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Digestive Diseases and Sciences Jul 2016
Topics: Humans; Proton Pump Inhibitors; Pyrroles; Sulfonamides
PubMed: 27074922
DOI: 10.1007/s10620-016-4164-8 -
Angewandte Chemie (International Ed. in... Dec 2018Herein we report the biocatalytic synthesis of substituted pyrazines and pyrroles using a transaminase (ATA) to mediate the key amination step of the ketone precursors....
Herein we report the biocatalytic synthesis of substituted pyrazines and pyrroles using a transaminase (ATA) to mediate the key amination step of the ketone precursors. Treatment of α-diketones with ATA-113 in the presence of a suitable amine donor yielded the corresponding α-amino ketones which underwent oxidative dimerization to the pyrazines. Selective amination of α-diketones in the presence of β-keto esters afforded substituted pyrroles in a biocatalytic equivalent of the classical Knorr pyrrole synthesis. Finally we have shown that pyrroles can be prepared by internal amine transfer catalyzed by a transaminase in which no external amine donor is required.
Topics: Molecular Structure; Pyrazines; Pyrroles; Transaminases
PubMed: 30335228
DOI: 10.1002/anie.201810555 -
Microbiology Spectrum Apr 2022Due to the emergence of multidrug-resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at...
Antifungal Activity of Fibrate-Based Compounds and Substituted Pyrroles That Inhibit the Enzyme 3-Hydroxy-methyl-glutaryl-CoA Reductase of (CgHMGR), Thus Decreasing Yeast Viability and Ergosterol Synthesis.
Due to the emergence of multidrug-resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of three different series of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase and thus affect ergosterol synthesis and yeast viability. Compounds 1c (α-asarone-related) and 5b (with a pyrrolic core) were selected as the best antifungal candidates among over 20 synthetic compounds studied. Both inhibited the growth of fluconazole-resistant and fluconazole-susceptible C. glabrata strains. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway. A greater recovery of yeast growth occurred for the C. glabrata 43 fluconazole-resistant (versus fluconazole-susceptible) strain and after treatment with 1c (versus 5b). Given that the compounds decreased the concentration of ergosterol in the yeast strains, they probably target ergosterol synthesis. According to the docking analysis, the inhibitory effect of 1c and 5b could possibly be mediated by their interaction with the amino acid residues of the catalytic site of the enzyme. Since 1c displayed higher binding energy than α-asarone and 5b, it is the best candidate for further research, which should include structural modifications to increase its specificity and potency. The derivatives could then be examined with animal models using a therapeutic dose. Within the context of the COVID-19 pandemic, there is currently an epidemiological alert in health care services due to outbreaks of Candida auris, Candida glabrata, and other fungal species multiresistant to conventional antifungals. Therefore, it is important to propose alternative molecular targets, as well as new antifungals. The three series of synthetic compounds herein designed and synthesized are inhibitors of ergosterol synthesis in yeasts. Of the more than 20 compounds studied, two were selected as the best antifungal candidates. These compounds were able to inhibit the growth and synthesis of ergosterol in C. glabrata strains, whether susceptible or resistant to fluconazole. The rational design of antifungal compounds derived from clinical drugs (statins, fibrates, etc.) has many advantages. Future studies are needed to modify the structure of the two present test compounds to obtain safer and less toxic antifungals. Moreover, it is important to carry out a more in-depth mechanistic approach.
Topics: Acyl Coenzyme A; Animals; Antifungal Agents; COVID-19; Candida glabrata; Drug Resistance, Fungal; Ergosterol; Fibric Acids; Fluconazole; Humans; Hydroxymethylglutaryl CoA Reductases; Microbial Sensitivity Tests; Pandemics; Pyrroles
PubMed: 35377226
DOI: 10.1128/spectrum.01642-21 -
Molecules (Basel, Switzerland) Dec 2015The emergence of antibiotic resistance is currently considered one of the most important global health problem. The continuous onset of multidrug-resistant Gram-positive... (Review)
Review
The emergence of antibiotic resistance is currently considered one of the most important global health problem. The continuous onset of multidrug-resistant Gram-positive and Gram-negative bacterial strains limits the clinical efficacy of most of the marketed antibiotics. Therefore, there is an urgent need for new antibiotics. Pyrrolomycins are a class of biologically active compounds that exhibit a broad spectrum of biological activities, including antibacterial, antifungal, anthelmintic, antiproliferative, insecticidal, and acaricidal activities. In this review we focus on the antibacterial activity and antibiofilm activity of pyrrolomycins against Gram-positive and Gram-negative pathogens. Their efficacy, combined in some cases with a low toxicity, confers to these molecules a great potential for the development of new antimicrobial agents to face the antibiotic crisis.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Biofilms; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Pyrroles
PubMed: 26690095
DOI: 10.3390/molecules201219797 -
Drug Discovery Today. Technologies Apr 2019The Ubiquitin/Proteasome System comprises an essential cellular mechanism for regulated protein degradation. Ubiquitination may also promote the assembly of protein... (Review)
Review
The Ubiquitin/Proteasome System comprises an essential cellular mechanism for regulated protein degradation. Ubiquitination may also promote the assembly of protein complexes that initiate intracellular signaling cascades. Thus, proper regulation of substrate protein ubiquitination is essential for maintaining normal cellular physiology. Deubiquitinases are the class of enzymes responsible for removing ubiquitin modifications from target proteins and have been implicated in regulating human disease. As such, deubiquitinases are now recognized as emerging drug targets. Small molecule deubiquitinase inhibitors have been developed; among those, inhibitors for the deubiquitinases USP7 and USP14 are the best-characterized given that they are structurally validated. In this review we discuss the normal physiological roles of the USP7 and USP14 deubiquitinases as well as the pathological conditions associated with their dysfunction, with a focus on oncology and neurodegenerative diseases. We also review structural biology of USP7 and USP14 enzymes and the characterization of their respective inhibitors, highlighting the various molecular mechanisms by which these deubiquitinases may be functionally inhibited. Finally, we summarize the cellular and in vivo studies performed using the structurally-validated USP7 and USP14 inhibitors.
