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Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating 1,2,4-triazine moieties.
Bioorg Med Chem Lett. 2004 Nov 01; 14(21):5427-33.BM

Abstract

A series of benzenesulfonamide derivatives incorporating triazine moieties in their molecules was obtained by reaction of cyanuric chloride with sulfanilamide, homosulfanilamide, or 4-aminoethylbenzenesulfonamide. The dichlorotriazinyl-benzenesulfonamides intermediates were subsequently derivatized by reaction with various nucleophiles, such as water, methylamine, or aliphatic alcohols (methanol and ethanol). The library of sulfonamides incorporating triazinyl moieties was tested for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic hCA I and II, and the transmembrane, tumor-associated hCA IX. The new compounds reported here inhibited hCA I with K(I)s in the range of 75-136nM, hCA II with K(I)s in the range of 13-278nM, and hCA IX with K(I)s in the range of 0.12-549nM. The first hCA IX-selective inhibitors were thus detected, as the chlorotriazinyl-sulfanilamide and the bis-ethoxytriazinyl derivatives of sulfanilamide/homosulfanilamide showed selectivity ratios for CA IX over CA II inhibition in the range of 166-706. Furthermore, some of these compounds have subnanomolar affinity for hCA IX, with K(I)s in the range 0.12-0.34nM. These derivatives are interesting candidates for the development of novel unconventional anticancer strategies targeting the hypoxic areas of tumors. Clear renal cell carcinoma, which is the most lethal urologic malignancy and is both characterized by very high CA IX expression and chemotherapy unresponsiveness, could be the leading candidate of such novel therapies.

Authors+Show Affiliations

Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15454239

Citation

Garaj, Vladimir, et al. "Carbonic Anhydrase Inhibitors: Synthesis and Inhibition of Cytosolic/tumor-associated Carbonic Anhydrase Isozymes I, II, and IX With Sulfonamides Incorporating 1,2,4-triazine Moieties." Bioorganic & Medicinal Chemistry Letters, vol. 14, no. 21, 2004, pp. 5427-33.
Garaj V, Puccetti L, Fasolis G, et al. Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating 1,2,4-triazine moieties. Bioorg Med Chem Lett. 2004;14(21):5427-33.
Garaj, V., Puccetti, L., Fasolis, G., Winum, J. Y., Montero, J. L., Scozzafava, A., Vullo, D., Innocenti, A., & Supuran, C. T. (2004). Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating 1,2,4-triazine moieties. Bioorganic & Medicinal Chemistry Letters, 14(21), 5427-33.
Garaj V, et al. Carbonic Anhydrase Inhibitors: Synthesis and Inhibition of Cytosolic/tumor-associated Carbonic Anhydrase Isozymes I, II, and IX With Sulfonamides Incorporating 1,2,4-triazine Moieties. Bioorg Med Chem Lett. 2004 Nov 1;14(21):5427-33. PubMed PMID: 15454239.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating 1,2,4-triazine moieties. AU - Garaj,Vladimir, AU - Puccetti,Luca, AU - Fasolis,Giuseppe, AU - Winum,Jean-Yves, AU - Montero,Jean-Louis, AU - Scozzafava,Andrea, AU - Vullo,Daniela, AU - Innocenti,Alessio, AU - Supuran,Claudiu T, PY - 2004/06/02/received PY - 2004/07/07/revised PY - 2004/07/28/accepted PY - 2004/9/30/pubmed PY - 2005/5/6/medline PY - 2004/9/30/entrez SP - 5427 EP - 33 JF - Bioorganic & medicinal chemistry letters JO - Bioorg. Med. Chem. Lett. VL - 14 IS - 21 N2 - A series of benzenesulfonamide derivatives incorporating triazine moieties in their molecules was obtained by reaction of cyanuric chloride with sulfanilamide, homosulfanilamide, or 4-aminoethylbenzenesulfonamide. The dichlorotriazinyl-benzenesulfonamides intermediates were subsequently derivatized by reaction with various nucleophiles, such as water, methylamine, or aliphatic alcohols (methanol and ethanol). The library of sulfonamides incorporating triazinyl moieties was tested for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic hCA I and II, and the transmembrane, tumor-associated hCA IX. The new compounds reported here inhibited hCA I with K(I)s in the range of 75-136nM, hCA II with K(I)s in the range of 13-278nM, and hCA IX with K(I)s in the range of 0.12-549nM. The first hCA IX-selective inhibitors were thus detected, as the chlorotriazinyl-sulfanilamide and the bis-ethoxytriazinyl derivatives of sulfanilamide/homosulfanilamide showed selectivity ratios for CA IX over CA II inhibition in the range of 166-706. Furthermore, some of these compounds have subnanomolar affinity for hCA IX, with K(I)s in the range 0.12-0.34nM. These derivatives are interesting candidates for the development of novel unconventional anticancer strategies targeting the hypoxic areas of tumors. Clear renal cell carcinoma, which is the most lethal urologic malignancy and is both characterized by very high CA IX expression and chemotherapy unresponsiveness, could be the leading candidate of such novel therapies. SN - 0960-894X UR - https://www.unboundmedicine.com/medline/citation/15454239/Carbonic_anhydrase_inhibitors:_synthesis_and_inhibition_of_cytosolic/tumor_associated_carbonic_anhydrase_isozymes_I_II_and_IX_with_sulfonamides_incorporating_124_triazine_moieties_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(04)00988-6 DB - PRIME DP - Unbound Medicine ER -