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Synthesis of 6-tetrazolyl-substituted sulfocoumarins acting as highly potent and selective inhibitors of the tumor-associated carbonic anhydrase isoforms IX and XII.
Bioorg Med Chem. 2014 Mar 01; 22(5):1522-8.BM

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.

Authors+Show Affiliations

Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia.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, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia. Electronic address: raivis@osi.lv.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, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.

Pub Type(s)

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

Language

eng

PubMed ID

24513186

Citation

Grandane, Aiga, et al. "Synthesis of 6-tetrazolyl-substituted Sulfocoumarins Acting as Highly Potent and Selective Inhibitors of the Tumor-associated Carbonic Anhydrase Isoforms IX and XII." Bioorganic & Medicinal Chemistry, vol. 22, no. 5, 2014, pp. 1522-8.
Grandane A, Tanc M, Zalubovskis R, et al. Synthesis of 6-tetrazolyl-substituted sulfocoumarins acting as highly potent and selective inhibitors of the tumor-associated carbonic anhydrase isoforms IX and XII. Bioorg Med Chem. 2014;22(5):1522-8.
Grandane, A., Tanc, M., Zalubovskis, R., & Supuran, C. T. (2014). Synthesis of 6-tetrazolyl-substituted sulfocoumarins acting as highly potent and selective inhibitors of the tumor-associated carbonic anhydrase isoforms IX and XII. Bioorganic & Medicinal Chemistry, 22(5), 1522-8. https://doi.org/10.1016/j.bmc.2014.01.043
Grandane A, et al. Synthesis of 6-tetrazolyl-substituted Sulfocoumarins Acting as Highly Potent and Selective Inhibitors of the Tumor-associated Carbonic Anhydrase Isoforms IX and XII. Bioorg Med Chem. 2014 Mar 1;22(5):1522-8. PubMed PMID: 24513186.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis of 6-tetrazolyl-substituted sulfocoumarins acting as highly potent and selective inhibitors of the tumor-associated carbonic anhydrase isoforms IX and XII. AU - Grandane,Aiga, AU - Tanc,Muhammet, AU - Zalubovskis,Raivis, AU - Supuran,Claudiu T, Y1 - 2014/02/01/ PY - 2013/12/28/received PY - 2014/01/21/revised PY - 2014/01/23/accepted PY - 2014/2/12/entrez PY - 2014/2/12/pubmed PY - 2014/12/15/medline KW - Carbonic anhydrase KW - Inhibitor KW - Sulfocoumarin KW - Tetrazole KW - Tumor-associated isoform IX, XII SP - 1522 EP - 8 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 22 IS - 5 N2 - 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/24513186/Synthesis_of_6_tetrazolyl_substituted_sulfocoumarins_acting_as_highly_potent_and_selective_inhibitors_of_the_tumor_associated_carbonic_anhydrase_isoforms_IX_and_XII_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(14)00071-6 DB - PRIME DP - Unbound Medicine ER -