-
Marine Drugs May 2022Over the past few decades (covering 1972 to 2022), astounding progress has been made in the elucidation of structures, bioactivities and biosynthesis of polyene... (Review)
Review
Over the past few decades (covering 1972 to 2022), astounding progress has been made in the elucidation of structures, bioactivities and biosynthesis of polyene macrolactams (PMLs), but they have only been partially summarized. PMLs possess a wide range of biological activities, particularly distinctive fungal inhibitory abilities, which render them a promising drug candidate. Moreover, the unique biosynthetic pathways including β-amino acid initiation and pericyclic reactions were presented in PMLs, leading to more attention from inside and outside the natural products community. According to current summation, in this review, the chem- and bio-diversity of PMLs from marine and terrestrial sources are considerably rich. A systematic, critical and comprehensive overview is in great need. This review described the PMLs' general structural features, production strategies, biosynthetic pathways and the mechanisms of bioactivities. The challenges and opportunities for the research of PMLs are also discussed.
Topics: Biological Products; Biosynthetic Pathways; Polyenes
PubMed: 35736163
DOI: 10.3390/md20060360 -
Current Medicinal Chemistry Jun 2004Polyenes constitute a large class of natural metabolites produced by giant multifunctional enzymes in a process resembling fatty acid biosynthesis. Like fatty acids,... (Review)
Review
Polyenes constitute a large class of natural metabolites produced by giant multifunctional enzymes in a process resembling fatty acid biosynthesis. Like fatty acids, polyene macrolides and other polyketides are assembled by decarboxylative condensations of simple carboxylic acids. But while fatty acid intermediates are fully reduced, polyene macrolide intermediates suffer the suppression of reduction or dehydration reactions at given biosynthetic steps. In the last years, much progress has been made in our understanding of the linear and modular organization of the gene clusters, and the enzymes encoded by them, responsible for the biosynthesis of these macrocyclic metabolites. This know-how about the rules that govern polyene chain growth has provided the basis for the first rational manipulations of these fascinating systems for the production of engineered derivatives and promises a new era of novel polyene development, which will hopefully yield new molecules with improved pharmacological properties.
Topics: Antifungal Agents; Drug Design; Macrolides; Polyenes; Structure-Activity Relationship
PubMed: 15180569
DOI: 10.2174/0929867043365044 -
Journal of Ocular Pharmacology and... 2019Polyenes and azoles constitute 2 major drug classes in the antifungal armamentarium used to treat fungal infections of the eye such as fungal keratitis, endophthalmitis,... (Review)
Review
Polyenes and azoles constitute 2 major drug classes in the antifungal armamentarium used to treat fungal infections of the eye such as fungal keratitis, endophthalmitis, conjunctivitis, and blepharitis. These classes of drugs have come to occupy an important niche in ophthalmic antifungal therapy due to their broad spectrum of activity against a variety of filamentous and yeast-like fungi. Natamycin suspension (Natacyn), a polyene antifungal drug, is currently the only US FDA-approved formulation for treating ophthalmic fungal infections, whereas the other polyene and azole antifungals such as amphotericin B, fluconazole, itraconazole, ketoconazole, miconazole, voriconazole, and posaconazole are routinely used off-label in the clinical setting. Despite potent antifungal activity, the clinical utility of these agents in ophthalmic infections has been challenged by their physicochemical properties, the unique ocular anatomy and physiology, selective antifungal activity, ocular and systemic toxicity, emergence of resistance and cross-resistance, and absence of reliable techniques for developing a robust in vitro-in vivo correlation. This review discusses the aforementioned challenges and the common approaches undertaken to circumnavigate the difficulties associated with the polyene- and azole-based pharmacotherapy of ophthalmic fungal infections.
Topics: Animals; Antifungal Agents; Azoles; Eye Infections, Fungal; Humans; Microbial Sensitivity Tests; Ophthalmic Solutions; Polyenes
PubMed: 30481082
DOI: 10.1089/jop.2018.0089 -
Organic & Biomolecular Chemistry Jul 2015Cyanines are indispensable fluorophores that form the chemical basis of many fluorescence-based applications. A feature that distinguishes cyanines from other common... (Review)
Review
Cyanines are indispensable fluorophores that form the chemical basis of many fluorescence-based applications. A feature that distinguishes cyanines from other common fluorophores is an exposed polyene linker that is both crucial to absorption and emission and subject to covalent reactions that dramatically alter these optical properties. Over the past decade, reactions involving the cyanine polyene have been used as foundational elements for a range of biomedical techniques. These include the optical sensing of biological analytes, super-resolution imaging, and near-IR light-initiated uncaging. This review surveys the chemical reactivity of the cyanine polyene and the biomedical methods enabled by these reactions. The overarching goal is to highlight the multifaceted nature of cyanine chemistry and biology, as well as to point out the key role of reactivity-based insights in this promising area.
Topics: Biomedical Technology; Carbocyanines; Coloring Agents; Molecular Conformation; Polyenes
PubMed: 26052876
DOI: 10.1039/c5ob00788g -
Applied Microbiology and Biotechnology May 2003Over the past 15 years the biosynthetic gene clusters for numerous bioactive polyketides have been intensively studied and recently this work has been extended to the... (Review)
Review
Over the past 15 years the biosynthetic gene clusters for numerous bioactive polyketides have been intensively studied and recently this work has been extended to the antifungal polyene macrolides. These compounds consist of large macrolactone rings that have a characteristic series of conjugated double bonds, as well as an exocyclic carboxyl group and an unusual mycosamine sugar. The biosynthetic gene clusters for nystatin, pimaricin, amphotericin and candicidin have been investigated in detail. These clusters contain the largest modular polyketide synthase genes reported to date. This body of work also provides insights into the enzymes catalysing the unusual post-polyketide modifications, and the genes regulating antibiotic biosynthesis. The sequences also provide clues about the evolutionary origins of polyene biosynthetic genes. Successful genetic manipulation of the producing organisms leading to production of polyene analogues indicates good prospects for generating improved antifungal compounds via genetic engineering.
