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Marine Drugs Oct 2012Capoamycin-type antibiotics (2-5) and polyene acids (6, 7) were isolated from marine Streptomyces fradiae strain PTZ0025. Their structures were established by extensive...
Capoamycin-type antibiotics (2-5) and polyene acids (6, 7) were isolated from marine Streptomyces fradiae strain PTZ0025. Their structures were established by extensive nuclear magnetic resonance (NMR) and high resolution electron spray ionization mass spectroscopy (HRESIMS) analyses and chemical degradation. Compounds 3, 4, 6, 7 were found to be new and named as fradimycins A (3) and B (4), and fradic acids A (6) and B (7). Compounds 3-5 showed in vitro antimicrobial activity against Staphylococcus aureus with a minimal inhibitory concentration (MIC) of 2.0 to 6.0 μg/mL. Interestingly, Compounds 3-5 also significantly inhibited cell growth of colon cancer and glioma with IC₅₀ values ranging from 0.13 to 6.46 μM. Fradimycin B (4), the most active compound, was further determined to arrest cell cycle and induce apoptosis in tumor cells. The results indicated that fradimycin B (4) arrested the cell cycle at the G₀/G₁ phase and induced apoptosis and necrosis in colon cancer and glioma cells. Taken together, the results demonstrated that the marine natural products 3-5, particularly fradimycin B (4), possessed potent antimicrobial and antitumor activities.
Topics: Animals; Anthraquinones; Anti-Bacterial Agents; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Colonic Neoplasms; Glioma; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Polyenes; Rats; Spectrometry, Mass, Electrospray Ionization; Staphylococcus aureus; Streptomyces
PubMed: 23203266
DOI: 10.3390/md10112388 -
Clinical Microbiology and Infection :... Jan 2003The vast number and variety of chemotherapeutic agents isolated from microbial natural products and used to treat bacterial infections have greatly contributed to the... (Review)
Review
The vast number and variety of chemotherapeutic agents isolated from microbial natural products and used to treat bacterial infections have greatly contributed to the improvement of human health during the past century. However, only a limited number of antifungal agents (polyenes and azoles, plus the recently introduced caspofungin acetate) are currently available for the treatment of life-threatening fungal infections. Furthermore, the prevalence of systemic fungal infections has increased significantly during the past decade. For this reason, the development of new antifungal agents, preferably with novel mechanisms of action, is an urgent medical need. A selection of antifungal agents in early stages of development, produced by micro-organisms, is summarized in this review. The compounds are classified according to their mechanisms of action, covering inhibitors of the synthesis of cell wall components (glucan, chitin and mannoproteins), of sphingolipid synthesis (serine palmitoyltransferase, ceramide synthase, inositol phosphoceramide synthase and fatty acid elongation) and of protein synthesis (sordarins). In addition, some considerations related to the chemotaxonomy of the producing organisms and some issues relevant to antifungal drug discovery are also discussed.
Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Azoles; Biological Products; Caspofungin; Chitin; Echinocandins; Glucans; Humans; Lipopeptides; Membrane Glycoproteins; Mycoses; Peptides; Peptides, Cyclic; Polyenes; Protein Synthesis Inhibitors; Sphingolipids
PubMed: 12691539
DOI: 10.1046/j.1469-0691.2003.00489.x -
Revista Espanola de Quimioterapia :... Nov 2023New antifungal agents are needed to overcome limitations of available ones such as poor pharmacokinetic traits, toxicity, drug-drug interactions, limited clinical... (Review)
Review
New antifungal agents are needed to overcome limitations of available ones such as poor pharmacokinetic traits, toxicity, drug-drug interactions, limited clinical efficacy, and emerging antifungal resistance. New antifungal drugs belong to well-known families (azoles, polyenes, or beta-d-glucan synthase inhibitors) or to drug families showing completely new mechanisms of action. Some drugs have a head start in terms of potential to reach the clinical setting and are here reviewed.
Topics: Humans; Antifungal Agents; Mycoses; Azoles; Drug Resistance, Fungal; Polyenes
PubMed: 37997874
DOI: 10.37201/req/s01.14.2023 -
Future Medicinal Chemistry Jan 2014Invasive fungal infections are associated with very high mortality rates ranging from 20-90% for opportunistic fungal pathogens such as Candida albicans, Cryptococcus... (Review)
Review
Invasive fungal infections are associated with very high mortality rates ranging from 20-90% for opportunistic fungal pathogens such as Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. Fungal resistance to antimycotic treatment can be genotypic (due to resistant strains) as well as phenotypic (due to more resistant fungal lifestyles, such as biofilms). With regard to the latter, biofilms are considered to be critical in the development of invasive fungal infections. However, there are only very few antimycotics, such as miconazole (azoles), echinocandins and liposomal formulations of amphotericin B (polyenes), which are also effective against fungal biofilms. Interestingly, these antimycotics all induce reactive oxygen species (ROS) in fungal (biofilm) cells. This review provides an overview of the different classes of antimycotics and novel antifungal compounds that induce ROS in fungal planktonic and biofilm cells. Moreover, different strategies to further enhance the antibiofilm activity of such ROS-inducing antimycotics will be discussed.
