Resorcylic Acid Lactones

Napolitano, Carmela; Murphy, Paul V.

doi:10.1002/9783527666911.ch7

Cited by 7 publications

(7 citation statements)

References 117 publications

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“…The 14-membered and benzannulated macrolides known as the resorcylic acid lactones (RALs) are mycotoxins that have been isolated from a range of fungi . The first members of what is now a rather large family of natural products were described more than 50 years ago, and new ones continue to be reported on a regular basis. , The extraordinary range of biological properties displayed by the RALs, which include (among other things) antimalarial, antiviral, antifungal, nematocidal, and antiparasitic activities, has attracted significant attention although probably not as much as the capacities of some of them to act as potent and highly selective inhibitors of kinases and the chaperone heat shock protein 90 (Hsp90). , As such, certain RALs have come to be regarded as important leads for the development of new oncolytic agents. Certainly, an impressive range of derivatization and analoguing programs , has been launched on this basis and such efforts have even led to a number of clinical trials …”

Section: Introductionmentioning

confidence: 99%

Modular Total Syntheses of the Marine-Derived Resorcylic Acid Lactones Cochliomycins A and B Using a Late-Stage Nozaki–Hiyama–Kishi Macrocyclization Reaction

et al. 2014

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The natural products cochliomycin A (1) and cochliomycin B (2), two resorcylic acid lactones obtained from marine sources, have been prepared in a concise and stereocontrolled manner from the readily accessible building blocks 4-6. Olefin cross-metathesis, trans-esterification and Nozaki-Hiyama-Kishi (NHK) macrocyclization reactions were employed in the key steps. Hydrolysis of the immediate precursor to cochliomycin B affords the resorcylic acid lactone zeaenol (24).

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Section: Introductionmentioning

confidence: 99%

Modular Total Syntheses of the Marine-Derived Resorcylic Acid Lactones Cochliomycins A and B Using a Late-Stage Nozaki–Hiyama–Kishi Macrocyclization Reaction

et al. 2014

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“…BDLs such as desmethyl-lasiodiplodin 5 show potent cytotoxicity against various cancer cells ( 57 , 58 ). Thus, we evaluated the toxicities of lasilarin 1 and its 7- O -sulfate 1a against untransformed Vero cells (African green monkey kidney epithelium) and human cancer cell lines HeLa (cervical cancer), HepG2 (hepatocellular carcinoma), MCF-7 (breast cancer), and A549 (lung cancer) as the targets.…”

Section: Resultsmentioning

confidence: 99%

Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from Fusarium graminearum PH-1

Xie

Xiao

Wang

et al. 2020

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Total biosynthesis or whole-cell biocatalytic production of sulfated small molecules relies on the discovery and implementation of appropriate sulfotransferase enzymes. Although fungi are prominent biocatalysts and have been used to sulfate drug-like phenolics, no gene encoding a sulfotransferase enzyme has been functionally characterized from these organisms. Here, we identify a phenolic sulfotransferase, FgSULT1, by genome mining from the plant-pathogenic fungus Fusarium graminearum PH-1. We expressed FgSULT1 in a Saccharomyces cerevisiae chassis to modify a broad range of benzenediol lactones and their nonmacrocyclic congeners, together with an anthraquinone, with the resulting unnatural natural product (uNP) sulfates displaying increased solubility. FgSULT1 shares low similarity with known animal and plant sulfotransferases. Instead, it forms a sulfotransferase family with putative bacterial and fungal enzymes for phase II detoxification of xenobiotics and allelochemicals. Among fungi, putative FgSULT1 homologues are encoded in the genomes of Fusarium spp. and a few other genera in nonsyntenic regions, some of which may be related to catabolic sulfur recycling. Computational structure modeling combined with site-directed mutagenesis revealed that FgSULT1 retains the key catalytic residues and the typical fold of characterized animal and plant sulfotransferases. Our work opens the way for the discovery of hitherto unknown fungal sulfotransferases and provides a synthetic biological and enzymatic platform that can be adapted to produce bioactive sulfates, together with sulfate ester standards and probes for masked mycotoxins, precarcinogenic toxins, and xenobiotics. IMPORTANCE Sulfation is an expedient strategy to increase the solubility, bioavailability, and bioactivity of nutraceuticals and clinically important drugs. However, chemical or biological synthesis of sulfoconjugates is challenging. Genome mining, heterologous expression, homology structural modeling, and site-directed mutagenesis identified FgSULT1 of Fusarium graminearum PH-1 as a cytosolic sulfotransferase with the typical fold and active site architecture of characterized animal and plant sulfotransferases, despite low sequence similarity. FgSULT1 homologues are sparse in fungi but form a distinct clade with bacterial sulfotransferases. This study extends the functionally characterized sulfotransferase superfamily to the kingdom Fungi and demonstrates total biosynthetic and biocatalytic synthetic biological platforms to produce unnatural natural product (uNP) sulfoconjugates. Such uNP sulfates may be utilized for drug discovery in human and veterinary medicine and crop protection. Our synthetic biological methods may also be adapted to generate masked mycotoxin standards for food safety and environmental monitoring applications and to expose precarcinogenic xenobiotics.

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“…The resorcylic acid lactones (RALs) are a class of natural products derived from various organisms and are comprised of a β-resorcylate moiety annulated with 12- or 14-membered macrolactone (Figure ). Although the structures of most of these compounds are similar to each other, they display varied biological activities such as antimalarial, antifungal, cytotoxic, antiplasmodial, estrogenic, and nematicidal properties, and several members of these RALs acts as potent kinase and ATPase inhibitors . For example, radicicol ( 1 ) showed potent HSP90 inhibitory activity, − while some other RALs exhibited mitogen-activated protein kinase inhibition irreversibly and cytotoxicity against human cells through CDK/GSK-3 inhibition .…”

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confidence: 99%

Total Synthesis and Structural Revision of Monocillin VII

et al. 2019

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The first asymmetric total synthesis of macrolactone monocillin VII and its C-10′ epimer was achieved starting from a known chiral pure epoxide in 16 longest linear sequences. The present synthesis highlights the macrolactone formation involving an alkyne−dicobalt carbonyl complex under De Brabander's conditions followed by an unexpected regioselective hydration. The asymmetric total synthesis resulted in the revision of the configuration at C10′ and reassignment of the absolute configuration of the natural product.

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Resorcylic Acid Lactones

Cited by 7 publications

References 117 publications

Modular Total Syntheses of the Marine-Derived Resorcylic Acid Lactones Cochliomycins A and B Using a Late-Stage Nozaki–Hiyama–Kishi Macrocyclization Reaction

Modular Total Syntheses of the Marine-Derived Resorcylic Acid Lactones Cochliomycins A and B Using a Late-Stage Nozaki–Hiyama–Kishi Macrocyclization Reaction

Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from Fusarium graminearum PH-1

Total Synthesis and Structural Revision of Monocillin VII

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