2. Academic Validation
  3. Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites

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

  • Bioorg Med Chem. 2017 Oct 15;25(20):5238-5246. doi: 10.1016/j.bmc.2017.07.041.
Noemi D Paguigan 1,  Mohammed H Al-Huniti 1,  Huzefa A Raja 1,  Austin Czarnecki 2,  Joanna E Burdette 2,  Mariana González-Medina 3,  José L Medina-Franco 3,  Stephen J Polyak 4,  Cedric J Pearce 5,  Mitchell P Croatt 1,  Nicholas H Oberlies 6
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, USA.
  • 2 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA.
  • 3 Department of Pharmacy, School of Chemistry, Universidad Nacional Autónoma de México, Avenida Universidad 3000, Mexico City 04510, Mexico.
  • 4 Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA; Department of Global Health, University of Washington, Seattle, WA 98104, USA; Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
  • 5 Mycosynthetix Inc., 505 Meadowlands Drive, Suite 103, Hillsborough, NC 27278, USA.
  • 6 Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, USA. Electronic address: nicholas_oberlies@uncg.edu.
PMID: 28802670 DOI: 10.1016/j.bmc.2017.07.041
Abstract

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.

Keywords

Antifungal; Cytotoxicity; Fluorination; Griseofulvin; Selectfluor; Xylaria cubensis.

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