biological processes is an important asset of modern cell biology. Selectively reacting fluorophores herein are an important tool and click chemistry reactions take a large share in these events. 5-Ethynyl-2′-deoxyuridine (EdU) is well known for visualizing DNA replication, but [...] Read more.

In vivo imaging of biological processes is an important asset of modern cell biology. Selectively reacting fluorophores herein are an important tool and click chemistry reactions take a large share in these events. 5-Ethynyl-2′-deoxyuridine (EdU) is well known for visualizing DNA replication, but does not show any selectivity for incorporation into DNA. Striving for specific visualization of virus replication, in particular HIV replication, a series of propargylated purine deoxynucleosides were prepared aiming for selective incorporation by HIV reverse transcriptase (RT). We here report on the synthesis and preliminary biological effects (cellular toxicity, HIV inhibitory effects, and feasibility of the click reaction) of these nucleoside analogues. Full article

(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)

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20 pages, 2712 KiB

Open AccessArticle

Aminoribosylated Analogues of Muraymycin Nucleoside Antibiotics

by Daniel Wiegmann, Stefan Koppermann and Christian Ducho

Molecules 2018, 23(12), 3085; https://doi.org/10.3390/molecules23123085 - 26 Nov 2018

Cited by 14 | Viewed by 2872

Abstract

Nucleoside antibiotics are uridine-derived natural products that inhibit the bacterial membrane protein MraY. MraY is a key enzyme in the membrane-associated intracellular stages of peptidoglycan biosynthesis and therefore considered to be a promising, yet unexploited target for novel antibacterial agents. Muraymycins are one [...] Read more.

Nucleoside antibiotics are uridine-derived natural products that inhibit the bacterial membrane protein MraY. MraY is a key enzyme in the membrane-associated intracellular stages of peptidoglycan biosynthesis and therefore considered to be a promising, yet unexploited target for novel antibacterial agents. Muraymycins are one subclass of such naturally occurring MraY inhibitors. As part of structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report on novel derivatives with different attachment of one characteristic structural motif, i.e., the aminoribose moiety normally linked to the muraymycin glycyluridine core unit. Based on considerations derived from an X-ray co-crystal structure, we designed and synthesised muraymycin analogues having the aminoribose attached (via a linker) to either the glycyluridine amino group or to the uracil nucleobase. Reference compounds bearing the non-aminoribosylated linker units were also prepared. It was found that the novel aminoribosylated analogues were inactive as MraY inhibitors in vitro, but that the glycyluridine-modified reference compound retained most of the inhibitory potency relative to the unmodified parent muraymycin analogue. These results point to 6′-N-alkylated muraymycin analogues as a potential novel variation of the muraymycin scaffold for future SAR optimisation. Full article

(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)

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18 pages, 1641 KiB

Open AccessArticle

Novel 5′-Norcarbocyclic Pyrimidine Derivatives as Antibacterial Agents

by Anastasia L. Khandazhinskaya, Liudmila A. Alexandrova, Elena S. Matyugina, Pavel N. Solyev, Olga V. Efremenkova, Karen W. Buckheit, Maggie Wilkinson, Robert W. Buckheit, Jr., Larisa N. Chernousova, Tatiana G. Smirnova, Sofya N. Andreevskaya, Olga G. Leonova, Vladimir I. Popenko, Sergey N. Kochetkov and Katherine L. Seley-Radtke

Molecules 2018, 23(12), 3069; https://doi.org/10.3390/molecules23123069 - 23 Nov 2018

Cited by 20 | Viewed by 3543

Abstract

A series of novel 5′-norcarbocyclic derivatives of 5-alkoxymethyl or 5-alkyltriazolyl-methyl uracil were synthesized and the activity of the compounds evaluated against both Gram-positive and Gram-negative bacteria. The growth of Mycobacterium smegmatis was completely inhibited by the most active compounds at a MIC₉₉ [...] Read more.

A series of novel 5′-norcarbocyclic derivatives of 5-alkoxymethyl or 5-alkyltriazolyl-methyl uracil were synthesized and the activity of the compounds evaluated against both Gram-positive and Gram-negative bacteria. The growth of Mycobacterium smegmatis was completely inhibited by the most active compounds at a MIC₉₉ of 67 μg/mL (mc²155) and a MIC₉₉ of 6.7–67 μg/mL (VKPM Ac 1339). Several compounds also showed the ability to inhibit the growth of attenuated strains of Mycobacterium tuberculosis ATCC 25177 (MIC₉₉ 28–61 μg/mL) and Mycobacterium bovis ATCC 35737 (MIC₉₉ 50–60 μg/mL), as well as two virulent strains of M. tuberculosis; a laboratory strain H37Rv (MIC₉₉ 20–50 μg/mL) and a clinical strain with multiple drug resistance MS-115 (MIC₉₉ 20–50 μg/mL). Transmission electron microscopy (TEM) evaluation of M. tuberculosis H37Rv bacterial cells treated with one of the compounds demonstrated destruction of the bacterial cell wall, suggesting that the mechanism of action for these compounds may be related to their interactions with bacteria cell walls. Full article