Topics: Antifungal Agents; Azoles; Biofilms; Drug Resistance, Fungal; Echinocandins; Fungi; Polyenes; Reactive Oxygen Species
PubMed: 24358949
DOI: 10.4155/fmc.13.189 -
Organic Letters Mar 2021Although substituted benzimidazoles are common substructures in bioactive small molecules, synthetic methods for their derivatization are still limited. Previously,...
Although substituted benzimidazoles are common substructures in bioactive small molecules, synthetic methods for their derivatization are still limited. Previously, several enantioselective allylation reactions of benzimidazoles were reported that functionalize the nucleophilic nitrogen atom. Herein we describe a reversal of this inherent selectivity toward -allylation by using electrophilic -OPiv benzimidazoles with readily available 1,3-dienes as nucleophile precursors. This CuH-catalyzed approach utilizes mild reaction conditions, exhibits broad functional-group compatibility, and exclusively forms the C2-allylated product with excellent stereoselectivity.
Topics: Allyl Compounds; Benzimidazoles; Catalysis; Copper; Molecular Structure; Polyenes; Stereoisomerism
PubMed: 33646778
DOI: 10.1021/acs.orglett.1c00306 -
Biology of Blood and Marrow... Feb 2004Invasive fungal infections pose major management problems for clinicians caring for hematopoietic cell transplant patients. Two major fungal genera, Candida and... (Review)
Review
Invasive fungal infections pose major management problems for clinicians caring for hematopoietic cell transplant patients. Two major fungal genera, Candida and Aspergillus, account for most fungal infections. Rates of systemic Candida infection range from 15% to 25%, mostly in the pre-engraftment period. Prophylaxis by fluconazole has dramatically reduced the frequency of early Candida infections. Caspofungin has recently been shown to offer an excellent alternative to amphotericin B (with less toxicity) or fluconazole (with a broader spectrum) for therapy of systemic Candida infections. Aspergillus infections occur in 15% to 20% of allogeneic hematopoietic cell transplant patients, most frequently in the post-engraftment period; they are associated with a severe diminution of cell-mediated immune responses by graft-versus-host disease and prolonged corticosteroid use. Voriconazole, a recently introduced broad-spectrum azole, has excellent activity against Aspergillus and is generally well tolerated. Voriconazole currently offers the best prospect for success and tolerance as a first-line treatment for aspergillosis. Second-line therapies include lipid formulations of amphotericin B, caspofungin, or intravenous itraconazole. Unfortunately, early initiation of therapy for aspergillosis is frequently not possible because of inaccurate diagnostics. One new diagnostic, the galactomannan assay, has recently been approved, and others are in development; these offer promise for earlier diagnosis without the need for invasive procedures. It is hoped that these new therapies and new diagnostics will usher in a new era of antifungal therapy.
Topics: Antifungal Agents; Azoles; Echinocandins; Fungal Proteins; Hematopoietic Stem Cell Transplantation; Humans; Mycoses; Nucleosides; Peptides; Peptides, Cyclic; Polyenes
PubMed: 14750074
DOI: 10.1016/j.bbmt.2003.09.014 -
The Journal of Organic Chemistry Feb 2021Systematic evaluation of 1,5-dienes bearing 3,3-electron-withdrawing groups and 4-methylation results in the discovery of a Cope rearrangement for Meldrum's...
Systematic evaluation of 1,5-dienes bearing 3,3-electron-withdrawing groups and 4-methylation results in the discovery of a Cope rearrangement for Meldrum's acid-containing substrates that have unexpectedly favorable kinetic and thermodynamic profiles. The protocol is quite general due to a concise and convergent synthesis from abundant starting materials. Furthermore, products with an embedded Meldrum's acid moiety are prepared, which, in turn, can yield complex amides under neutral conditions. We have now expanded the scope of the reductive Cope rearrangement, which, via chemoselective reduction, can promote thermodynamically unfavorable [3,3] sigmatropic rearrangements of 3,3-dicyano-1,5-dienes to form reduced Cope rearrangement products. The Cope rearrangement is found to be stereospecific and can yield enantioenriched building blocks when chiral, nonracemic 1,3-disubstituted allylic electrophiles are utilized. We expand further the use of Cope rearrangements for the synthesis of highly valuable building blocks for complex- and drug-like molecular synthesis.
