Discovery and preliminary structure–activity relationship studies on tecomaquinone I and tectol as novel farnesyltransferase and plasmodial inhibitors |
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| Institution: | 1. School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;2. Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS, Muséum National d’Histoire Naturelle, 57 rue Cuvier (C.P. 54), 75005 Paris, France;3. Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France;4. Université de Toulouse, PHARMA-DEV, UMR 152 IRD-UPS, UPS, 118 Route de Narbonne, F-31062 Toulouse Cedex 9, France;1. GHD Centre Level 3, 27 Napier Street, Freemans Bay, PO Box 6543, Wellesley Street, Auckland 1011, New Zealand;2. Department of Civil & Environmental Engineering, Faculty of Engineering, The University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand;1. ACT Health Diabetes Service and Australian National University Medical School, Canberra, ACT, Australia 2606;2. Diabetes Research Unit, Boston University Medical Center, Boston, MA, USA;3. CR-CHUM and Montreal Diabetes Research Center and Departments of Nutrition and Biochemistry, University of Montreal, Montreal, QC, Canada;1. Ministry of Education Key Laboratory of Interface Science and Engineering in Advanced Materials, Research Center of Advanced Materials Science and Technology, Taiyuan University of Technology, Taiyuan 030024, PR China;2. Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China;3. College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, PR China;1. Department of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology, 10691 Stockholm, Sweden;2. Leiden Observatory, Leiden University, PO Box 9513, NL 2300 RA Leiden, The Netherlands;3. Sackler Laboratory for Astrophysics, Leiden Observatory, Leiden University, P.O. Box 9513, NL 2300 RA Leiden, The Netherlands;1. Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, United Kingdom;2. Dept. of Organic Chemistry, Faculty of Chemistry, University of Seville, Prof. García González 1, E-41012 Seville, Spain |
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| Abstract: | Biological screening of a library of synthesized benzoc]chromene-7,10-dione natural products against human farnesyltransferase (FTase) has identified tecomaquinone I (IC50 of 0.065 ± 0.004 μM) as being one of the more potent natural product inhibitors identified to date. Anti-plasmodial screening of the same library against a drug-resistant strain of Plasmodium falciparum identified the structurally-related dichromenol tectol as a moderately active growth inhibitor with an IC50 3.44 ± 0.20 μM. Two novel series of analogues, based on the benzoc]chromene-7,10-dione scaffold, were subsequently synthesized, with one analogue exhibiting farnesyltransferase inhibitory activity in the low micromolar range. A preliminary structure–activity relationship (SAR) study has identified different structural requirements for anti-malarial activity in comparison to FTase activities for these classes of natural products. Our results identify tecomaquinone I as a novel scaffold from which more potent inhibitors of human and parasitic FTase could be developed. |
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| Keywords: | Tecomaquinone I Natural product Dimerization FTase inhibitor Anti-plasmodial |
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