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Molecules (Basel, Switzerland) Aug 2023Tolyporphins were discovered some 30 years ago as part of a global search for antineoplastic compounds from cyanobacteria. To date, the culture HT-58-2, comprised of a... (Review)
Review
Tolyporphins were discovered some 30 years ago as part of a global search for antineoplastic compounds from cyanobacteria. To date, the culture HT-58-2, comprised of a cyanobacterium-microbial consortium, is the sole known producer of tolyporphins. Eighteen tolyporphins are now known-each is a free base tetrapyrrole macrocycle with a dioxobacteriochlorin (14), oxochlorin (3), or porphyrin (1) chromophore. Each compound displays two, three, or four open β-pyrrole positions and two, one, or zero appended -glycoside (or -OH or -OAc) groups, respectively; the appended groups form part of a geminal disubstitution motif flanking the oxo moiety in the pyrroline ring. The distinct structures and repertoire of tolyporphins stand alone in the large pigments-of-life family. Efforts to understand the cyanobacterial origin, biosynthetic pathways, structural diversity, physiological roles, and potential pharmacological properties of tolyporphins have attracted a broad spectrum of researchers from diverse scientific areas. The identification of putative biosynthetic gene clusters in the HT-58-2 cyanobacterial genome and accompanying studies suggest a new biosynthetic paradigm in the tetrapyrrole arena. The present review provides a comprehensive treatment of the rich science concerning tolyporphins.
Topics: Tetrapyrroles; Cyanobacteria; Porphyrins; Cardiac Glycosides
PubMed: 37630384
DOI: 10.3390/molecules28166132 -
Nature Reviews. Clinical Oncology Sep 2023
Topics: Humans; Disease Progression; Pyrimidines; Pyrroles
PubMed: 37311901
DOI: 10.1038/s41571-023-00790-x -
The Journal of Organic Chemistry Jul 2023Herein, we report the total synthesis of nagelamide W (), a pyrrole imidazole alkaloid of the nagelamide family isolated in 2013. The key approach in this work involves...
Herein, we report the total synthesis of nagelamide W (), a pyrrole imidazole alkaloid of the nagelamide family isolated in 2013. The key approach in this work involves the construction of the 2-aminoimidazoline core of nagelamide W from alkene 6 through a cyanamide bromide intermediate. The synthesis of nagelamide W was accomplished with an overall yield of 6.0%.
Topics: Molecular Structure; Pyrroles; Alkaloids
PubMed: 37314002
DOI: 10.1021/acs.joc.3c00867 -
Pharmacology & Therapeutics Jan 2024Pexidartinib (PLX3397) is a small molecule receptor tyrosine kinase inhibitor of colony stimulating factor 1 receptor (CSF1R) with moderate selectivity over other... (Review)
Review
Pexidartinib (PLX3397) is a small molecule receptor tyrosine kinase inhibitor of colony stimulating factor 1 receptor (CSF1R) with moderate selectivity over other members of the platelet derived growth factor receptor family. It is approved for treatment of tenosynovial giant cell tumors (TGCT). CSF1R is highly expressed by microglia, which are macrophages of the central nervous system (CNS) that defend the CNS against injury and pathogens and contribute to synapse development and plasticity. Challenged by pathogens, apoptotic cells, debris, or inflammatory molecules they adopt a responsive state to propagate the inflammation and eventually return to a homeostatic state. The phenotypic switch may fail, and disease-associated microglia contribute to the pathophysiology in neurodegenerative or neuropsychiatric diseases or long-lasting detrimental brain inflammation after brain, spinal cord or nerve injury or ischemia/hemorrhage. Microglia also contribute to the growth permissive tumor microenvironment of glioblastoma (GBM). In rodents, continuous treatment for 1-2 weeks via pexidartinib food pellets leads to a depletion of microglia and subsequent repopulation from the remaining fraction, which is aided by peripheral monocytes that search empty niches for engraftment. The putative therapeutic benefit of such microglia depletion or forced renewal has been assessed in almost any rodent model of CNS disease or injury or GBM with heterogeneous outcomes, but a tendency of partial beneficial effects. So far, microglia monitoring e.g. via positron emission imaging is not standard of care for patients receiving Pexidartinib (e.g. for TGCT), so that the depletion and repopulation efficiency in humans is still largely unknown. Considering the virtuous functions of microglia, continuous depletion is likely no therapeutic option but short-lasting transient partial depletion to stimulate microglia renewal or replace microglia in genetic disease in combination with e.g. stem cell transplantation or as part of a multimodal concept in treatment of glioblastoma appears feasible. The present review provides an overview of the preclinical evidence pro and contra microglia depletion as a therapeutic approach.
