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

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Mohammed Al-Huniti, Research Scientist (Creator)
Mitchell Croatt, Assistant Professor (Creator)
Nicholas Oberlies, Patricia A. Sullivan Distinguished Professor of Chemistry (Creator)
Cedric J Pearce, Adjunct Professor (Creator)
Huzefa A. Raja, Research Scientist (Creator)
The University of North Carolina at Greensboro (UNCG )
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Abstract: [2017-2018 UNCG University Libraries Open Access Publishing Fund Grant Winner.] 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.

Additional Information

Bioorganic & Medicinal Chemistry. 2017;25, 20: 5238-5246
Language: English
Date: 2017
Griseofulvin, Xylaria cubensis, Fluorination, Selectfluor, Cytotoxicity, Antifungal

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