Dual carbonic anhydrase/matrix metalloproteinase inhibitors incorporating bisphosphonic acid moieties targeting bone tumors |
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| Affiliation: | 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, Dipartimento di Chimica, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy;3. Università degli Studi di Firenze, Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, Via U. Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy;1. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan;2. Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka 1000, Bangladesh;3. Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh;1. Department of Chemistry & Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy;2. Molecular Simulation Engineering (MOSE) Laboratory, DI3, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy;1. CNRS, SRSMC, UMR 7565, Vandœuvre-lès-Nancy, F-54506, France;2. Université de Lorraine, SRSMC, UMR 7565, Nancy F-54001, France;3. ABC Platform®, Nancy F-54001, France;3. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114;4. Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114;5. Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts 02113 |
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| Abstract: | A set of bisphosphonate matrix metalloproteinase (MMP) inhibitors was investigated for inhibitory activity against several carbonic anhydrase (CA, EC 4.2.1.1) isozymes, some of which are overexpressed in hypoxic tumors. Some of the bisphosphonate revealed to be very potent inhibitors (in the low nanomolar range) of the cytosolic isoform CA II and the membrane-bound CA IX, XII and XIV isozymes, a feature useful for considering them as interesting compounds for bone resorption inhibition applications. We suggest here that it is possible to develop dual enzyme inhibitors bearing bisphosphonate moieties that may target both MMPs and CAs, two families of enzymes involved in tumor formation, growth, and metastasis. |
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| Keywords: | Carbonic anhydrase Enzyme inhibitor Bisphosphonate Bone resorption inhibitor Matrix metalloproteinase inhibitor |
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