Strategies for improving the solubility and metabolic stability of griseofulvin analogues

Eur J Med Chem. 2016 Jun 30:116:210-215. doi: 10.1016/j.ejmech.2016.03.071.

A B Petersen ¹, G Konotop ², N H M Hanafiah ², P Hammershøj ¹, M S Raab ², A Krämer ³, M H Clausen ⁴

Affiliations

1 Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK-2800, Kgs. Lyngby, Denmark.
2 Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ), Germany.
3 Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
4 Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK-2800, Kgs. Lyngby, Denmark. Electronic address: mhc@kemi.dtu.dk.

PMID: 27061984 DOI: 10.1016/j.ejmech.2016.03.071

Abstract

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.

Keywords

Anticancer; Antifungal; Griseofulvin analogues; Metabolic stability; Synthesis.

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