Synthesis and evaluation of homofarnesoyl-substituted CAAX-peptidomimetics as farnesyltransferase inhibitors and antiproliferative agents |
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| Authors: | Schlitzer M Sattler I Dahse H M |
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| Institution: | 1. Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, D-35032 Marburg, Germany;2. Hans-Knöll-Institut für Naturstoff-Forschung e.V., Beutenbergstraße 11, D-07745 Jena, Germany;1. Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran;2. Department of Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Science, Tehran, Iran;3. Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;4. Biochemistry Department, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran;1. College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China;2. Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China;1. Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany;2. Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115-5000, USA;3. Munich Center for Integrated Protein Science (CiPSM), Ludwig-Maximilians-Universität München, Butenandtstrasse 13, 81377 Munich, Germany;1. College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China;2. Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China |
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| Abstract: | Several CAAX-peptidomimetics were linked to homofarnesoic acid via a beta-alanyl spacer with the intention to obtain a novel type of bisubstrate analogue farnesyltransferase inhibitors. However, the compounds were found to be only weakly active in the farnesyltransferase inhibition assay. Nevertheless, they displayed antiproliferative activity against different tumor cell lines in the low micromolar range. Replacement of the beta-alanine moiety by aspartic acid-1-methyl ester resulted in a compound which inhibited the farnesyltransferase with an IC50 of 860 nM. The corresponding free acid showed a eightfold loss in activity (IC50 = 6.9 microM). |
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