Pro-apoptotic meiogynin A derivatives that target Bcl-xL and Mcl-1 |
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| Affiliation: | 1. Institut de Chimie des Substances Naturelles, CNRS UPR 2301, 1 avenue de la terrasse, 91198 Gif-sur-Yvette Cedex, France;2. UMR CNRS 8126, Université Paris-Sud, Institut Gustave Roussy, 114 rue Edouard-Vaillant, 94805 Villejuif Cedex, France;1. Instituto de Química Física – Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, San Lorenzo 456, 4000 Tucumán, Argentina;2. INQUINOA UNT CONICET, Ayacucho 471, 4000 Tucumán, Argentina;3. Institut für Physikalische und Theoretische Chemie, Universität Tübingen, 72076 Tübingen, Germany;1. Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, United States;2. Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium;1. Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA;2. Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA;1. Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom;2. Structural Genomics Consortium, University of Oxford, Old Road Campus Roosvelt Drive, Headington OX3 7DQ, United Kingdom;1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt;2. Pharmacognosy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt;3. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2N8, Canada;1. College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA;2. Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131, USA;3. Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA;4. Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA;5. Department of Dermatology, University of New Mexico, Albuquerque, NM 87131, USA |
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| Abstract: | The biological evaluation of a natural sesquiterpene dimer meiogynin A 1, is described as well as that of five non-natural analogues. Although active on a micromolar range on the inhibition of Bcl-xL/Bak and Mcl-1/Bid interaction, meiogynin A 1 is not cytotoxic on three cell lines that overexpress Bcl-xL and Mcl-1. Contrarily, one of its analogues 6 with an inverted configuration on the side chain and an aromatic moiety replacing the cyclohexane ring was active on both target proteins, cytotoxic on a micromolar range and was found to induce apoptosis through a classical pathway. |
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| Keywords: | Sesquiterpene dimer Apoptosis Bcl-xL Mcl-1 Molecular docking |
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