1. Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites
- Author
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Austin A. Czarnecki, Joanna E. Burdette, Nicholas H. Oberlies, Cedric J. Pearce, Noemi D. Paguigan, Stephen J. Polyak, Huzefa A. Raja, Mohammed H. Al-Huniti, Mitchell P. Croatt, José L. Medina-Franco, and Mariana González-Medina
- Subjects
Antifungal ,Antifungal Agents ,Halogenation ,Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,Antifungal drug ,Pharmaceutical Science ,Antineoplastic Agents ,Microsporum gypseum ,Single step ,Microbial Sensitivity Tests ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Griseofulvin ,Xylaria cubensis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,Microsporum ,Organic chemistry ,Molecular Biology ,Cell Proliferation ,Principal Component Analysis ,Dose-Response Relationship, Drug ,Molecular Structure ,Xylariales ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Chemical space ,0104 chemical sciences ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Selectfluor ,Medical Informatics - 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.
- Published
- 2017