Arylamino bisphosphonates: Potent and selective inhibitors of the tumor-associated carbonic anhydrase XII |
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| Institution: | 1. Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi ‘Aldo Moro’ di Bari, Via Orabona 4, 70126 Bari, Italy;2. Università degli Studi di Firenze, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy;3. Università degli Studi di Firenze, Polo Scientifico, Dipartimento NEIROFABA, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy;1. Organic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;2. Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, India;3. Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;1. Department of Biology, National Center for Behavioral Genomics, and Volen Center for Complex Systems, Brandeis University, Waltham, MA 02454, United States;2. Department of Chemistry, Brandeis University, Waltham, MA 02454, United States;1. Department of Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;2. Department of In Vitro Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;3. Department of Pharmacology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;4. Department of Drug Metabolism, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;5. Department of Basic Pharmaceutical Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;6. Department of Oncology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA |
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| Abstract: | A set of matrix metalloproteinases (MMPs) inhibitors, containing a bisphosphonate moiety (BP), has been evaluated for the inhibitory activity of carbonic anhydrases (CAs, EC 4.2.1.1). Human (h) isoforms hCA I, II, IX, XII and XIV were included in the study due to their involvement in crucial physiologic and pathologic processes. Some of these molecules selectively inhibited CA XII in the nanomolar range, showing an attractive dual mechanism (anti-MMP and anti-CA) of action as potential antitumor agents. The BP inhibitors investigated in this study are also excellent leads for obtaining even more effective compounds able to selectively target membrane-bound CA XII and having the potential to be used as tools for understanding physiologic processes regulated by this isoform. |
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| Keywords: | Carbonic anhydrase Bisphosphonate Matrix metalloproteinase inhibitor Antitumor agent Isoform-selective inhibitor |
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