Winum, J. Y., Vullo, D, Casini, Angela ![]() |
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: | 31 Oct 2022 10:38 |
URI: | https://orca.cardiff.ac.uk/id/eprint/85542 |
Citation Data
Cited 76 times in Scopus. View in Scopus. Powered By Scopus® Data
Actions (repository staff only)
![]() |
Edit Item |