-
Natural Product Reports Jul 2014Covering: up to 2014. Dithiolopyrrolone (DTP) group antibiotics were first isolated in the early half of the 20th century, but only recently has research been reawakened... (Review)
Review
Covering: up to 2014. Dithiolopyrrolone (DTP) group antibiotics were first isolated in the early half of the 20th century, but only recently has research been reawakened by insights gained from the synthesis and biosynthesis of this structurally intriguing class of molecules. DTPs are characterized by an electronically unique bicyclic structure, which contains a compact disulfide bridge between two ene-thiols. Points of diversity within the compound class occur outside of the bicyclic core, at the two amide nitrogens. Such modifications distinguish three of the most well studied members of the class, holomycin, thiolutin, and aureothricin; the DTP core has also more recently been identified in the marine antibiotic thiomarinol, in which it is linked to a marinolic acid moiety, analog of the FDA-approved topical antibiotic Bactroban® (GlaxoSmithKline). Dithiolopyrrolones exhibit relatively broad-spectrum antibiotic activity against many Gram-positive and Gram-negative bacteria, as well as strains of Mycobacterium tuberculosis. Additionally, they have been shown to exhibit potent and selective anti-cancer activity. Despite this promising profile, there is still much unknown about the mechanisms of action for DTPs. Early reports suggested that they inhibit yeast growth at the level of transcription and that this effect is largely responsible for their distinctive microbial static properties; a similar mechanism is supported in bacteria. Elucidation of biosynthetic pathways for holomycin in Streptomyces clavuligerus and Yersinia ruckeri and thiomarinol in Alteromonas rava sp. nov. SANK 73390, have contributed evidence suggesting that multiple mechanisms may be operative in the activity of these compounds. This review will comprehensively cover the history and development of dithiolopyrrolones with particular emphasis on the biosynthesis, synthesis, biological activity and mechanism of action.
Topics: Anti-Bacterial Agents; Biological Products; Disulfides; Molecular Structure; Pyrroles; Sulfhydryl Compounds
PubMed: 24835149
DOI: 10.1039/c3np70106a -
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 -
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 -
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 -
World Journal of Gastroenterology Apr 2019() antimicrobial resistance is an urgent, global issue. In 2017, the World Health Organization designated clarithromycin-resistant as a high priority bacterium for... (Review)
Review
() antimicrobial resistance is an urgent, global issue. In 2017, the World Health Organization designated clarithromycin-resistant as a high priority bacterium for antibiotic research and development. In addition to clarithromycin, resistance to metronidazole and fluoroquinolones has also increased worldwide. Recent international guidelines for management of infection recommend bismuth or non-bismuth quadruple therapy for 14 d as a first-line treatment for in areas of high clarithromycin and/or metronidazole resistance. Although these treatment regimens provide acceptable eradication rates, the regimens used should not contribute to future resistance of to antimicrobials. Moreover, these regimens can promote resistance, due to prolonged therapy with multiple antibiotics. A new strategy that can eradicate as well as reduce the antibiotics used is required to prevent future antimicrobial resistance in . Dual-therapy with vonoprazan and amoxicillin could be a breakthrough for eradication in an era of growing antimicrobial resistance. This regimen may provide a satisfactory eradication rate of and also minimize antimicrobial resistance due to single antibiotic use and the strong inhibitory effect of vonoprazan on gastric acid secretion.
Topics: Amoxicillin; Antacids; Anti-Bacterial Agents; Bismuth; Disease Eradication; Drug Resistance, Bacterial; Drug Therapy, Combination; Helicobacter Infections; Helicobacter pylori; Humans; Proton Pump Inhibitors; Pyrroles; Sulfonamides; Time Factors
PubMed: 31086459
DOI: 10.3748/wjg.v25.i16.1907 -
Chemistry (Weinheim An Der Bergstrasse,... Jan 2020Dearomatisation of indole derivatives to the corresponding isatin derivatives has been achieved with the aid of visible light and oxygen. It should be noted that isatin...