(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)

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20 pages, 3099 KiB

Open AccessFeature PaperArticle

Membrane-Permeable Octanoyloxybenzyl-Masked cNMPs As Novel Tools for Non-Invasive Cell Assays

by Alexandra Ruthenbeck, Elisa Marangoni, Björn-Ph. Diercks, Aileen Krüger, Alexander Froese, Nadja I. Bork, Viacheslav O. Nikolaev, Andreas H. Guse and Chris Meier

Molecules 2018, 23(11), 2960; https://doi.org/10.3390/molecules23112960 - 13 Nov 2018

Cited by 1 | Viewed by 3903

Abstract

Adenine nucleotide (AN) 2nd messengers, such as 3′,5′-cyclic adenosine monophosphate (cAMP), are central elements of intracellular signaling, but many details of their underlying processes remain elusive. Like all nucleotides, cyclic nucleotide monophosphates (cNMPs) are net-negatively charged at physiologic pH which limits their applicability [...] Read more.

Adenine nucleotide (AN) 2nd messengers, such as 3′,5′-cyclic adenosine monophosphate (cAMP), are central elements of intracellular signaling, but many details of their underlying processes remain elusive. Like all nucleotides, cyclic nucleotide monophosphates (cNMPs) are net-negatively charged at physiologic pH which limits their applicability in cell-based settings. Thus, many cellular assays rely on sophisticated techniques like microinjection or electroporation. This setup is not feasible for medium- to high-throughput formats, and the mechanic stress that cells are exposed to raises the probability of interfering artefacts or false-positives. Here, we present a short and flexible chemical route yielding membrane-permeable, bio-reversibly masked cNMPs for which we employed the octanoyloxybenzyl (OB) group. We further show hydrolysis studies on chemical stability and enzymatic activation, and present results of real-time assays, where we used cAMP and Ca²⁺ live cell imaging to demonstrate high permeability and prompt intracellular conversion of some selected masked cNMPs. Based on these results, our novel OB-masked cNMPs constitute valuable precursor-tools for non-invasive studies on intracellular signaling. Full article

(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)

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11 pages, 1661 KiB

Open AccessArticle

Enhanced Stability of DNA Oligonucleotides with Partially Zwitterionic Backbone Structures in Biological Media

by Melissa Meng, Boris Schmidtgall and Christian Ducho

Molecules 2018, 23(11), 2941; https://doi.org/10.3390/molecules23112941 - 10 Nov 2018

Cited by 11 | Viewed by 3930

Abstract

Deficient stability towards nuclease-mediated degradation is one of the most relevant tasks in the development of oligonucleotide-derived biomedical agents. This hurdle can be overcome through modifications to the native oligonucleotide backbone structure, with the goal of simultaneously retaining the unique hybridization properties of [...] Read more.

Deficient stability towards nuclease-mediated degradation is one of the most relevant tasks in the development of oligonucleotide-derived biomedical agents. This hurdle can be overcome through modifications to the native oligonucleotide backbone structure, with the goal of simultaneously retaining the unique hybridization properties of nucleic acids. The nucleosyl amino acid (NAA)-modification is a recently introduced artificial cationic backbone linkage. Partially zwitterionic NAA-modified oligonucleotides had previously shown hybridization with DNA strands with retained base-pairing fidelity. In this study, we report the significantly enhanced stability of NAA-modified oligonucleotides towards 3′- and 5′-exonuclease-mediated degradation as well as in complex biological media such as human plasma and whole cell lysate. This demonstrates the potential versatility of the NAA-motif as a backbone modification for the development of biomedically active oligonucleotide analogues. Full article

(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)

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20 pages, 2897 KiB

Open AccessArticle

Analogues of Muraymycin Nucleoside Antibiotics with Epimeric Uridine-Derived Core Structures

by Anatol P. Spork, Stefan Koppermann, Stephanie Schier (née Wohnig), Ruth Linder and Christian Ducho

Molecules 2018, 23(11), 2868; https://doi.org/10.3390/molecules23112868 - 03 Nov 2018

Cited by 15 | Viewed by 3060

Abstract

Nucleoside analogues have found widespread application as antiviral and antitumor agents, but not yet as antibacterials. Naturally occurring uridine-derived ‘nucleoside antibiotics’ target the bacterial membrane protein MraY, an enzyme involved in peptidoglycan biosynthesis and a promising target for the development of novel antibacterial [...] Read more.

