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Carbonic anhydrase inhibitors: Inhibition of transmembrane, tumor-associated isozyme IX, and cytosolic Isozymes I and II with aliphatic sulfamates

Winum, J. Y., Vullo, D, Casini, Angela, Montero, J. L., Scozzafava, A and Supuran, C. T. 2003. Carbonic anhydrase inhibitors: Inhibition of transmembrane, tumor-associated isozyme IX, and cytosolic Isozymes I and II with aliphatic sulfamates. Journal of Medicinal Chemistry 46 (25) , pp. 5471-5477. 10.1021/jm030911u

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Abstract

A series of aliphatic sulfamates and related derivatives incorporating cyclic/polycyclic (steroidal) moieties in their molecules has been synthesized and assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA) and, more precisely, of the cytosolic isozymes CA I and II and the transmembrane, tumor-associated isozyme CA IX. The most potent CA I inhibitor was n-tetradecyl sulfamate and some (substituted)benzyl/phenethyl sulfamates (inhibition constants in the low micromolar range). Against CA II, low nanomolar inhibitors (0.7-3.4 nM) were n-decyl sulfamate and the (substituted)benzyl/phenethyl derivatives mentioned above. Effective CA II inhibition was also observed for the hydroxy/keto derivatives of dehydroepiandrosterone sulfamate. Efficient CA IX inhibitory properties, with inhibition constants in the range of 9-23 nM, were observed for the aliphatic sulfamates C10-C16 (with the most potent inhibitor being the n-dodecyl derivative) and the (substituted)benzyl/phenethyl sulfamates. The inhibition profile of the three investigated isozymes with this type of compound was rather different, allowing us to hope that the preparation of CA IX-selective inhibitors is possible (selectivity ratios toward hCA IX versus hCA II in the range of 5-63 has been observed for some of these compounds, whereas for the clinically used sulfonamides this parameter is in the range of 0.23-0.51). These data are critical for the design of novel antitumor therapies, mainly for hypoxic tumors that overexpress CA IX, which are nonresponsive to radiation or chemotherapy.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Uncontrolled Keywords: Antigens, Neoplasm; Antineoplastic Agents; Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrases; Cytosol; Enzyme Inhibitors; Humans; Isoenzymes; Membrane Proteins; Neoplasm Proteins; Neoplasms; Structure-Activity Relationship; Sulfonic Acids
Publisher: American Chemical Society
ISSN: 0022-2623
Last Modified: 04 Jun 2017 08:49
URI: http://orca.cf.ac.uk/id/eprint/85542

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