Synthesis and Biological Activity of Octaketides from the Cytosporone Family

Delius, Max von; Le, Christine M.; Ellinger, Bernhard; Kuzikov, Maria; Gul, Sheraz; Dong, Vy M.

doi:10.1002/ijch.201700023

Cited by 12 publications

(8 citation statements)

References 36 publications

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“…Recently, novel, structurally similar octaketides have been isolated and a few approaches for the synthesis of these molecules were reported (Meza et al 2015, Cochrane et al 2016, Zamberlam et al 2012, Dos Santos et al 2009, Zhenga et al 2019, Dos Santos et al 2020. These findings also revealed that cytosporones are potentially pharmaceutical and agrochemical agents (Meza et al 2015, von Delius et al 2017. The most representative compounds in this class of resorcinolic lipids are cytosporones A-E (1-5, Figure 1), isolated from the endophytic fungi Cytospora sp.…”

Section: Introductionmentioning

confidence: 86%

Straightforward synthesis of cytosporone analogs AMS35AA and AMS35BB

Vitor

Meza

Gomes

et al. 2021

An. Acad. Bras. Ciênc.

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Cytosporones, a class of octaketide resorcinolic lipids, have drawn the attention of researchers for exhibiting a number of notable biological properties. Herein, we describe routes to synthesize the bioactive synthetic resorcinolic lipids AMS35AA and AMS35BB with excellent overall yields using 3,5-dimethoxybenzoic acid as the starting material. The methods proved remarkably effi cient to achieve the target compounds and comprise the synthesis of AMS35AA catalyzed by ascorbic acid (vitamin C).

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Section: Introductionmentioning

confidence: 86%

Straightforward synthesis of cytosporone analogs AMS35AA and AMS35BB

Vitor

Meza

Gomes

et al. 2021

An. Acad. Bras. Ciênc.

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“…Interestingly, compound 14 that features a longer alkyl side chain with an alcohol functionality was not active against any of the tested cancer cell lines, similar to earlier findings about diminished cytotoxicity of cytosporone B (5) analogues with hydroxy-functionalized alkyl chains. 22 S16). Among the 14 tested cytosporones, trihydroxy-isochroman-3one cytosporone D (2) exhibited excellent activity against C. albicans ATCC 10261 (minimum inhibitory concentration [MIC] = 6.25−3.12 μg/mL; minimum fungicidal concentration [MFC] = 50 μg/mL) and all the tested Gram-positive bacteria (MICs ranging 1.56−12.5 μg/mL; minimum bactericidal concentrations [MBCs] 6.25−50 μg/mL), 19,20 including the antibiotics-resistant S. aureus MRSA strain ATCC 33592 (MIC = 6.25−3.12, MBC = 25 μg/mL).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Biosynthesis of Cytosporones in Leotiomycetous Filamentous Fungi

Li,

Zhong,

Liu

et al. 2024

J. Am. Chem. Soc.

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Polyketides with the isochroman-3-one pharmacophore are rare among fungal natural products as their biosynthesis requires an unorthodox S-type aromatic ring cyclization. Genome mining uncovered a conserved gene cluster in select leotiomycetous fungi that encodes the biosynthesis of cytosporones, including isochroman-3-one congeners. Combinatorial biosynthesis in total biosynthetic and biocatalytic formats in Saccharomyces cerevisiae and in vitro reconstitution of key reactions with purified enzymes revealed how cytosporone structural and bioactivity diversity is generated. The S-type acyl dihydroxyphenylacetic acid (ADA) core of cytosporones is assembled by a collaborating polyketide synthase pair. Thioesterase domain-catalyzed transesterification releases ADA esters, some of which are known Nur77 modulators. Alternatively, hydrolytic release allows C6 hydroxylation by a flavin-dependent monooxygenase, yielding a trihydroxybenzene moiety. Reduction of the C9 carbonyl by a short chain dehydrogenase/reductase initiates isochroman-3-one formation, affording cytosporones with cytotoxic and antimicrobial activity. Enoyl di-or trihydroxyphenylacetic acids are generated as shunt products, while isocroman-3,4diones are formed by autoxidation. The cytosporone pathway offers novel polyketide biosynthetic enzymes for combinatorial synthetic biology to advance the production of "unnatural" natural products for drug discovery.

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“…We prepared eight biologically active octaketide natural products (i.e., dothiorelones, cytosporones, and phomopsin C). In a related study, we synthesized 12 analogs of the cytosporone family and ultimately found an increase in cytotoxicity with a densely fluorinated acyl carbogenic chain …”

Section: Aldehyde C–h Bond Functionalizationmentioning

confidence: 99%

Teaching Aldehydes New Tricks Using Rhodium- and Cobalt-Hydride Catalysis

2021

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Conspectus By using transition metal catalysts, chemists have altered the “logic of chemical synthesis” by enabling the functionalization of carbon–hydrogen bonds, which have traditionally been considered inert. Within this framework, our laboratory has been fascinated by the potential for aldehyde C–H bond activation. Our approach focused on generating acyl-metal-hydrides by oxidative addition of the formyl C–H bond, which is an elementary step first validated by Tsuji in 1965. In this Account, we review our efforts to overcome limitations in hydroacylation. Initial studies resulted in new variants of hydroacylation and ultimately spurred the development of related transformations (e.g., carboacylation, cycloisomerization, and transfer hydroformylation). Sakai and co-workers demonstrated the first hydroacylation of olefins when they reported that 4-pentenals cyclized to cyclopentanones, using stoichiometric amounts of Wilkinson’s catalyst. This discovery sparked significant interest in hydroacylation, especially for the enantioselective and catalytic construction of cyclopentanones. Our research focused on expanding the asymmetric variants to access medium-sized rings (e.g., seven- and eight-membered rings). In addition, we achieved selective intermolecular couplings by incorporating directing groups onto the olefin partner. Along the way, we identified Rh and Co catalysts that transform dienyl aldehydes into a variety of unique carbocycles, such as cyclopentanones, bicyclic ketones, cyclohexenyl aldehydes, and cyclobutanones. Building on the insights gained from olefin hydroacylation, we demonstrated the first highly enantioselective hydroacylation of carbonyls. For example, we demonstrated that ketoaldehydes can cyclize to form lactones with high regio- and enantioselectivity. Following these reports, we reported the first intermolecular example that occurs with high stereocontrol. Ketoamides undergo intermolecular carbonyl hydroacylation to furnish α-acyloxyamides that contain a depsipeptide linkage. Finally, we describe how the key acyl-metal-hydride species can be diverted to achieve a C–C bond-cleaving process. Transfer hydroformylation enables the preparation of olefins from aldehydes by a dehomologation mechanism. Release of ring strain in the olefin acceptor offers a driving force for the isodesmic transfer of CO and H2. Mechanistic studies suggest that the counterion serves as a proton-shuttle to enable transfer hydroformylation. Collectively, our studies showcase how transition metal catalysis can transform a common functional group, in this case aldehydes, into structurally distinct motifs. Fine-tuning the coordination sphere of an acyl-metal-hydride species can promote C–C and C–O bond-forming reactions, as well as C–C bond-cleaving processes.

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Synthesis and Biological Activity of Octaketides from the Cytosporone Family

Cited by 12 publications

References 36 publications

Straightforward synthesis of cytosporone analogs AMS35AA and AMS35BB

Straightforward synthesis of cytosporone analogs AMS35AA and AMS35BB

Biosynthesis of Cytosporones in Leotiomycetous Filamentous Fungi

Teaching Aldehydes New Tricks Using Rhodium- and Cobalt-Hydride Catalysis

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