Dearomatisation of indole derivatives to the corresponding isatin derivatives has been achieved with the aid of visible light and oxygen. It should be noted that isatin derivatives are highly important for the synthesis of pharmaceuticals and bioactive compounds. Notably, this chemistry works excellently with N-protected and protection-free indoles. Additionally, this methodology can also be applied to dearomatise pyrrole derivatives to generate cyclic imides in a single step. Later this methodology was applied for the synthesis of four pharmaceuticals and a pesticide called dianthalexin B. Detailed mechanistic studies revealed the actual role of oxygen and photocatalyst.
Topics: Catalysis; Imides; Indoles; Light; Pesticides; Pharmaceutical Preparations; Pyrroles
PubMed: 31596010
DOI: 10.1002/chem.201904168 -
Molecules (Basel, Switzerland) Jun 2021Novel symmetrical bis-pyrrolo[2,3-]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung...
Novel symmetrical bis-pyrrolo[2,3-]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-]pyrimidine monomer with 4,4'-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.
Topics: A549 Cells; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cycloaddition Reaction; Density Functional Theory; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Pyrimidines; Pyrroles
PubMed: 34206076
DOI: 10.3390/molecules26113334 -
Drug Design, Development and Therapy 2016The outlook for patients with psoriasis has improved significantly over the last 10 years with the introduction of targeted therapies. Cytokines exert their effects by... (Review)
Review
The outlook for patients with psoriasis has improved significantly over the last 10 years with the introduction of targeted therapies. Cytokines exert their effects by activating intracellular signaling and transcription pathways, among which there are Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) pathways. JAKs are intracellular second messengers that are crucial for transmitting extracellular cytokine signals to the cell. JAK inhibition interrupts intracellular signaling and can suppress immune cell activation and inflammation in T-cell-mediated disorders, such as psoriasis. Consequently, JAKs are the subject of intensive research activity, since they represent possible therapeutic targets. Tofacitinib is an orally available compound belonging to a novel category of nonbiologic drugs, the "JAK inhibitors", which target JAKs. Recently, oral and topical formulations of tofacitinib have been demonstrated to be safe and effective for the treatment of plaque psoriasis in randomized clinical trials. In particular, a 10 mg bid dose of tofacitinib was shown to be noninferior to etanercept 50 mg subcutaneously twice weekly. Questions remain unresolved regarding the safety risk beyond the 5 mg bid dose. This review, assessing the available scientific literature, focuses on the profile of tofacitinib, as investigational compound in the treatment of plaque psoriasis. An overview of the efficacy and safety data from randomized clinical trials is provided. In addition, the authors highlight future potential applications of tofacitinib in other skin diseases, in particular alopecia areata and vitiligo.
Topics: Chronic Disease; Clinical Trials as Topic; Humans; Janus Kinase 3; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles
PubMed: 26889081
DOI: 10.2147/DDDT.S82599 -
Marine Drugs Mar 2022Two new cyclized thiolopyrrolone derivatives, namely, thiolopyrrolone A () and 2,2-dioxidothiolutin (), together with the kn own compound, thiolutin () were identified...
Two new cyclized thiolopyrrolone derivatives, namely, thiolopyrrolone A () and 2,2-dioxidothiolutin (), together with the kn own compound, thiolutin () were identified from a marine-derived sp. BTBU20218885, which was isolated from a mud sample collected from the coastal region of Xiamen, China. Their chemical structures were determined using spectroscopic data, including HRESIMS, 1D and 2D NMR techniques. possessed a unique unsymmetrical sulfur-containing thiolopyrrolone structure. All the compounds were tested for bioactivities against , , Bacille Calmette-Guérin (BCG), , and . displayed antibacterial activities against BCG, , and with minimum inhibitory concentration (MIC) values of 10, 10, and 100 μg/mL, respectively. Thiolutin () showed antibacterial activities against , BCG, , and with MIC values of 6.25, 0.3125, 0.625, and 3.125 μg/mL, respectively.
Topics: Anti-Infective Agents; Aquatic Organisms; Biological Products; Candida albicans; Cyclization; Microbial Sensitivity Tests; Pyrroles; Streptomyces
PubMed: 35323513
DOI: 10.3390/md20030214 -
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