Fluorescent analogs of peptoid-based HDAC inhibitors: Synthesis,biological activity and cellular uptake kinetics |
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| Institution: | 1. Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Medical Faculty, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany;2. Rudolf Boehm Institute of Pharmacology and Toxicology, Medical Faculty, Leipzig University, Härtelstraße 16-18, 04107 Leipzig, Germany;3. Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Liebigstraße 20, 04103 Leipzig, Germany;4. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany;5. John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC) and Institute for Complex Systems – Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Straße, 52428 Jülich, Germany;6. Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Leipzig University, Deutscher Platz 5, 04103 Leipzig, Germany;7. Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, 04103 Leipzig, Germany;1. Faculty of Agriculture, Kindai University, Nakamachi, Nara 631-8505, Japan;2. Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan;3. Osaka University of Pharmaceutical Science, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan;1. Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji''nan, Shandong, 250012, PR China;2. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji''nan, Shandong, 250012, PR China;3. Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, SC, 29425, United States;4. Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong, 261061, PR China;1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, 250012 Ji’nan, Shandong, PR China;2. School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012 Ji’nan, Shandong, PR China |
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| Abstract: | Fluorescent tagging of bioactive molecules is a powerful tool to study cellular uptake kinetics and is considered as an attractive alternative to radioligands. In this study, we developed fluorescent histone deacetylase (HDAC) inhibitors and investigated their biological activity and cellular uptake kinetics. Our approach was to introduce a dansyl group as a fluorophore in the solvent-exposed cap region of the HDAC inhibitor pharmacophore model. Three novel fluorescent HDAC inhibitors were synthesized utilizing efficient submonomer protocols followed by the introduction of a hydroxamic acid or 2-aminoanilide moiety as zinc-binding group. All compounds were tested for their inhibition of selected HDAC isoforms, and docking studies were subsequently performed to rationalize the observed selectivity profiles. All HDAC inhibitors were further screened in proliferation assays in the esophageal adenocarcinoma cell lines OE33 and OE19. Compound 2, 6-((N-(2-(benzylamino)-2-oxoethyl)-5-(dimethylamino)naphthalene)-1-sulfonamido)-N-hydroxyhexanamide, displayed the highest HDAC inhibitory capacity as well as the strongest anti-proliferative activity. Fluorescence microscopy studies revealed that compound 2 showed the fastest uptake kinetic and reached the highest absolute fluorescence intensity of all compounds. Hence, the rapid and increased cellular uptake of 2 might contribute to its potent anti-proliferative properties. |
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| Keywords: | Cancer Histone deacetylase HDAC inhibitor Peptoid Fluorescent probes |
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