Carbonic anhydrase inhibitors: inhibition of transmembrane, tumor-associated isozyme IX, and cytosolic isozymes I and II with aliphatic sulfamates.
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 C(10)-C(16) (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.
Winum
Jean-Yves
JY
Laboratoire de Chimie Biomoléculaire, UMR 5032, Ecole Nationale Supérieure de Chimie de Montpellier, Université Montpellier II, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France.
Vullo
Daniela
D
Casini
Angela
A
Montero
Jean-Louis
JL
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000951:Antigens, Neoplasm / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors* / Q000737:chemistry; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000737:chemistry; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009369:Neoplasms / Q000201:enzymology; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D013451:Sulfonic Acids; C005741:sulfamic acid; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases