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The American Journal of Gastroenterology Aug 2023
Topics: Humans; Rifabutin; Cost-Benefit Analysis; Anti-Bacterial Agents; Pyrroles; Drug Therapy, Combination; Proton Pump Inhibitors; Helicobacter pylori
PubMed: 37094105
DOI: 10.14309/ajg.0000000000002248 -
Cell Death & Disease Aug 2023Pancreatic cancer is a highly aggressive cancer, and is primarily treated with gemcitabine, with increasing resistance. SIRT6 as a member of sirtuin family plays...
Pancreatic cancer is a highly aggressive cancer, and is primarily treated with gemcitabine, with increasing resistance. SIRT6 as a member of sirtuin family plays important roles in lifespan and diverse diseases, such as cancer, diabetes, inflammation and neurodegenerative diseases. Considering the role of SIRT6 in the cytoprotective effect, it might be a potential anticancer drug target, and is associated with resistance to anticancer therapy. However, very few SIRT6 inhibitors have been reported. Here, we reported the discovery of a pyrrole-pyridinimidazole derivative, 8a, as a new non-competitive SIRT6 inhibitor, and studied its roles and mechanisms in the antitumor activity and sensitization of pancreatic cancer to gemcitabine. Firstly, we found a potent SIRT6 inhibitor compound 8a by virtual screening and identified by molecular and cellular SIRT6 activity assays. 8a could effectively inhibit SIRT6 deacetylation activity with IC values of 7.46 ± 0.79 μM in FLUOR DE LYS assay, and 8a significantly increased the acetylation levels of H3 in cells. Then, we found that 8a could inhibit the cell proliferation and induce cell apoptosis in pancreatic cancer cells. We further demonstrate that 8a sensitize pancreatic cancer cells to gemcitabine via reversing the activation of PI3K/AKT/mTOR and ERK signaling pathways induced by gemcitabine and blocking the DNA damage repair pathway. Moreover, combination of 8a and gemcitabine induces cooperative antitumor activity in pancreatic cancer xenograft model in vivo. Overall, we demonstrate that 8a, a novel SIRT6 inhibitor, could be a promising potential drug candidate for pancreatic cancer treatment.
Topics: Humans; Apoptosis; Cell Line, Tumor; Gemcitabine; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Pyrroles; Sirtuins; Xenograft Model Antitumor Assays
PubMed: 37542062
DOI: 10.1038/s41419-023-06018-1 -
BMJ Open Diabetes Research & Care Sep 2020Progressive distal symmetrical axonal neuropathy, a complication of diabetes mellitus (DM), has an unknown cause. Normal physiological metabolism and diabetic...
INTRODUCTION
Progressive distal symmetrical axonal neuropathy, a complication of diabetes mellitus (DM), has an unknown cause. Normal physiological metabolism and diabetic dysmetabolism are associated with the generation of γ-diketones. γ-Diketones form pyrroles with protein amines, notably with axonal proteins required for the maintenance of nerve fiber integrity, especially elongate, large-diameter peripheral nerve fibers innervating the extremities. We tested the hypothesis that neuropathy-associated γ-diketone pyrroles are elevated in DM.
RESEARCH DESIGN AND METHODS
We measured the urinary concentration of γ-diketone pyrroles in age-matched and gender-matched elderly (60-84 years) persons with (n=267) or without (n=267) indicators of DM based in a community population (9411 community older adults aged ≥60 years) in Shenzhen city, Guangdong, China. We used statistical methods, including a generalized linear model, multivariate logistic regression analysis and restricted cubic splines, to assess linear and nonlinear relationships between urinary γ-diketone pyrroles and indicators of DM.
RESULTS
Compared with healthy controls, those with DM had significantly higher levels of fasting blood glucose, glycated hemoglobin A1c, urinary ketone bodies and urinary γ-diketone pyrroles. The median concentration of urinary γ-diketone pyrrole adducts was significantly higher (p<0.0001) in individuals with DM (7.5 (5.4) μM) compared with healthy controls (5.9 (4.3) μM). Both linear and non-linear relations were found between urinary γ-diketone pyrroles and indicators of DM.
CONCLUSIONS
Diabetic dysmetabolism includes increased generation and excretion of neuropathy-associated γ-diketone pyrroles. These findings form the foundation for studies to test whether γ-diketone pyrrole concentration correlates with quantitative sensory (vibration and temperature) and electrodiagnostic testing.
Topics: Aged; Aged, 80 and over; Axons; China; Diabetes Mellitus; Humans; Middle Aged; Peripheral Nervous System Diseases; Pyrroles
PubMed: 32912928
DOI: 10.1136/bmjdrc-2020-001575 -
Microbiology Spectrum Jun 2022Typhoid fever is caused primarily by the enteric microbe Salmonella enterica serovar Typhi and remains a major global health problem with approximately 14 million new...
Typhoid fever is caused primarily by the enteric microbe Salmonella enterica serovar Typhi and remains a major global health problem with approximately 14 million new infections and 136,000 fatalities annually. While there are antibiotic options available to treat the disease, the global increase in multidrug-resistant strains necessitates alternative therapeutic options. Host-targeted therapeutics present a promising anti-infective strategy against intracellular bacterial pathogens. A cell-based assay identified a compound that inhibits proliferation in infected cells, 2-(3-hydroxypropyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione (KH-1), which is devoid of direct activity against . The compound inhibits the growth of both antibiotic-sensitive and -resistant strains inside macrophages and reduces lactate dehydrogenase (LDH) release from -infected cells. Subsequent screening of KH-1 commercial analogs identified 2-(4-fluorobenzyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c] pyrrole-3,9-dione (KH-1-2), which is more effective in controlling growth inside macrophages. KH-1-2 treatment of infection resulted in an 8- to 10-fold reduction in bacterial load in infected macrophages. In combination with suboptimal ciprofloxacin treatment, KH-1-2 further reduces growth inside macrophages. The toxicity and efficacy of KH-1-2 in controlling infection were examined using a mouse model of typhoid fever. No significant compound-related clinical signs and histological findings of the liver, spleen, or kidney were observed from uninfected mice that were intraperitoneally treated with KH-1-2. KH-1-2 significantly protected mice from a lethal dose of infection by an antibiotic-resistant strain. Thus, our study provides support that this is a promising lead compound for the development of a novel host-targeted therapeutic agent to control typhoid fever. spp. cause significant morbidity and mortality worldwide. Typhoidal spp. (e.g., Typhi) cause a systemic disease typically treated with antibiotics. However, growing antibiotic resistance is resulting in increased treatment failures. We screened a compound library for those that would reduce -induced macrophage toxicity, identifying compound KH-1. KH-1 has no direct effects on the bacteria but limits survival in macrophages and protects against lethal infection in a mouse model of typhoid fever. A suboptimal concentration of ciprofloxacin worked in conjunction with the compound to further decrease survival in macrophages. An analog (KH-1-2) was identified that possessed increased activity in macrophages and against both antibiotic-sensitive and -resistant strains. Thus, we report the identification of a lead compound that may be a useful scaffold as a host-directed antimicrobial against typhoid fever.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Ciprofloxacin; Humans; Pyrroles; Salmonella; Salmonella typhi; Typhoid Fever
PubMed: 35579463
DOI: 10.1128/spectrum.00619-22 -
Marine Drugs Oct 2013Dithiolopyrrolones are a class of antibiotics that possess the unique pyrrolinonodithiole (4H-[1,2] dithiolo [4,3-b] pyrrol-5-one) skeleton linked to two variable acyl... (Review)
Review
Dithiolopyrrolones are a class of antibiotics that possess the unique pyrrolinonodithiole (4H-[1,2] dithiolo [4,3-b] pyrrol-5-one) skeleton linked to two variable acyl groups. To date, there are approximately 30 naturally occurring dithiolopyrrolone compounds, including holomycin, thiolutin, and aureothricin, and more recently thiomarinols, a unique class of hybrid marine bacterial natural products containing a dithiolopyrrolone framework linked by an amide bridge with an 8-hydroxyoctanoyl chain linked to a monic acid. Generally, dithiolopyrrolone antibiotics have broad-spectrum antibacterial activity against various microorganisms, including Gram-positive and Gram-negative bacteria, and even parasites. Holomycin appeared to be active against rifamycin-resistant bacteria and also inhibit the growth of the clinical pathogen methicillin-resistant Staphylococcus aureus N315. Its mode of action is believed to inhibit RNA synthesis although the exact mechanism has yet to be established in vitro. A recent work demonstrated that the fish pathogen Yersinia ruckeri employs an RNA methyltransferase for self-resistance during the holomycin production. Moreover, some dithiolopyrrolone derivatives have demonstrated promising antitumor activities. The biosynthetic gene clusters of holomycin have recently been identified in S. clavuligerus and characterized biochemically and genetically. The biosynthetic gene cluster of thiomarinol was also identified from the marine bacterium Pseudoalteromonas sp. SANK 73390, which was uniquely encoded by two independent pathways for pseudomonic acid and pyrrothine in a novel plasmid. The aim of this review is to give an overview about the isolations, characterizations, synthesis, biosynthesis, bioactivities and mode of action of this unique family of dithiolopyrrolone natural products, focusing on the period from 1940s until now.
