scholarly journals Aminoribosylated Analogues of Muraymycin Nucleoside Antibiotics

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3085 ◽  
Author(s):  
Daniel Wiegmann ◽  
Stefan Koppermann ◽  
Christian Ducho
Keyword(s):  
Structural Motif ◽  
The Novel ◽  
Reference Compound ◽  
Inhibitory Potency ◽  
Nucleoside Antibiotics ◽  
Peptidoglycan Biosynthesis ◽  
Sar Studies ◽  
Naturally Occurring ◽  
Key Enzyme

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.

scholarly journals Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

2016 ◽  
Vol 12 ◽  
pp. 769-795 ◽  
Author(s):  
Daniel Wiegmann ◽  
Stefan Koppermann ◽  
Marius Wirth ◽  
Giuliana Niro ◽  
Kristin Leyerer ◽  
...  
Keyword(s):  
Natural Products ◽  
Antibacterial Agents ◽  
Peptide Antibiotics ◽  
Peptidoglycan Biosynthesis ◽  
Sar Studies ◽  
Current State ◽  
Naturally Occurring ◽  
Structure Activity ◽  
Key Enzyme ◽  
State Of Research

Muraymycins are a promising class of antimicrobial natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muraymycins and their analogues, some structure–activity relationship (SAR) studies and first insights into muraymycin biosynthesis. It therefore provides an overview on the current state of research, as well as an outlook on possible future developments in this field.

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

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2868 ◽  
Author(s):  
Anatol Spork ◽  
Stefan Koppermann ◽  
Stephanie Schier (née Wohnig) ◽  
Ruth Linder ◽  
Christian Ducho
Keyword(s):  
Antitumor Agents ◽  
Widespread Application ◽  
Core Motif ◽  
Nucleoside Antibiotics ◽  
Drug Candidates ◽  
Peptidoglycan Biosynthesis ◽  
Sar Studies ◽  
Naturally Occurring ◽  
Promising Target ◽  
Order Of Magnitude

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.

scholarly journals Towards an Improvement of Anticancer Activity of Benzyl Adenosine Analogs

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7146
Author(s):  
Verdiana Covelli ◽  
Manuela Grimaldi ◽  
Rosario Randino ◽  
Mohammad Firoznezhad ◽  
Maria Chiara Proto ◽  
...  
Keyword(s):  
Enzymatic Assays ◽  
Mva Pathway ◽  
Farnesyl Pyrophosphate Synthase ◽  
Anticancer Effects ◽  
Naturally Occurring ◽  
Molecular Action ◽  
Colorectal Cancer Cells ◽  
Key Enzyme

N6-Isopentenyladenosine (i6A) is a naturally occurring modified nucleoside displaying in vitro and in vivo antiproliferative and pro-apoptotic properties. In our previous studies, including an in silico inverse virtual screening, NMR experiments and in vitro enzymatic assays, we demonstrated that i6A targeted farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway and prenylation of downstream proteins, which are aberrant in several cancers. Following our interest in the anticancer effects of FPPS inhibition, we developed a panel of i6A derivatives bearing bulky aromatic moieties in the N6 position of adenosine. With the aim of clarifying molecular action of N6-benzyladenosine analogs on the FPPS enzyme inhibition and cellular toxicity and proliferation, herein we report the evaluation of the N6-benzyladenosine derivatives’ (compounds 2a–m) effects on cell viability and proliferation on HCT116, DLD-1 (human) and MC38 (murine) colorectal cancer cells (CRC). We found that compounds 2, 2a and 2c showed a persistent antiproliferative effect on human CRC lines and compound 2f exerted a significant effect in impairing the prenylation of RAS and Rap-1A proteins, confirming that the antitumor activity of 2f was related to the ability to inhibit FPPS activity.

Lactoferrin as potential preventative and treatment for COVID-19

2020 ◽  
Author(s):  
Raymond Chang ◽  
Wei-Zen Sun ◽  
Tzi Bun Ng
Keyword(s):  
Nutritional Supplement ◽  
Personal Health ◽  
The Novel ◽  
Adjunct Treatment ◽  
Health Measures ◽  
Naturally Occurring ◽  
Wide Range ◽  
Novel Coronavirus ◽  
Unique Potential

