title: 6-Substituted sulfocoumarins are selective carbonic anhdydrase IX and XII inhibitors with significant cytotoxicity against colorectal cancer cells.
abstract: 6-Substituted sulfocoumarins bearing the carboxamido, trimethylammonium as well as the cyano and methoxy moieties with interesting inhibitory activity/selectivity against the tumor associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA IX and XII are reported. Moieties leading to the best inhibition were tert-butylcarboxamido, phenylcarboxamido, and 4-pyridylcarboxamido, with K(I) values of 2.1-8.1 nM. No inhibition of the off-target hCA II and I was observed. A number of these compounds were evaluated against HT-29 colon cancer cell lines ex vivo. Compounds 9c and 9e revealed effective cytotoxic effects after 72 h of incubation in both normoxic and hypoxic conditions, unlike sulfonamide CA inhibitors that show such effects only in hypoxia. These results may be of particular importance for the choice of future drug candidates targeting hypoxic tumors and metastases, considering the fact that a sulfonamide CA IX inhibitor (SLC-0111) is presently in phase I clinical trials.
authors: †Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia.
authors: Aiga
authors: A
authors: Grandane
authors: ‡NEUROFARBA Department, Section of Pharmaceutical Chemistry, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.|§Laboratorio di Chimica Bioinorganica, Polo Scientifico, Università degli Studi di Firenze, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors: Muhammet
authors: M
authors: Tanc
authors: ∥NEUROFARBA Department, Section of Pharmacology and Toxicology, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
authors: Lorenzo
authors: L
authors: Di Cesare Mannelli
authors: §Laboratorio di Chimica Bioinorganica, Polo Scientifico, Università degli Studi di Firenze, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors: Fabrizio
authors: F
authors: Carta
authors: ∥NEUROFARBA Department, Section of Pharmacology and Toxicology, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
authors: Carla
authors: C
authors: Ghelardini
authors: †Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia.
authors: Raivis
authors: R
authors: Žalubovskis
authors: ‡NEUROFARBA Department, Section of Pharmaceutical Chemistry, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.|§Laboratorio di Chimica Bioinorganica, Polo Scientifico, Università degli Studi di Firenze, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors: Claudiu T
authors: CT
authors: Supuran
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000599959:2-bromo-N-(2,2-dioxido-1,2-benzoxathiin-6-yl)benzamide; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001549:Benzamides; D002257:Carbonic Anhydrase Inhibitors; D003499:Cyclic S-Oxides; D007527:Isoenzymes; C000599958:N-(2,2-dioxido-1,2-benzoxathiin-6-yl)benzamide; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII