New pyrazolo[4,3-e][1,2,4]triazine sulfonamides as carbonic anhydrase inhibitors.
New sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine were synthesized and investigated as antitumor agents through carbonic anhydrase (CA, EC 4.2.1.1) inhibition. The newly prepared compounds were tested for their anticancer activity against human breast cancer cell lines (MCF-7, MDA-MB-231) using a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA. Preliminary biological studies with several CA isoforms, revealed that the new derivatives were ineffective as CA I and II inhibitors, but they showed activity against tumor-associated enzymes, such as CA IX. The most effective inhibitor against CA IX was compound 8e that exhibited an inhibition constant KI of 13.8nM, and derivatives 8c-8d with moderate activity (8c: KI=25.4nM; 8d: KI=24.5nM). Compounds 8g-8h exhibited acceptable activity (8g: KI=27.7nM; 8d: KI=26.6nM). The detailed synthesis, spectroscopic and biological data are also reported.
Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland. Electronic address: mmojzych@yahoo.com.
Mariusz
M
Mojzych
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy; Università degli Studi di Firenze, NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
Mariangela
M
Ceruso
Department of Medicinal Chemistry and Drug Technology, Medical University of Bialystok, Bialystok, Poland.
Anna
A
Bielawska
Department of Medicinal Chemistry and Drug Technology, Medical University of Bialystok, Bialystok, Poland.
Krzysztof
K
Bielawski
Department of Chemistry, Laboratory of Separation and Spectroscopic Method Applications, Center for Interdisciplinary Research, The John Paul II Catholic University of Lublin, al. Krasnicka 102, 20-718 Lublin, Poland.
Emilia
E
Fornal
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy; Università degli Studi di Firenze, NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
Claudiu T
CT
Supuran
D000951:Antigens, Neoplasm / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology; D014316:Tritium
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D014227:Triazines; D014316:Tritium; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D013936:Thymidine
Carbonic anhydrase inhibitors; Cytotoxicity; MCF-7; Pyrazolo[4,3-e][1,2,4]triazine; Sulfonamides