Topics: Humans; Microglia; Glioblastoma; Aminopyridines; Pyrroles; Tumor Microenvironment
PubMed: 38052308
DOI: 10.1016/j.pharmthera.2023.108565 -
Journal of Cystic Fibrosis : Official... May 2024Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor/tezacaftor/ivacaftor (ETI), significantly improve outcomes and quality of...
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor/tezacaftor/ivacaftor (ETI), significantly improve outcomes and quality of life for people with cystic fibrosis (CF). However, little is known about how lung transplant recipients (LTRs) perceive the use of ETI. We conducted a survey to assess perspectives on ETI among LTRs with CF at our lung transplant program. Of 81 CF LTRs, 46 participants (58 %) responded. The majority of respondents (88 %) were aware of ETI. Over 80 % considered treating non-lung symptoms of CF to be very important. Concerns regarding ETI included potential drug interactions with transplant medications (77 %), side effects (53 %), cost of medication (49 %), and lack of clinical trial data for LTRs (43 %). Half reported they would only consider taking ETI if their CF or transplant doctor recommended it. The findings suggest that CF LTRs seek informational support and shared decision-making about ETI from their clinicians.
Topics: Humans; Lung Transplantation; Cystic Fibrosis; Benzodioxoles; Female; Male; Indoles; Adult; Aminophenols; Quinolones; Pyridines; Pyrazoles; Chloride Channel Agonists; Pyrroles; Drug Combinations; Middle Aged; Transplant Recipients; Quality of Life; Surveys and Questionnaires; Pyrrolidines
PubMed: 37798159
DOI: 10.1016/j.jcf.2023.09.017 -
JAAPA : Official Journal of the... Sep 2023Acute migraine affects millions of people and is one of the most common primary care complaints in the United States. Available first-line abortive treatments are...
Acute migraine affects millions of people and is one of the most common primary care complaints in the United States. Available first-line abortive treatments are limited and vary in efficacy. Newer medications such as calcitonin gene-related peptide (CGRP) receptor antagonists may be a useful alternative. This article describes the use of ubrogepant, a new CGRP receptor antagonist, in a patient with contraindications to traditional medications used for acute migraine.
Topics: Humans; Pyridines; Pyrroles; Migraine Disorders
PubMed: 37668477
DOI: 10.1097/01.JAA.0000931424.73007.a5 -
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 Annals of Pharmacotherapy Oct 2023To describe the pharmacology, efficacy, safety, and potential role of vonoprazan with amoxicillin or amoxicillin and clarithromycin for the treatment of infection in... (Review)
Review
OBJECTIVES
To describe the pharmacology, efficacy, safety, and potential role of vonoprazan with amoxicillin or amoxicillin and clarithromycin for the treatment of infection in adults.
DATA SOURCES
PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched using the terms: (vonoprazan OR voquezna) AND ("" OR "") AND amoxicillin with no date limitations up to November 3, 2022.
STUDY SELECTION AND DATA EXTRACTION
Studies assessing the efficacy and safety of vonoprazan with amoxicillin and/or clarithromycin were included and divided into 3 groups based on different comparisons between treatment regimens used in each group.
DATA SYNTHESIS
Ten clinical trials and 17 observational studies were included. Vonoprazan-based therapy demonstrated greater acid inhibition and similar or higher efficacy than proton-pump inhibitor (PPI)-based therapy in treatment-naïve patients and with clarithromycin-resistant infections.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Proton-pump inhibitor-based therapies have not reached the desired successful eradication rate of 90% for infection. Vonoprazan-based therapies being at least as effective as PPI-based therapies offer an alternative for patients with infection.
CONCLUSION
Vonoprazan-based therapies were effective and well tolerated for the treatment of infection in adults. These regimens provide an important alternative with prolonged acid inhibition, lower potential for CYP2C19 polymorphism, and at least comparable efficacy and safety versus PPI-based therapies in patients with infections. Thus, vonoprazan-based therapy should be considered for certain patients, for example, those with failure to PPI-based treatments.
Topics: Adult; Humans; Clarithromycin; Amoxicillin; Helicobacter Infections; Anti-Bacterial Agents; Proton Pump Inhibitors; Drug Therapy, Combination; Helicobacter pylori; Pyrroles; Treatment Outcome
PubMed: 36688309
DOI: 10.1177/10600280221149708 -
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 -
Alimentary Pharmacology & Therapeutics Dec 2023
Topics: Humans; Gastroesophageal Reflux; Proton Pump Inhibitors; Pyrroles; Sulfonamides
PubMed: 37986601
DOI: 10.1111/apt.17737