Synthesis of 6-tetrazolyl-substituted sulfocoumarins acting as highly potent and selective inhibitors of the tumor-associated carbonic anhydrase isoforms IX and XII |
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| Affiliation: | 1. Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia;2. Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy;3. Università degli Studi di Firenze, NEUROFARBA Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;1. Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy;2. Department of Chemistry, Faculty of Art & Science, Balikesir University, Balikesir, Turkey;3. Istituto di Biochimica delle Proteine—CNR, Via P. Castellino 111, 80131 Napoli, Italy;4. Department of Biology, Faculty of Art & Science, Balikesir University, Balikesir, Turkey;5. Università degli Studi di Firenze, Polo Scientifico, Dipartimento NEUROFABA, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy;1. Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Polo Scientifico, Sesto Fiorentino, Firenze, Italy;2. Istituto di Biochimica delle Proteine—CNR, Via P. Castellino 111, 80131 Napoli, Italy;3. Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy;4. Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia;1. Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;2. Department of Chemistry, Kulliyyah of Science, International Islamic University Malaysia, PO Box 141, 25710 Kuantan, Pahang Darul Makmur, Malaysia;3. Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, PO Box 173, Alkharj 11942, Saudi Arabia;4. Department of Chemistry, College of Science, King Saud University, Riyadh 11362, Saudi Arabia;1. Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy;2. Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Farmacologia, Viale G. Pieraccini 6, 50139 Florence, Italy;3. Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA;4. Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;1. Chemistry Department, Faculty of Arts and Science, Dumlupınar University, 43100 Kütahya, Turkey;2. Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, 50019 Sesto Fiorentino (Florence), Italy;3. Biochemistry Department, Faculty of Arts and Science, Dumlupınar University, 43100 Kütahya, Turkey;1. Saint Petersburg State University, Saint Petersburg 199034, Russian Federation;2. Department of Organic Chemistry, Faculty of Science, RUDN University, 117198, Russian Federation;3. The Ushinsky Yaroslavl State Pedagogical University, Yaroslavl 150000, Russian Federation;4. Department of Pharmacy, University of Pisa, 56126 Pisa, Italy;5. Neurofarba Department, Universita degli Studi di Firenze, Florence, Italy |
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| Abstract: | A series of 6-substituted sulfocoumarins incorporating substituted-1,2,3,4-tetrazol-5-yl moieties were synthesized by reaction of 6-iodo-sulfocoumarin and the corresponding tetrazole via the CH activation reaction. The new sulfocoumarins incorporating alkyl and substituted aryl moieties at the 1-position of the tetrazole, were investigated for the inhibition of four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, the cytosolic hCA I and II; and the transmembrane, tumor-associated hCA IX and XII. The tetrazole-substituted sulfocoumarins did not inhibit the ubiquitous, off-target cytosolic isoforms (KIs >10 μM) but showed effective inhibition against the two transmembrane CAs, with KIs ranging from 6.5 to 68.6 nM against hCA IX, and between 4.3 and 59.8 nM against hCA XII. As hCA IX and XII are validated anti-tumor targets, such prodrug, isoform-selective inhibitors as the sulfocoumarins reported here, may be useful for identifying suitable drug candidates for clinical trials. |
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| Keywords: | Carbonic anhydrase Inhibitor Sulfocoumarin Tumor-associated isoform IX, XII Tetrazole |
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