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Carbonic anhydrase inhibitors: novel sulfonamides incorporating 1,3,5-triazine moieties as inhibitors of the cytosolic and tumour-associated carbonic anhydrase isozymes I, II and IX.
Bioorg Med Chem Lett. 2005 Jun 15; 15(12):3102-8.BM

Abstract

A new series of aromatic benzenesulfonamides incorporating 1,3,5-triazine moieties in their molecules is reported. This series was obtained by reaction of cyanuric chloride with sulfanilamide, homosulfanilamide or 4-aminoethylbenzenesulfonamide. The prepared dichlorotriazinyl-benzenesulfonamides were subsequently derivatized by reacting them with various nucleophiles, such as ammonia, hydrazine, primary and secondary amines, amino acid derivatives or phenol. 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, tumour-associated hCA IX. The new compounds inhibited hCA I with inhibition constants in the range of 31-8500 nM, hCA II with inhibition constants in the range of 14-765 nM and hCA IX with inhibition constants in the range of 1.0-640 nM. Structure-activity relationship was straightforward and rather simple in this class of CA inhibitors, with the compounds incorporating compact moieties at the triazine ring (such as amino, hydrazino, ethylamino, dimethylamino or amino acyl) being the most active ones, and the derivatives incorporating such bulky moieties (n-propyl, n-butyl, diethylaminoethyl, piperazinylethyl, pyridoxal amine or phenoxy) being less effective hCA I, II and IX inhibitors. Some of the new derivatives also showed selectivity for inhibition of hCA IX over hCA II (selectivity ratios of 23.33-32.00), thus constituting excellent leads for the development of novel approaches for the management of hypoxic tumours.

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

15905091

Citation

Garaj, Vladimir, et al. "Carbonic Anhydrase Inhibitors: Novel Sulfonamides Incorporating 1,3,5-triazine Moieties as Inhibitors of the Cytosolic and Tumour-associated Carbonic Anhydrase Isozymes I, II and IX." Bioorganic & Medicinal Chemistry Letters, vol. 15, no. 12, 2005, pp. 3102-8.
Garaj V, Puccetti L, Fasolis G, et al. Carbonic anhydrase inhibitors: novel sulfonamides incorporating 1,3,5-triazine moieties as inhibitors of the cytosolic and tumour-associated carbonic anhydrase isozymes I, II and IX. Bioorg Med Chem Lett. 2005;15(12):3102-8.
Garaj, V., Puccetti, L., Fasolis, G., Winum, J. Y., Montero, J. L., Scozzafava, A., Vullo, D., Innocenti, A., & Supuran, C. T. (2005). Carbonic anhydrase inhibitors: novel sulfonamides incorporating 1,3,5-triazine moieties as inhibitors of the cytosolic and tumour-associated carbonic anhydrase isozymes I, II and IX. Bioorganic & Medicinal Chemistry Letters, 15(12), 3102-8.
Garaj V, et al. Carbonic Anhydrase Inhibitors: Novel Sulfonamides Incorporating 1,3,5-triazine Moieties as Inhibitors of the Cytosolic and Tumour-associated Carbonic Anhydrase Isozymes I, II and IX. Bioorg Med Chem Lett. 2005 Jun 15;15(12):3102-8. PubMed PMID: 15905091.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carbonic anhydrase inhibitors: novel sulfonamides incorporating 1,3,5-triazine moieties as inhibitors of the cytosolic and tumour-associated carbonic anhydrase isozymes I, II and IX. 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 - 2005/01/05/received PY - 2005/03/29/revised PY - 2005/04/12/accepted PY - 2005/5/21/pubmed PY - 2005/9/20/medline PY - 2005/5/21/entrez SP - 3102 EP - 8 JF - Bioorganic & medicinal chemistry letters JO - Bioorg. Med. Chem. Lett. VL - 15 IS - 12 N2 - A new series of aromatic benzenesulfonamides incorporating 1,3,5-triazine moieties in their molecules is reported. This series was obtained by reaction of cyanuric chloride with sulfanilamide, homosulfanilamide or 4-aminoethylbenzenesulfonamide. The prepared dichlorotriazinyl-benzenesulfonamides were subsequently derivatized by reacting them with various nucleophiles, such as ammonia, hydrazine, primary and secondary amines, amino acid derivatives or phenol. 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, tumour-associated hCA IX. The new compounds inhibited hCA I with inhibition constants in the range of 31-8500 nM, hCA II with inhibition constants in the range of 14-765 nM and hCA IX with inhibition constants in the range of 1.0-640 nM. Structure-activity relationship was straightforward and rather simple in this class of CA inhibitors, with the compounds incorporating compact moieties at the triazine ring (such as amino, hydrazino, ethylamino, dimethylamino or amino acyl) being the most active ones, and the derivatives incorporating such bulky moieties (n-propyl, n-butyl, diethylaminoethyl, piperazinylethyl, pyridoxal amine or phenoxy) being less effective hCA I, II and IX inhibitors. Some of the new derivatives also showed selectivity for inhibition of hCA IX over hCA II (selectivity ratios of 23.33-32.00), thus constituting excellent leads for the development of novel approaches for the management of hypoxic tumours. SN - 0960-894X UR - https://www.unboundmedicine.com/medline/citation/15905091/Carbonic_anhydrase_inhibitors:_novel_sulfonamides_incorporating_135_triazine_moieties_as_inhibitors_of_the_cytosolic_and_tumour_associated_carbonic_anhydrase_isozymes_I_II_and_IX_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(05)00541-X DB - PRIME DP - Unbound Medicine ER -