The novel coronavirus 2019 (COVID-19) pandemic is rapidly advancing across the globe despite public and personal health measures. Antivirals and nutritional supplements have been proposed as potentially useful against SARS-CoV-2 (virus that causes COVID-19), but few have been clinically established. Lactoferrin (Lf) is a naturally occurring and non-toxic glycoprotein that is orally available as a nutritional supplement and has established in vitro anti-viral efficacy against a wide range of virus including SARS-CoV, a closely related corona virus to SARS-CoV-2 (virus that causes COVID-19). Furthermore, Lf possesses unique immunomodulatory and anti-inflammatory effects that maybe especially relevant to the pathophysiology of severe COVID-19 cases. We review the underlying biological mechanisms of Lf as antiviral and immune regulator, and propose its unique potential as preventative and adjunct treatment for COVID-19. We hope that further research and development of Lf nutritional supplementation would establish its role for COVID-19.

scholarly journals Muraymycin Nucleoside Antibiotics: Structure-Activity Relationship for Variations in the Nucleoside Unit

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 22 ◽  
Author(s):  
Anna Heib ◽  
Giuliana Niro ◽  
Stefanie C. Weck ◽  
Stefan Koppermann ◽  
Christian Ducho
Keyword(s):  
Structure Activity Relationship ◽  
Significant Loss ◽  
Activity Relationship ◽  
Antibacterial Drug ◽  
Vitro Assay ◽  
Nucleoside Antibiotics ◽  
Future Design ◽  
Peptidoglycan Biosynthesis ◽  
Structure Activity

Muraymycins are a subclass of naturally occurring nucleoside antibiotics with promising antibacterial activity. They inhibit the bacterial enzyme translocase I (MraY), a clinically yet unexploited target mediating an essential intracellular step of bacterial peptidoglycan biosynthesis. Several structurally simplified muraymycin analogues have already been synthesized for structure–activity relationship (SAR) studies. We now report on novel derivatives with unprecedented variations in the nucleoside unit. For the synthesis of these new muraymycin analogues, we employed a bipartite approach facilitating the introduction of different nucleosyl amino acid motifs. This also included thymidine- and 5-fluorouridine-derived nucleoside core structures. Using an in vitro assay for MraY activity, it was found that the introduction of substituents in the 5-position of the pyrimidine nucleobase led to a significant loss of inhibitory activity towards MraY. The loss of nucleobase aromaticity (by reduction of the uracil C5-C6 double bond) resulted in a ca. tenfold decrease in inhibitory potency. In contrast, removal of the 2′-hydroxy group furnished retained activity, thus demonstrating that modifications of the ribose moiety might be well-tolerated. Overall, these new SAR insights will guide the future design of novel muraymycin analogues for their potential development towards antibacterial drug candidates.

scholarly journals Bisphosphonates and Cancer: What Opportunities from Nanotechnology?

2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
Giuseppe De Rosa ◽  
Gabriella Misso ◽  
Giuseppina Salzano ◽  
Michele Caraglia
Keyword(s):  
Anticancer Agent ◽  
Mevalonate Pathway ◽  
Drug Level ◽  
The Body ◽  
Antiangiogenic Effect ◽  
Naturally Occurring ◽  
Kill Cancer Cell ◽  
Key Enzyme ◽  
State Of Art

Bisphosphonates (BPs) are synthetic analogues of naturally occurring pyrophosphate compounds. They are used in clinical practice to inhibit bone resorption in bone metastases, osteoporosis, and Paget's disease. BPs induce apoptosis because they can be metabolically incorporated into nonhydrolyzable analogues of adenosine triphosphate. In addition, the nitrogen-containing BPs (N-BPs), second-generation BPs, act by inhibiting farnesyl diphosphate (FPP) synthase, a key enzyme of the mevalonate pathway. These molecules are able to induce apoptosis of a number of cancer cells in vitro. Moreover, antiangiogenic effect of BPs has also been reported. However, despite these promising properties, BPs rapidly accumulate into the bone, thus hampering their use to treat extraskeletal tumors. Nanotechnologies can represent an opportunity to limit BP accumulation into the bone, thus increasing drug level in extraskeletal sites of the body. Thus, nanocarriers encapsulating BPs can be used to target macrophages, to reduce angiogenesis, and to directly kill cancer cell. Moreover, nanocarriers can be conjugated with BPs to specifically deliver anticancer agent to bone tumors. This paper describes, in the first part, the state-of-art on the BPs, and, in the following part, the main studies in which nanotechnologies have been proposed to investigate new indications for BPs in cancer therapy.

scholarly journals Deoxyribonucleoside Kinases Activate Nucleoside Antibiotics in Severely Pathogenic Bacteria

