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Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites
- Source :
- Bioorganic & Medicinal Chemistry. 25:5238-5246
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
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.
- 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
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....3bbd935c9b8ef3044860344ac51f9974