Carbonic anhydrase inhibitors. Inhibition of cytosolic isozymes I and II and transmembrane, tumor-associated isozyme IX with sulfamates including EMATE also acting as steroid sulfatase inhibitors.

Abstract

A series of sulfamates or bis-sulfamates incorporating aliphatic, aromatic, polycyclic (steroidal), and sugar 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 andII, and the transmembrane, tumor-associated isozymes CA IX. Some of these compounds were previously reported to act as inhibitors of steroid sulfatases, among which estrone sulfatase (ES) and dehydroepiandrosterone sulfatase (DHEAS) are the key therapeutic targets for estrogen-dependent tumors. Very potent (nanomolar) inhibitors were detected against the three investigated CA isozymes. Best CA I inhibitors were phenylsulfamate and some of its 4-halogeno derivatives, as well as the aliphatic compound n-octyl sulfamate. Against CA II, low nanomolar inhibitors (1.1-5 nM) were phenylsulfamate and some of its 4-halogeno/nitro derivatives, n-octyl sulfamate, and estradiol 3,17beta-disulfamate among others. All the investigated sulfamates showed efficient CA IX inhibitory properties, with inhibition constants in the range of 18-63 nM. The best CA IX inhibitor detected so far was 4-chlorophenylsulfamate. These data are critical for the design of novel antitumor properties, mainly for hypoxic tumors that overexpress CA IX, which are nonresponsive to radiation or chemotherapy. The antitumor properties of the ES/DHEAS inhibitors in clinical trials may on the other hand also be due to their potent inhibitory properties of CA isozymes involved in tumorigenicity, such as CA II and CA IX.

• Authors: Jean-Yves Winum, Daniela Vullo, Angela Casini, Jean-Louis Montero, Andrea Scozzafava, Claudiu T Supuran
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 46 Issue 11 Pg. 2197-204 (May 22 2003) ISSN: 0022-2623 [Print] United States
• PMID: 12747791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Biomarkers, Tumor
• Enzyme Inhibitors
• Membrane Proteins
• Neoplasm Proteins
• Sulfonic Acids
• estrone-3-O-sulfamate
• Estrone
• sulfamic acid
• Arylsulfatases
• Steryl-Sulfatase
• Carbonic Anhydrase I
• Carbonic Anhydrase II
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases

Topics

• Antigens, Neoplasm (chemistry)
• Arylsulfatases (antagonists & inhibitors, chemistry)
• Biomarkers, Tumor
• Carbonic Anhydrase I (antagonists & inhibitors, chemistry)
• Carbonic Anhydrase II (antagonists & inhibitors, chemistry)
• Carbonic Anhydrase IX
• Carbonic Anhydrases (chemistry)
• Cytosol (enzymology)
• Enzyme Inhibitors (chemical synthesis, chemistry)
• Estrone (analogs & derivatives, chemical synthesis, chemistry)
• Humans
• Membrane Proteins (antagonists & inhibitors, chemistry)
• Neoplasm Proteins (antagonists & inhibitors, chemistry)
• Steryl-Sulfatase
• Structure-Activity Relationship
• Sulfonic Acids (chemical synthesis, chemistry)