title: Strategies for improving the solubility and metabolic stability of griseofulvin analogues.
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.
authors.affiliation: Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK-2800, Kgs. Lyngby, Denmark.
authors.forename: A B
authors.initials: AB
authors.lastname: Petersen
authors.affiliation: Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ), Germany.
authors.forename: G
authors.initials: G
authors.lastname: Konotop
authors.affiliation: Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ), Germany.
authors.forename: N H M
authors.initials: NHM
authors.lastname: Hanafiah
authors.affiliation: Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK-2800, Kgs. Lyngby, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Hammershøj
authors.affiliation: Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ), Germany.
authors.forename: M S
authors.initials: MS
authors.lastname: Raab
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Krämer
authors.affiliation: 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.
authors.forename: M H
authors.initials: MH
authors.lastname: Clausen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D004355:Drug Stability; D006118:Griseofulvin / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D006118:Griseofulvin
keywords: Anticancer; Antifungal; Griseofulvin analogues; Metabolic stability; Synthesis