title: Synthesis and formulation studies of griseofulvin analogues with improved solubility and metabolic stability.
abstract: Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low μM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2'-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro.
authors.affiliation: Center for Nanomedicine and Theranostics & Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK-2800 Kgs, Lyngby, Denmark.
authors.forename: Asger B
authors.initials: AB
authors.lastname: Petersen
authors.affiliation: Center for Nanomedicine and Theranostics & Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK-2800 Kgs, Lyngby, Denmark.
authors.forename: Nikolaj S
authors.initials: NS
authors.lastname: Andersen
authors.affiliation: Max-Eder Research Group "Experimental Therapies for Hematologic Malignancies", German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Gleb
authors.initials: G
authors.lastname: Konotop
authors.affiliation: Max-Eder Research Group "Experimental Therapies for Hematologic Malignancies", German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany; Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, Malaysia.
authors.forename: Nur Hafzan Md
authors.initials: NH
authors.lastname: Hanafiah
authors.affiliation: Max-Eder Research Group "Experimental Therapies for Hematologic Malignancies", German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Raab
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center and Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Alwin
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: Mads H
authors.initials: MH
authors.lastname: Clausen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004355:Drug Stability; D006118:Griseofulvin / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006801:Humans; D051379:Mice; D012995:Solubility; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006118:Griseofulvin
keywords: Cancer; Centrosomal clustering; Formulations; Griseofulvin; Griseofulvin (PubChem CID: 441140); Pharmacokinetics; Solubility