Strategies for improving the solubility and metabolic stability of griseofulvin analogues

We report two types of modifications to the natural product griseofulvin as strategies to improve solubility and metabolic stability: the conversion of aryl methyl ethers into aryl difluoromethyl ethers at metabolic hotspots and the conversion of the C-ring ketone into polar oximes. The syntheses of...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2016-06, Vol.116, p.210-215
Main Authors: Petersen, A.B., Konotop, G., Hanafiah, N.H.M., Hammershøj, P., Raab, M.S., Krämer, A., Clausen, M.H.
Format: Article
Language:English
Subjects:
Animals
Anticancer
Antifungal
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Drug Stability
Griseofulvin - chemical synthesis
Griseofulvin - chemistry
Griseofulvin - metabolism
Griseofulvin - pharmacology
Griseofulvin analogues
HeLa Cells
Humans
Male
Metabolic stability
Mice
Microsomes - metabolism
Oxidation-Reduction
Rats
Solubility
Structure-Activity Relationship
Synthesis
Thermodynamics
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Summary:We report two types of modifications to the natural product griseofulvin as strategies to improve solubility and metabolic stability: the conversion of aryl methyl ethers into aryl difluoromethyl ethers at metabolic hotspots and the conversion of the C-ring ketone into polar oximes. The syntheses of the analogues are described together with their solubility, metabolic half-life in vitro and antiproliferative effect in two cancer cell lines. We conclude that on balance, the formation of polar oximes is the most promising strategy for improving the properties of the analogues. [Display omitted] •Synthesis of analogs of the natural product griseofulvin are presented.•Their solubility, microsomal stability and cytotoxicity are reported.•Difluoromethyl substitution at metabolic hotspots leads to re-routed oxidative metabolism.•Increasing polarity by introducing oxime substitution increases solubility and metabolic half-life.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2016.03.071