Topics: Kinetics; Polyenes; Thermodynamics
PubMed: 33476142
DOI: 10.1021/acs.joc.0c02690 -
Molecules (Basel, Switzerland) Jun 2019is a small but well-known genus of actinomycetes for production of ansamitocin, the payload component of antibody-drug conjugates against cancers. However, the...
is a small but well-known genus of actinomycetes for production of ansamitocin, the payload component of antibody-drug conjugates against cancers. However, the secondary metabolite production profile of ATCC 31565, the most famous producer of ansamitocin, has never been fully explored. Our antiSMASH analysis of the genomic DNA of ATCC 31565 revealed a NRPS-PKS gene cluster for polyene macrolactam. The gene cluster is very similar to gene clusters for mirilactam and salinilactam, two 26-membered polyene macrolactams from and , respectively. Guided by this bioinformatics prediction, we characterized a novel 26-membered polyene macrolactam from ATCC 31565 and designated it pretilactam. The structure of pretilactam was elucidated by a comprehensive analysis of HRMS, 1D and 2D-NMR, with absolute configuration of chiral carbons predicted bioinformatically. Pretilactam features a dihydroxy tetrahydropyran moiety, and has a hexaene unit and a diene unit as its polyene system. A preliminary antibacterial assay indicated that pretilactam is inactive against and .
Topics: Actinobacteria; Biosynthetic Pathways; Chromatography, Liquid; Genes, Bacterial; Genome, Bacterial; Genome-Wide Association Study; Lactams; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Multigene Family; Open Reading Frames; Polyenes; Secondary Metabolism
PubMed: 31248172
DOI: 10.3390/molecules24122281 -
Nihon Ishinkin Gakkai Zasshi = Japanese... 2000Cell walls (0.1-0.5 microm in thickness) of dermatophytes, at least Trichophyton mentagrophytes and Epidermophyton floccosum, are built of microfibrils (20 nm in... (Review)
Review
Cell walls (0.1-0.5 microm in thickness) of dermatophytes, at least Trichophyton mentagrophytes and Epidermophyton floccosum, are built of microfibrils (20 nm in diameter) and matrix embedding the fibrils. These fibrils are composed of chitin (70-80%) and a small amount of glucans, and the matrix is composed of beta-1-3, beta1-6 glucan, glucomannan, galactomannan and peptides. Another characteristic structure is the outermost layer (20-50 nm in thickness) of the cell wall, which consists of hydrophobic protein rodlets. Lipids are thought to play important roles in the regulation of dimorphism and virulence in pathogenic fungus. Generally, the ratio of phospholipid/ergosterol is less than 1 in yeast form and 2-20 in mycelial form cells in Candida albicans and Sporothrix schenckii. During the transition from yeast to mycelial forms, phosphatidylinositol and phosphatidylserine are reduced, whereas phosphatidylcholine increases. Phospho-lipase D is activated on this transition. Phospholipase B is now known to be a virulence factor in C. albicans. Polyene antifungal agents bind to ergosterol in membrane to form complexes, which generate pores and destroy the structures and functions of membrane. Azole antifungal agents inhibit the synthesis of ergosterol leading to deficiency in ergosterol content in membrane, and impair the function of membranes in fungal cells. We show the effects of polyenes on the ultrastructure of fungal plasma membrane and impairment of ionomycin-induced calcium influx in T. mentagrophytes, so that we can compare the differences in mode of actions between these two groups of agents.
Topics: Antifungal Agents; Arthrodermataceae; Azoles; Calcium; Cell Wall; Chitin; Ergosterol; Glucans; Lysophospholipase; Membrane Lipids; Polyenes; Virulence
PubMed: 11064317
DOI: No ID Found -
Journal of Pharmacy & Pharmaceutical... 2003The purpose of this review article is to review the development of a number of liposomal polyene antibiotics. (Review)
Review
PURPOSE
The purpose of this review article is to review the development of a number of liposomal polyene antibiotics.
BACKGROUND
In the past thirty years, the increase in life-threatening pre-systemic and systemic fungal infections within cancer, diabetic and AIDS patients have reached alarming proportions. A number of antifungal agents have been developed to combat this problem. In particular, polyene antibiotics such as Amphotericin B (AmB) and Nystatin (Nys) have remained the most effective and widely used agents in the treatment of these infections. However, their administration is limited by dose-dependent toxicities. One such dose-limiting toxicity is renal toxicity. Polyene antibiotic-induced renal toxicity is believed to be mediated by the drug anchoring to cholesterol within the mammalian cell membrane, resulting in pore formation, abnormal electrolyte flux, decrease in adenosine triphosphate (ATP), and eventually a loss of cell viability.
CONCLUSION
In the 1980s and 90s a number of promising lipid-based AmB and Nys formulations were developed to overcome these toxicities. This article will review the development of these liposomal polyene antibiotics.
Topics: Adenosine Triphosphate; Amphotericin B; Animals; Antifungal Agents; Chemistry, Pharmaceutical; Cholesterol; Drug Carriers; Drug Delivery Systems; History, 20th Century; History, 21st Century; Humans; Liposomes; Nystatin; Polyenes
PubMed: 12753730
DOI: No ID Found