SLC-0111 enaminone analogs, 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides,as novel selective subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform IX |
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| Affiliation: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt;3. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy;4. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;5. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;6. Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt;3. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy;4. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, El-kasr Elaini Street, Cairo, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adiyaman University, 02040 Adiyaman, Turkey;2. Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt;3. Università degli Studi di Firenze, Department NEUROFARBA – Pharmaceutical and Nutraceutical section, University of Firenze, via Ugo Schiff 6, I-50019, Sesto Fiorentino, Firenze, Italy;4. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy;5. Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt;6. Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, P.O. Box 12622, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt;3. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy;4. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy;5. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt;6. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;7. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;8. Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, P.O. Box 12622, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt;3. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy;4. Department of NEUROFARBA – Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Via U. Schiff 6, Sesto Fiorentino, Firenze, 50019, Italy;5. The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt;6. Laboratory of Growth Regulators, Palacky University & Institute of Experimental Botany, The Czech Academy of Sciences, Slechtitelu 27, 78371, Olomouc, Czech Republic;7. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, El-kasr Elaini Street, Cairo, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt;3. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy;4. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy;5. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;6. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt |
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| Abstract: | SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report the synthesis of two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides 5a–i and 6a–j as SLC-0111 enaminone congeners. The prepared enaminones were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the enaminones reported here in variable degrees. The target tumor-associated isoform hCA IX was undeniably the most affected one (KIs: 0.21–7.1 nM), with 6- to 21-fold enhanced activity than SLC-0111 (KI = 45 nM). All the prepared enaminones displayed interesting selectivity towards hCA IX over hCA I (SI: 32 – >35714), hCA II (SI: 2 – 1689) and hCA IV (SI: 11 – >45454). Of particular interest, bioisosteric replacement of phenyl tail with the bulkier 2-naphthyl tail, sulfonamide 6h, achieved the higher II/IX selectivity herein reported with SI of 1689. |
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| Keywords: | Benzenesulfonamide Carbonic anhydrase Enaminones SLC-0111 Selective CA IX inhibitors |
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