The Chemistry of Griseofulvin

Petersen, Asger B.; Rønnest, Mads H.; Larsen, Thomas Ostenfeld; Clausen, Mads Hartvig

doi:10.1021/cr400368e

Cited by 118 publications

(83 citation statements)

References 144 publications

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“…3 The important biological applications and intriguing spirocyclic core of 3 make it a compound of interest to biochemists and synthetic chemists alike. The Tang group reported the genes in Penicillium aethiopicum responsible for the biosynthesis of 3 in 2010, 4 and subsequently determined the full biosynthetic pathway in 2013.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the P450-Catalyzed Oxidative Cyclization in the Biosynthesis of Griseofulvin

et al. 2016

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Griseofulvin is an anti-fungal agent which has recently been determined to have potential anti-viral and anti-cancer applications. The role of specific enzymes involved in the biosynthesis of this natural product has previously been determined, but the mechanism by which a p450, GsfF, catalyzes the key oxidative cyclization of griseophenone B remains unknown. Using density functional theory (DFT), we have determined the mechanism of this oxidation that forms the oxa-spiro core of griseofulvin. Computations show GsfF preferentially performs two sequential phenolic O-H abstractions rather than epoxidation to form an arene oxide intermediate. This conclusion is supported by experimental kinetic isotope effects.

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Section: Introductionmentioning

confidence: 99%

Mechanism of the P450-Catalyzed Oxidative Cyclization in the Biosynthesis of Griseofulvin

et al. 2016

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“…12–15 Since its isolation and discovery from a filamentous fungus in 1939, 16 most research has focused on the identification of griseofulvin analogues, either from nature or synthetically, but to date, only the original compound ( 1 ) has been developed into a marketable antifungal drug, first approved in 1959. 13 Recently, there has been a renewed interest in 1 due to its antimitotic and antiproliferative activities against various types of cancer cells. 17–21 Griseofulvin has a mode of action that is still not well understood, but disruption of the microtubule dynamics in both fungal and mammalian cells has been proposed.…”

Section: Introductionmentioning

confidence: 99%

“…17–21 Griseofulvin has a mode of action that is still not well understood, but disruption of the microtubule dynamics in both fungal and mammalian cells has been proposed. 13, 22, 23 Thus, aside from being an antifungal drug, it may also be a clinically-viable candidate for cancer chemotherapy. 21–26 Due to these reasons, it was decided that the isolation and semi-synthesis of griseofulvin analogues was worth further investigation.…”

Section: Introductionmentioning

confidence: 99%

Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites

Paguigan

Al‐Huniti

Raja

et al. 2017

Bioorganic & Medicinal Chemistry

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Griseofulvin is a fungal metabolite and antifungal drug used for the treatment of dermatophytosis in both humans and animals. Recently, griseofulvin and its analogues have attracted renewed attention due to reports of their potential anticancer effects. In this study griseofulvin (1) and related analogues (2–6, with 4 being new to literature) were isolated from Xylaria cubensis. Six fluorinated analogues (7–12) were synthesized, each in a single step using the isolated natural products and Selectflour, so as to examine the effects of fluorine incorporation on the bioactivities of this structural class. The isolated and synthesized compounds were screened for activity against a panel of cancer cell lines (MDA-MB-435, MDA-MB-231, OVCAR3, and Huh7.5.1) and for antifungal activity against Microsporum gypseum. A comparison of the chemical space occupied by the natural and fluorinated analogues was carried out by using principal component analysis, documenting that the isolated and fluorinated analogues occupy complementary regions of chemical space. However, the most active compounds, including two fluorinated derivatives, were centered around the chemical space that was occupied by the parent compound, griseofulvin, suggesting that modifications must preserve certain attributes of griseofulvin to conserve its activity.

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“…Mycophenolic acid is a known immunosuppressant for organ-transplant patients but has shown potential as a method of inducing apoptosis in tumor cells through inosine monophosphate dehydrogenase (IMPDH) inhibition (Bentley, 2000). Griseofulvin was launched as antifungal agent in the 1950s and has now attracted renewed attention for its anticancer and antiviral activities (Petersen et al, 2014). However, there are fungal polyketides hazardous to human health, such as aflatoxins, which are the primary mycotoxins produced by some Aspergillus sp.…”

Section: Introductionmentioning

confidence: 99%

Saccharomyces cerevisiae as a tool for mining, studying and engineering fungal polyketide synthases

Bond

Tang

2016

Fungal Genetics and Biology

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Small molecule secondary metabolites produced by organisms such as plants, bacteria, and fungi form a fascinating and important group of natural products, many of which have shown promise as medicines. Fungi in particular have been important sources of natural product polyketide pharmaceuticals. While the structural complexity of these polyketides makes them interesting and useful bioactive compounds, these same features also make them difficult and expensive to prepare and scale-up using synthetic methods. Currently, nearly all commercial polyketides are prepared through fermentation or semi-synthesis. However, elucidation and engineering of polyketide pathways in the native filamentous fungi hosts are often hampered due to a lack of established genetic tools and of understanding of the regulation of fungal secondary metabolisms. Saccharomyces cerevisiae has many advantages beneficial to the study and development of polyketide pathways from filamentous fungi due to its extensive genetic toolbox and well-studied metabolism. This review highlights the benefits S. cerevisiae provides as a tool for mining, studying, and engineering fungal polyketide synthases (PKSs), as well as notable insights this versatile tool has given us into the mechanisms and products of fungal PKSs.

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The Chemistry of Griseofulvin

Cited by 118 publications

References 144 publications

Mechanism of the P450-Catalyzed Oxidative Cyclization in the Biosynthesis of Griseofulvin

Mechanism of the P450-Catalyzed Oxidative Cyclization in the Biosynthesis of Griseofulvin

Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites

Saccharomyces cerevisiae as a tool for mining, studying and engineering fungal polyketide synthases

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