2007 ◽  
Vol 51 (8) ◽  
pp. 2726-2732 ◽  
Author(s):  
Michael P. B. Sandrini ◽  
Oonagh Shannon ◽  
Anders R. Clausen ◽  
Lars Björck ◽  
Jure Piškur
Keyword(s):  
Pathogenic Bacteria ◽  
Systemic Infection ◽  
Nucleoside Analogs ◽  
Promising Alternative ◽  
Health Crisis ◽  
Nucleoside Antibiotics ◽  
Adult Mice ◽  
Key Enzyme ◽  
Deoxyribonucleoside Kinases

ABSTRACT Common bacterial pathogens are becoming progressively more resistant to traditional antibiotics, representing a major public-health crisis. Therefore, there is a need for a variety of antibiotics with alternative modes of action. In our study, several nucleoside analogs were tested against pathogenic staphylococci and streptococci. We show that pyrimidine-based nucleoside analogs, like 3′-azido-3′-deoxythymidine (AZT) and 2′,2′-difluoro-2′deoxycytidine (gemcitabine), are specifically activated by the endogenous bacterial deoxyribonucleoside kinases, leading to cell death. Deoxyribonucleoside kinase-deficient Escherichia coli strains become highly susceptible to nucleoside analogs when they express recombinant kinases from Staphylococcus aureus or Streptococcus pyogenes. We further demonstrate that recombinant S. aureus deoxyadenosine kinase efficiently phosphorylates the anticancer drug gemcitabine in vitro and is therefore the key enzyme in the activation pathway. When adult mice were infected intraperitoneally with a fatal dose of S. pyogenes strain AP1 and afterwards received gemcitabine, they failed to develop a systemic infection. Nucleoside analogs may therefore represent a promising alternative for combating pathogenic bacteria.

Neurotoxicity of Pesticides: The Roadmap for the Cubic Mode of Action

2020 ◽  
Vol 27 (1) ◽  
pp. 54-77 ◽  
Author(s):  
Bogdan Bumbăcilă ◽  
Mihai V. Putz
Keyword(s):  
Biological Activity ◽  
Wiener Index ◽  
Laboratory Animals ◽  
Covalent Bonds ◽  
Organophosphate Compounds ◽  
Sar Studies ◽  
Structure Activity ◽  
Cubic Structure

Pesticides are used today on a planetary-wide scale. The rising need for substances with this biological activity due to an increasing consumption of agricultural and animal products and to the development of urban areas makes the chemical industry to constantly investigate new molecules or to improve the physicochemical characteristics, increase the biological activities and improve the toxicity profiles of the already known ones. Molecular databases are increasingly accessible for in vitro and in vivo bioavailability studies. In this context, structure-activity studies, by their in silico - in cerebro methods, are used to precede in vitro and in vivo studies in plants and experimental animals because they can indicate trends by statistical methods or biological activity models expressed as mathematical equations or graphical correlations, so a direction of study can be developed or another can be abandoned, saving financial resources, time and laboratory animals. Following this line of research the present paper reviews the Structure-Activity Relationship (SAR) studies and proposes a correlation between a topological connectivity index and the biological activity or toxicity made as a result of a study performed on 11 molecules of organophosphate compounds, randomly chosen, with a basic structure including a Phosphorus atom double bounded to an Oxygen atom or to a Sulfur one and having three other simple covalent bonds with two alkoxy (-methoxy or -ethoxy) groups and to another functional group different from the alkoxy groups. The molecules were packed on a cubic structure consisting of three adjacent cubes, respecting a principle of topological efficiency, that of occupying a minimal space in that cubic structure, a method that was called the Clef Method. The central topological index selected for correlation was the Wiener index, since it was possible this way to discuss different adjacencies between the nodes in the graphs corresponding to the organophosphate compounds molecules packed on the cubic structure; accordingly, "three dimensional" variants of these connectivity indices could be considered and further used for studying the qualitative-quantitative relationships for the specific molecule-enzyme interaction complexes, including correlation between the Wiener weights (nodal specific contributions to the total Wiener index of the molecular graph) and the biochemical reactivity of some of the atoms. Finally, when passing from SAR to Q(uantitative)-SAR studies, especially by the present advanced method of the cubic molecule (Clef Method) and its good assessment of the (neuro)toxicity of the studied molecules and of their inhibitory effect on the target enzyme - acetylcholinesterase, it can be seen that a predictability of the toxicity and activity of different analogue compounds can be ensured, facilitating the in vivo experiments or improving the usage of pesticides.

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