Topics: Animals; Humans; Molecular Structure; Pyrroles; Ubiquitin Thiolesterase
PubMed: 31200854
DOI: 10.1016/j.ddtec.2019.02.003 -
Nanomedicine (London, England) Oct 2020This article is written to provide an up-to-date review of pyrrole-based biomedical materials. Porphyrins and other tetrapyrrolic molecules possess unique magnetic,... (Review)
Review
This article is written to provide an up-to-date review of pyrrole-based biomedical materials. Porphyrins and other tetrapyrrolic molecules possess unique magnetic, optical and other photophysical properties that make them useful for bioimaging and therapy. This review touches briefly on some of the synthetic strategies to obtain porphyrin- and tetrapyrrole-based nanoparticles, as well as the variety of applications in which crosslinked, self-assembled, porphyrin-coated and other nanoparticles are utilized. We explore examples of these nanoparticles' applications in photothermal therapy, drug delivery, photodynamic therapy, stimuli response, fluorescence imaging, photoacoustic imaging, magnetic resonance imaging, computed tomography and positron emission tomography. We anticipate that this review will provide a comprehensive summary of pyrrole-derived nanoparticles and provide a guideline for their further development.
Topics: Nanoparticles; Optical Imaging; Photochemotherapy; Porphyrins; Pyrroles
PubMed: 32975469
DOI: 10.2217/nnm-2020-0125 -
Angiogenesis Oct 2015To improve the efficacy of radiotherapy (RTx), there is a growing interest in combining RTx with drugs that inhibit angiogenesis, i.e., the process of neo-vessel... (Review)
Review
To improve the efficacy of radiotherapy (RTx), there is a growing interest in combining RTx with drugs that inhibit angiogenesis, i.e., the process of neo-vessel formation out of preexisting capillaries. A frequently used drug to inhibit angiogenesis is sunitinib (Sutent, SU11248), a receptor tyrosine kinase inhibitor that is currently FDA approved for the treatment of several cancer types. The current review presents an overview of the preclinical studies and clinical trials that combined sunitinib with RTx. We discuss the findings from preclinical and clinical observations with a focus on dose scheduling and commonly reported toxicities. In addition, the effects of combination therapy on tumor response and patient survival are described. Finally, the lessons learned from preclinical and clinical studies are summarized and opportunities and pitfalls for future clinical trials are presented.
Topics: Animals; Chemoradiotherapy; Humans; Indoles; Neoplasms; Neovascularization, Pathologic; Pyrroles; Sunitinib
PubMed: 26202788
DOI: 10.1007/s10456-015-9476-3 -
Molecules (Basel, Switzerland) Aug 2022Bionanocomposites based on natural bioactive entities have gained importance due to their abundance; renewable and environmentally benign nature; and outstanding... (Review)
Review
Bionanocomposites based on natural bioactive entities have gained importance due to their abundance; renewable and environmentally benign nature; and outstanding properties with applied perspective. Additionally, their formulation with biological molecules with antimicrobial, antioxidant, and anticancer activities has been produced nowadays. The present review details the state of the art and the importance of this pyrrolic compound produced by microorganisms, with interest towards , including production strategies at a laboratory level and scale-up to bioreactors. Promising results of its biological activity have been reported to date, and the advances and applications in bionanocomposites are the most recent strategy to potentiate and to obtain new carriers for the transport and controlled release of prodigiosin. Prodigiosin, a bioactive secondary metabolite, produced by , is an effective proapoptotic agent against bacterial and fungal strains as well as cancer cell lines. Furthermore, this molecule presents antioxidant activity, which makes it ideal for treating wounds and promoting the general improvement of the immune system. Likewise, some of the characteristics of prodigiosin, such as hydrophobicity, limit its use for medical and biotechnological applications; however, this can be overcome by using it as a component of a bionanocomposite. This review focuses on the chemistry and the structure of the bionanocomposites currently developed using biorenewable resources. Moreover, the work illuminates recent developments in pyrrole-based bionanocomposites, with special insight to its application in the medical area.
Topics: Anti-Bacterial Agents; Bioreactors; Nanocomposites; Prodigiosin; Serratia marcescens
PubMed: 35956931
DOI: 10.3390/molecules27154982 -
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 -
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