Nucleoside analogues have found widespread application as antiviral and antitumor agents, but not yet as antibacterials. Naturally occurring uridine-derived ‘nucleoside antibiotics’ target the bacterial membrane protein MraY, an enzyme involved in peptidoglycan biosynthesis and a promising target for the development of novel antibacterial agents. Muraymycins represent a nucleoside-peptide subgroup of such MraY-inhibiting natural products. As part of detailed structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report novel insights into the effects of stereochemical variations in the nucleoside core structure. Using a simplified version of the muraymycin scaffold, it was shown that some formal inversions of stereochemistry led to about one order of magnitude loss in inhibitory potency towards the target enzyme MraY. In contrast, epimers of the core motif with retained inhibitory activity were also identified. These 5′,6′-anti-configured analogues might serve as novel chemically tractable variations of the muraymycin scaffold for the future development of uridine-derived drug candidates. Full article

(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)

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18 pages, 3251 KiB

Open AccessArticle

Anti-Hepatitis C Virus Activity of Uridine Derivatives of 2-Deoxy Sugars

by Ewelina Krol, Ilona Wandzik, Gabriela Pastuch-Gawolek and Boguslaw Szewczyk

Molecules 2018, 23(7), 1547; https://doi.org/10.3390/molecules23071547 - 27 Jun 2018

Cited by 3 | Viewed by 3293

Abstract

Hepatitis C virus (HCV), the etiological agent of the most common and dangerous diseases of the liver, is a major health problem worldwide. Despite many attempts, there is still no vaccine available. Although many drugs have been approved for use mostly in combination [...] Read more.

Hepatitis C virus (HCV), the etiological agent of the most common and dangerous diseases of the liver, is a major health problem worldwide. Despite many attempts, there is still no vaccine available. Although many drugs have been approved for use mostly in combination regimen, their high costs make them out of reach in less developed regions. Previously, we have synthesized a series of compounds belonging to uridine derivatives of 2-deoxy sugars and have proved that some of them possess antiviral activity against influenza A virus associated with N-glycosylation inhibition. Here, we analyze the antiviral properties of these compounds against HCV. Using cell culture-derived HCV (HCVcc), HCV pseudoparticles (HCVpp), and replicon cell lines, we have shown high anti-HCV activity of two compounds. Our results indicated that compounds 2 and 4 significantly reduced HCVcc propagation with IC₅₀ values in low μM range. Further experiments using the HCVpp system confirmed that both compounds significantly impaired the infectivity of produced HCVpp due to the inhibition of the correct maturation of viral glycoproteins. Overall, our results suggest that inhibiting the glycosylation process might be a good target for new therapeutics not only against HCV, but other important viral pathogens which contain envelopes with highly glycosylated proteins. Full article

(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)

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22 pages, 1561 KiB

Open AccessArticle

Phosphorus Pentachloride Promoted gem-Dichlorination of 2′- and 3′-Deoxynucleosides

by Fabio Da Paixao Soares, Elisabetta Groaz and Piet Herdewijn

Molecules 2018, 23(6), 1457; https://doi.org/10.3390/molecules23061457 - 15 Jun 2018

Cited by 1 | Viewed by 4134

Abstract

Halogen substitution at various positions of canonical nucleosides has generated a number of bioactive structural variants. Herein, the synthesis of two unique series of sugar modified nucleosides bearing a gem-dichloro group is presented. The synthetic plan entails the controlled addition of phosphorus [...] Read more.

Halogen substitution at various positions of canonical nucleosides has generated a number of bioactive structural variants. Herein, the synthesis of two unique series of sugar modified nucleosides bearing a gem-dichloro group is presented. The synthetic plan entails the controlled addition of phosphorus pentachloride to suitably protected 2′- or 3′-ketodeoxynucleoside intermediates as the key step, facilitating the rapid construction of such functionalized molecules. Under the same reaction conditions, the highest chemoselectivity was observed for the formation of 2′,2′-dichloro-2′,3′-dideoxynucleosides, while a competing 2′,3′-elimination process occurred in the case of the 3′,3′-dichloro counterparts. Full article

(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)

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Review

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17 pages, 2429 KiB

Open AccessReview

Biosynthetic and Synthetic Strategies for Assembling Capuramycin-Type Antituberculosis Antibiotics

by Ashley L. Biecker, Xiaodong Liu, Jon S. Thorson, Zhaoyong Yang and Steven G. Van Lanen

Molecules 2019, 24(3), 433; https://doi.org/10.3390/molecules24030433 - 25 Jan 2019

Cited by 10 | Viewed by 4441

Abstract

Mycobacterium tuberculosis (Mtb) has recently surpassed HIV/AIDS as the leading cause of death by a single infectious agent. The standard therapeutic regimen against tuberculosis (TB) remains a long, expensive process involving a multidrug regimen, and the prominence of multidrug-resistant (MDR), extensively drug-resistant (XDR), [...] Read more.

Mycobacterium tuberculosis (Mtb) has recently surpassed HIV/AIDS as the leading cause of death by a single infectious agent. The standard therapeutic regimen against tuberculosis (TB) remains a long, expensive process involving a multidrug regimen, and the prominence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant (TDR) strains continues to impede treatment success. An underexplored class of natural products—the capuramycin-type nucleoside antibiotics—have been shown to have potent anti-TB activity by inhibiting bacterial translocase I, a ubiquitous and essential enzyme that functions in peptidoglycan biosynthesis. The present review discusses current literature concerning the biosynthesis and chemical synthesis of capuramycin and analogs, seeking to highlight the potential of the capuramycin scaffold as a favorable anti-TB therapeutic that warrants further development. Full article

(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)

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