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Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, IX, and XII with N-hydroxysulfamides--a new zinc-binding function in the design of inhibitors.
Bioorg Med Chem Lett. 2005 May 02; 15(9):2353-8.BM

Abstract

A small library of N-hydroxysulfamides was synthesized by an original approach in order to investigate whether this zinc-binding function is efficient for the design of inhibitors targeting the cytosolic (hCA I and II) and transmembrane, tumor-associated (hCA IX and XII) isozymes of carbonic anhydrase (CA, EC 4.2.1.1). The parent derivative, N-hydroxysulfamide was a more potent inhibitor as compared to sulfamide or sulfamic acid against all isozymes, with inhibition constants in the range of 473 nM-4.05 microM. Its substituted n-decyl-, n-dodecyl-, benzyl-, and biphenylmethyl-derivatives were less inhibitory against hCA I (K(I)s in the range of 5.8-8.2 microM) but more inhibitory against hCA II (K(I)s in the range of 50.5-473 nM). The same situation was true for the tumor-associated isozymes, with K(I)s in the range of 353-790 nM against hCA IX and 372-874 nM against hCA XII. Some sulfamides/sulfamates possessing similar substitution patterns have also been investigated for the inhibition of these isozymes, being shown that in some particular cases sulfamides are more efficient inhibitors as compared to the corresponding sulfamates. Potent CA inhibitors targeting the cytosolic or tumor-associated CA isozymes can thus be designed from various classes of sulfonamides, sulfamides, or sulfamates and their derivatives, considering the extensive interactions in which the inhibitor and the enzyme active site are engaged, based on recent X-ray crystallographic data.

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 available

Pub Type(s)

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

Language

eng

PubMed ID

15837324

Citation

Winum, Jean-Yves, et al. "Carbonic Anhydrase Inhibitors: Synthesis and Inhibition of Cytosolic/tumor-associated Carbonic Anhydrase Isozymes I, II, IX, and XII With N-hydroxysulfamides--a New Zinc-binding Function in the Design of Inhibitors." Bioorganic & Medicinal Chemistry Letters, vol. 15, no. 9, 2005, pp. 2353-8.
Winum JY, Innocenti A, Nasr J, et al. Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, IX, and XII with N-hydroxysulfamides--a new zinc-binding function in the design of inhibitors. Bioorg Med Chem Lett. 2005;15(9):2353-8.
Winum, J. Y., Innocenti, A., Nasr, J., Montero, J. L., Scozzafava, A., Vullo, D., & Supuran, C. T. (2005). Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, IX, and XII with N-hydroxysulfamides--a new zinc-binding function in the design of inhibitors. Bioorganic & Medicinal Chemistry Letters, 15(9), 2353-8.
Winum JY, et al. Carbonic Anhydrase Inhibitors: Synthesis and Inhibition of Cytosolic/tumor-associated Carbonic Anhydrase Isozymes I, II, IX, and XII With N-hydroxysulfamides--a New Zinc-binding Function in the Design of Inhibitors. Bioorg Med Chem Lett. 2005 May 2;15(9):2353-8. PubMed PMID: 15837324.
* 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, IX, and XII with N-hydroxysulfamides--a new zinc-binding function in the design of inhibitors. AU - Winum,Jean-Yves, AU - Innocenti,Alessio, AU - Nasr,Jihane, AU - Montero,Jean-Louis, AU - Scozzafava,Andrea, AU - Vullo,Daniela, AU - Supuran,Claudiu T, PY - 2004/12/20/received PY - 2005/02/23/revised PY - 2005/02/28/accepted PY - 2005/4/20/pubmed PY - 2005/10/1/medline PY - 2005/4/20/entrez SP - 2353 EP - 8 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 15 IS - 9 N2 - A small library of N-hydroxysulfamides was synthesized by an original approach in order to investigate whether this zinc-binding function is efficient for the design of inhibitors targeting the cytosolic (hCA I and II) and transmembrane, tumor-associated (hCA IX and XII) isozymes of carbonic anhydrase (CA, EC 4.2.1.1). The parent derivative, N-hydroxysulfamide was a more potent inhibitor as compared to sulfamide or sulfamic acid against all isozymes, with inhibition constants in the range of 473 nM-4.05 microM. Its substituted n-decyl-, n-dodecyl-, benzyl-, and biphenylmethyl-derivatives were less inhibitory against hCA I (K(I)s in the range of 5.8-8.2 microM) but more inhibitory against hCA II (K(I)s in the range of 50.5-473 nM). The same situation was true for the tumor-associated isozymes, with K(I)s in the range of 353-790 nM against hCA IX and 372-874 nM against hCA XII. Some sulfamides/sulfamates possessing similar substitution patterns have also been investigated for the inhibition of these isozymes, being shown that in some particular cases sulfamides are more efficient inhibitors as compared to the corresponding sulfamates. Potent CA inhibitors targeting the cytosolic or tumor-associated CA isozymes can thus be designed from various classes of sulfonamides, sulfamides, or sulfamates and their derivatives, considering the extensive interactions in which the inhibitor and the enzyme active site are engaged, based on recent X-ray crystallographic data. SN - 0960-894X UR - https://www.unboundmedicine.com/medline/citation/15837324/Carbonic_anhydrase_inhibitors:_synthesis_and_inhibition_of_cytosolic/tumor_associated_carbonic_anhydrase_isozymes_I_II_IX_and_XII_with_N_hydroxysulfamides__a_new_zinc_binding_function_in_the_design_of_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(05)00298-2 DB - PRIME DP - Unbound Medicine ER -