Topics: Anti-Bacterial Agents; Bacteria; Biological Products; Humans; Lactams; Mupirocin; Pyrroles; Pyrrolidinones; Sulfhydryl Compounds
PubMed: 24141227
DOI: 10.3390/md11103970 -
Molecules (Basel, Switzerland) Nov 2021The 3-hydroxy-1,5-dihydro-2-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in...
The 3-hydroxy-1,5-dihydro-2-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones-based compounds with a 3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones, 3-amino-1,5-dihydro-2-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones, which were prepared their reaction with carbodiimides.
Topics: Amination; Amines; Carbodiimides; Drug Discovery; Molecular Structure; Pyrroles
PubMed: 34885757
DOI: 10.3390/molecules26237179 -
Organic & Biomolecular Chemistry Jan 2016An efficient and selective approach for the synthesis of polyfunctionalised 3-fluoropyrroles has been developed starting from commercial aldehydes. The methodology is...
An efficient and selective approach for the synthesis of polyfunctionalised 3-fluoropyrroles has been developed starting from commercial aldehydes. The methodology is concise, efficient and allows for the modular and systematic assembly of polysubstituted 3-fluoropyrroles. This synthesis provides an alternative and highly convergent strategy for the generation of these chemically and biologically important units.
Topics: Hydrocarbons, Fluorinated; Molecular Structure; Pyrroles
PubMed: 26555030
DOI: 10.1039/c5ob02155c -
Natural Product Reports Aug 2017Covering: up to June 2017Natural products and endogenous metabolites engage specific targets within tissues and cells through complex mechanisms. This review examines... (Review)
Review
Covering: up to June 2017Natural products and endogenous metabolites engage specific targets within tissues and cells through complex mechanisms. This review examines the extent to which natural systems have adopted the Paal-Knorr reaction to engage nucleophilic amine groups within biological targets. Current understanding of this mode of reactivity is limited by only a few examples of this reaction in a biological context. This highlight is intended to stimulate the scientific community to identify potential research directions and applications of the Paal-Knorr reaction in native and engineered biological systems.
Topics: Biological Products; Molecular Structure; Pyrroles
PubMed: 28808718
DOI: 10.1039/c7np00024c -
BMC Veterinary Research Aug 2008Ingestion of the poisonous weed ragwort (Senecio jacobea) by horses leads to irreversible liver damage. The principal toxins of ragwort are the pyrrolizidine alkaloids...
BACKGROUND
Ingestion of the poisonous weed ragwort (Senecio jacobea) by horses leads to irreversible liver damage. The principal toxins of ragwort are the pyrrolizidine alkaloids that are rapidly metabolised to highly reactive and cytotoxic pyrroles, which can escape into the circulation and bind to proteins. In this study a non-invasive in vitro model system has been developed to investigate whether pyrrole toxins induce specific modifications of equine blood proteins that are detectable by proteomic methods.
RESULTS
One dimensional gel electrophoresis revealed a significant alteration in the equine plasma protein profile following pyrrole exposure and the formation of a high molecular weight protein aggregate. Using mass spectrometry and confirmation by western blotting the major components of this aggregate were identified as fibrinogen, serum albumin and transferrin.
CONCLUSION
These findings demonstrate that pyrrolic metabolites can modify equine plasma proteins. The high molecular weight aggregate may result from extensive inter- and intra-molecular cross-linking of fibrinogen with the pyrrole. This model has the potential to form the basis of a novel proteomic strategy aimed at identifying surrogate protein biomarkers of ragwort exposure in horses and other livestock.
Topics: Animals; Biomarkers; Blood Proteins; Blotting, Western; Fibrinogen; Hemoglobins; Horse Diseases; Horses; Plant Poisoning; Plants, Toxic; Proteomics; Pyrroles; Pyrrolizidine Alkaloids; Senecio; Time Factors
PubMed: 18691403
DOI: 10.1186/1746-6148-4-30 -
Biomolecules Apr 2020The high sequence specificity of minor groove-binding -methylpyrrole--methylimidazole polyamides have made significant advances in cancer and disease biology, yet there... (Review)
Review
The high sequence specificity of minor groove-binding -methylpyrrole--methylimidazole polyamides have made significant advances in cancer and disease biology, yet there have been few comprehensive reports on their off-target effects, most likely as a consequence of the lack of available tools in evaluating genomic binding, an essential aspect that has gone seriously underexplored. Compared to other -heterocycles, the off-target effects of these polyamides and their specificity for the DNA minor groove and primary base pair recognition require the development of new analytical methods, which are missing in the field today. This review aims to highlight the current progress in deciphering the off-target effects of these -heterocyclic molecules and suggests new ways that next-generating sequencing can be used in addressing off-target effects.
Topics: Amides; Animals; DNA; Genomics; Humans; Imidazoles; Pyrroles
PubMed: 32260120
DOI: 10.3390/biom10040544