Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties |
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| Affiliation: | 1. Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria;2. Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria;3. Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, Olomouc, Czech Republic;4. Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvö u 6, 6720 Szeged, Hungary;5. Department of Life Sciences, University of Applied Sciences Krems, Piaristengasse 1, 3500 Krems, Austria;1. Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia (UTM), 81310 Skudai, Johor, Malaysia;2. School of Chemistry and Environment Studies, Faculty of Applied Sciences, Universiti Teknologi MARA (UiTM) Sarawak, Jalan Meranek, 94300 Kota Samarahan, Sarawak, Malaysia;3. Department of Bioscience and Health Sciences, Faculty of Biosciences and Medical Engineering, Universiti Teknologi Malaysia (UTM), 81310 Skudai, Johor, Malaysia;4. Medicinal Chemistry and Natural Products Research Group, School of Pharmacy and Biomolecular Sciences, Faculty of Science, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool L3 3AF, United Kingdom;1. Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, Prague-6 CZ-16610, Czech Republic;2. Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA;1. Department of ENT, Huai''an First People''s Hospital, Nanjing Medical University, Huai''an, China;2. Department of Ophthalmology, Huai''an First People''s Hospital, Nanjing Medical University, Huai''an, China;1. Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan;2. Graduate School of medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan;3. Advanced Science Research Centre, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-8640, Japan;1. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany;2. Department für Chemie und Pharmazie, Lehrstuhl für Physikalische Chemie I, Friedrich-Alexander-Universität Erlangen-Nürnberg, Egerlandstraße 3, 91058 Erlangen, Germany;3. Leibniz-Institut für Oberflächenmodifizierung e.V., Permoserstrasse 15, 04318 Leipzig, Germany |
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| Abstract: | Combretastatin A-4 (CA-4) is a highly cytotoxic natural product and several derivatives have been prepared which underwent clinical trial. These investigations revealed that the cis-stilbene moiety of the natural product is prone to undergo cis/trans isomerization under physiological conditions, reducing the overall activity of the drug candidates. Herein, we report the preparation of cis-restrained carbocyclic analogs of CA-4. The compounds, which differ by the size and hybridization of the carbocyclic ring have been evaluated for their cytotoxic properties and their ability to inhibit tubulin polymerization. Biological data, supported by molecular docking studies, identified cyclobutenyl and cyclobutyl derivatives of the natural product as highly promising drug candidates. |
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