Topics: Anti-Bacterial Agents; Bacteria; Evolution, Molecular; Genetic Engineering; Multigene Family; Polyenes
PubMed: 12698274
DOI: 10.1007/s00253-002-1183-5 -
Applied Microbiology and Biotechnology May 2016The polyene macrolide group includes important antifungal drugs, to which resistance does not arise readily. Chemical and biological methods have been used in attempts... (Review)
Review
The polyene macrolide group includes important antifungal drugs, to which resistance does not arise readily. Chemical and biological methods have been used in attempts to make polyene antibiotics with fewer toxic side effects. Genome sequencing of producer organisms is contributing to this endeavour, by providing access to new compounds and by enabling yield improvement for polyene analogues obtained by engineered biosynthesis. This recent work is also enhancing bioinformatic methods for deducing the structures of cryptic natural products from their biosynthetic enzymes. The stereostructure of candicidin D has recently been determined by NMR spectroscopy. Genes for the corresponding polyketide synthase have been uncovered in several different genomes. Analysis of this new information strengthens the view that protein sequence motifs can be used to predict double bond geometry in many polyketides.Chemical studies have shown that improved polyenes can be obtained by modifying the mycosamine sugar that is common to most of these compounds. Glycoengineered analogues might be produced by biosynthetic methods, but polyene glycosyltransferases show little tolerance for donors other than GDP-α-D-mycosamine. Genome sequencing has revealed extending glycosyltransferases that add a second sugar to the mycosamine of some polyenes. NppY of Pseudonocardia autotrophica uses UDP-N-acetyl-α-D-glucosamine as donor whereas PegA from Actinoplanes caeruleus uses GDP-α-D-mannose. These two enzymes show 51 % sequence identity and are also closely related to mycosaminyltransferases. These findings will assist attempts to construct glycosyltransferases that transfer alternative UDP- or (d)TDP-linked sugars to polyene macrolactones.
Topics: Anti-Bacterial Agents; Biosynthetic Pathways; Glucosyltransferases; Macrolides; Polyenes; Streptomyces
PubMed: 27023916
DOI: 10.1007/s00253-016-7474-z -
Journal of the American Chemical Society Apr 2022A new polyene cyclization strategy exploiting β-ionyl derivatives was developed. Photoinduced deconjugation of the extended π-system within these chromophores unveils...
A new polyene cyclization strategy exploiting β-ionyl derivatives was developed. Photoinduced deconjugation of the extended π-system within these chromophores unveils a contrathermodynamic polyene that engages in a Heck bicyclization to afford [4.4.1]-propellanes. This cascade improves upon the limited regioselectivity achieved using existing biomimetic tactics and tolerates both electron-rich and electron-deficient (hetero)aryl groups. The utility of this approach was demonstrated with the diverted total synthesis of taxodione and salviasperanol, two isomeric abietane diterpenes that were previously inaccessible along the same synthetic pathway.
Topics: Abietanes; Cyclization; Polyenes; Stereoisomerism
PubMed: 35377634
DOI: 10.1021/jacs.2c02144 -
International Journal of Toxicology Sep 2020The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of polyenes, which are reported to function in cosmetics primarily as film formers and... (Review)
Review
The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of polyenes, which are reported to function in cosmetics primarily as film formers and viscosity increasing agents. The Panel reviewed relevant data related to these ingredients, not inggaps in the available safety data for some of the polyenes in this safety assessment. The data available for many of the ingredients are sufficient and can be extrapolated to support the safety of the entire group because of the similarities in the chemical structures, chemical properties, use concentrations, and reported functions across the group. The Panel concluded that polyenes were safe in cosmetics in the present practices of use and concentration described in this safety assessment.
Topics: Animals; Consumer Product Safety; Cosmetics; Humans; Polyenes; Risk Assessment; Toxicity Tests
PubMed: 32975153
DOI: 10.1177/1091581820952385 -
Nature Reviews. Drug Discovery Jan 2024
Topics: Humans; Antifungal Agents; Polyenes
PubMed: 38040792
DOI: 10.1038/d41573-023-00196-5 -
Current Medicinal Chemistry Feb 2003Fungal infections represent a serious problem for patients with immune systems compromized either by HIV infection, or administration of immunosuppressive drugs during... (Review)
Review
Fungal infections represent a serious problem for patients with immune systems compromized either by HIV infection, or administration of immunosuppressive drugs during cancer therapy and organ transplantation. High dissemination and proliferation rates of many pathogenic fungi along with their insusceptibility to common antimicrobial drugs urge implementation of efficient and reliable antifungal therapy. Up to date, polyene macrolide antibiotics proved to be the most effective antifungal agents due to their potent fungicidal activity, broad spectrum, and relatively low frequency of resistance among the fungal pathogens. However, polyene macrolides are rather toxic, causing such serious side effects as renal failure, hypokalemia and thrombophlebitis, especially upon intravenous administration. Current views on the biosynthesis of polyene macrolides, their mode of action and structure-function relationship, as well as strategies used to overcome the toxicity problem are discussed in this review. In addition, some of the new potential applications for polyene macrolides in therapy of prion diseases, HIV infection and cancer are highlighted.
Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Humans; Macrolides; Polyenes; Structure-Activity Relationship
PubMed: 12570708
DOI: 10.2174/0929867033368448