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Inhibition of carbonic anhydrase isoforms I, II, IX and XII with novel Schiff bases: identification of selective inhibitors for the tumor-associated isoforms over the cytosolic ones.
Bioorg Med Chem. 2014 Nov 01; 22(21):5883-90.BM

Abstract

A series of new Schiff bases was obtained from sulfanilamide, 3-fluorosulfanilamide or 4-(2-aminoethyl)-benzenesulfonamide and aromatic/heterocyclic aldehydes incorporating both hydrophobic and hydrophilic moieties. The obtained sulfonamides were investigated as inhibitors of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, as well as the transmembrane, tumor-associated CA IX and XII. Most derivatives were medium potency or weak hCA I/II inhibitors, but several of them showed nanomolar affinity for CA IX and/or XII, making them an interesting example of isoform-selective compounds. The nature of the aryl/hetaryl moiety present in the initial aldehyde was the main factor influencing potency and isoform selectivity. The best and most CA IX-selective compounds incorporated moieties such as 4-methylthiophenyl, 4-cyanophenyl-, 4-(2-pyridyl)-phenyl and the 4-aminoethylbenzenesulfonamide scaffold. The best hCA XII inhibitors, also showing selectivity for this isoform, incorporated 2-methoxy-4-nitrophenyl-, 2,3,5,6-tetrafluorophenyl and 4-(2-pyridyl)-phenyl functionalities and were also derivatives of 4-aminoethylbenzenesulfonamide. The sulfanilamide and 3-fluorosulfanilamide derived Schiff bases were less active compared to the corresponding 4-aminoethyl-benzenesulfonamide derivatives. As hCA IX/XII selective inhibition is attractive for obtaining antitumor agents/diagnostic tools with a new mechanism of action, compounds of the type described here may be considered interesting preclinical candidates.

Authors+Show Affiliations

Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188, Italy; Neurofarba Department, Sezione di Scienze Farmaceutiche, Via U. Schiff 6, I-50019 Sesto Fiorentino (Firenze), Italy.Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188, Italy; Neurofarba Department, Sezione di Scienze Farmaceutiche, Via U. Schiff 6, I-50019 Sesto Fiorentino (Firenze), Italy.Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188, Italy; Neurofarba Department, Sezione di Scienze Farmaceutiche, Via U. Schiff 6, I-50019 Sesto Fiorentino (Firenze), Italy.Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188, Italy; Neurofarba Department, Sezione di Scienze Farmaceutiche, Via U. Schiff 6, I-50019 Sesto Fiorentino (Firenze), Italy. Electronic address: claudiu.supuran@unifi.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25267005

Citation

Sarikaya, Busra, et al. "Inhibition of Carbonic Anhydrase Isoforms I, II, IX and XII With Novel Schiff Bases: Identification of Selective Inhibitors for the Tumor-associated Isoforms Over the Cytosolic Ones." Bioorganic & Medicinal Chemistry, vol. 22, no. 21, 2014, pp. 5883-90.
Sarikaya B, Ceruso M, Carta F, et al. Inhibition of carbonic anhydrase isoforms I, II, IX and XII with novel Schiff bases: identification of selective inhibitors for the tumor-associated isoforms over the cytosolic ones. Bioorg Med Chem. 2014;22(21):5883-90.
Sarikaya, B., Ceruso, M., Carta, F., & Supuran, C. T. (2014). Inhibition of carbonic anhydrase isoforms I, II, IX and XII with novel Schiff bases: identification of selective inhibitors for the tumor-associated isoforms over the cytosolic ones. Bioorganic & Medicinal Chemistry, 22(21), 5883-90. https://doi.org/10.1016/j.bmc.2014.09.021
Sarikaya B, et al. Inhibition of Carbonic Anhydrase Isoforms I, II, IX and XII With Novel Schiff Bases: Identification of Selective Inhibitors for the Tumor-associated Isoforms Over the Cytosolic Ones. Bioorg Med Chem. 2014 Nov 1;22(21):5883-90. PubMed PMID: 25267005.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of carbonic anhydrase isoforms I, II, IX and XII with novel Schiff bases: identification of selective inhibitors for the tumor-associated isoforms over the cytosolic ones. AU - Sarikaya,Busra, AU - Ceruso,Mariangela, AU - Carta,Fabrizio, AU - Supuran,Claudiu T, Y1 - 2014/09/21/ PY - 2014/08/02/received PY - 2014/09/09/revised PY - 2014/09/10/accepted PY - 2014/10/1/entrez PY - 2014/10/1/pubmed PY - 2015/7/23/medline KW - Carbonic anhydrase KW - Imine KW - Isoform-selective inhibitor KW - Sulfonamide KW - Tumor-associated enzymes SP - 5883 EP - 90 JF - Bioorganic & medicinal chemistry JO - Bioorg. Med. Chem. VL - 22 IS - 21 N2 - A series of new Schiff bases was obtained from sulfanilamide, 3-fluorosulfanilamide or 4-(2-aminoethyl)-benzenesulfonamide and aromatic/heterocyclic aldehydes incorporating both hydrophobic and hydrophilic moieties. The obtained sulfonamides were investigated as inhibitors of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, as well as the transmembrane, tumor-associated CA IX and XII. Most derivatives were medium potency or weak hCA I/II inhibitors, but several of them showed nanomolar affinity for CA IX and/or XII, making them an interesting example of isoform-selective compounds. The nature of the aryl/hetaryl moiety present in the initial aldehyde was the main factor influencing potency and isoform selectivity. The best and most CA IX-selective compounds incorporated moieties such as 4-methylthiophenyl, 4-cyanophenyl-, 4-(2-pyridyl)-phenyl and the 4-aminoethylbenzenesulfonamide scaffold. The best hCA XII inhibitors, also showing selectivity for this isoform, incorporated 2-methoxy-4-nitrophenyl-, 2,3,5,6-tetrafluorophenyl and 4-(2-pyridyl)-phenyl functionalities and were also derivatives of 4-aminoethylbenzenesulfonamide. The sulfanilamide and 3-fluorosulfanilamide derived Schiff bases were less active compared to the corresponding 4-aminoethyl-benzenesulfonamide derivatives. As hCA IX/XII selective inhibition is attractive for obtaining antitumor agents/diagnostic tools with a new mechanism of action, compounds of the type described here may be considered interesting preclinical candidates. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/25267005/Inhibition_of_carbonic_anhydrase_isoforms_I_II_IX_and_XII_with_novel_Schiff_bases:_identification_of_selective_inhibitors_for_the_tumor_associated_isoforms_over_the_cytosolic_ones_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(14)00667-1 DB - PRIME DP - Unbound Medicine ER -