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Amides as bioisosteres of triazole-based geranylgeranyl diphosphate synthase inhibitors
Institution:1. Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA;2. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;3. Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1109, USA;1. Department of Chemistry, The University of Iowa, Iowa City, IA 52245, United States;2. Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States;3. Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, United States;4. Department of Pharmacology, University of Iowa, Iowa City, IA 52242, United States;1. College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, People’s Republic of China;2. Gansu International Scientific and Technological Cooperation Base of Water-Retention Chemical Functional Materials, Lanzhou, Gansu 730070, People’s Republic of China;1. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan;2. Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan;3. Faculty of Pharmacy, Department of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan;4. Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan;1. Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland;2. Department of Chemistry, Gdansk University, ul. Sobieskiego 18, 80-952 Gdańsk, Poland;3. Faculty of Chemistry, University of Opole, ul. Oleska 48, 45-052 Opole, Poland;1. The Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, United States;2. Department of Chemistry & Biochemistry, Texas Tech University, 1204, Boston Ave, Lubbock, TX 79409, United States;1. Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan;2. Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Abstract:Geranylgeranyl diphosphate synthase (GGDPS) inhibitors are of potential therapeutic interest as a consequence of their activity against the bone marrow cancer multiple myeloma. A series of bisphosphonates linked to an isoprenoid tail through an amide linkage has been prepared and tested for the ability to inhibit GGDPS in enzyme and cell-based assays. The amides were designed as analogues to triazole-based GGDPS inhibitors. Several of the new compounds show GGDPS inhibitory activity in both enzyme and cell assays, with potency dependent on chain length and olefin stereochemistry.
Keywords:Bisphosphonate  Geranylgeranyl diphosphate synthase  Inhibition  Isoprenoid biosynthesis  Amide  Triazole  Bioisostere  Myeloma
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