title: Inhibition of carbonic anhydrase II by steroidal and non-steroidal sulphamates.
abstract: Carbonic anhydrases (CAs) are expressed by many solid tumours where they may act to confer a growth advantage on malignant tissues. In this study we have examined the ability of a series of steroidal and non-steroidal sulphamates (originally developed as steroid sulphatase inhibitors) and related compounds to inhibit human CAII (hCAII) activity in vitro. Using a 96-well plate assay, oestrone-3-O-sulphamate (EMATE) and two coumarin-based sulphamate drugs (667 COUMATE and STX 118) were found to have IC(50) values of 25-59 nM for the inhibition of hCAII activity. These compounds therefore have a similar CAII inhibitory potency to that of acetazolamide (IC(50)=25 nM), a known hCAII inhibitor. Docking studies have been performed with selected compounds to the crystal structure of hCAII and excellent correlation of scores with biological activity was observed. This agrees with our recent observations when we were the first to report the inhibition of hCAII by STS inhibitors. These studies and initial results with docking to the crystal structure of the extracellular domain of hCAXII indicate that the STS sulphamate ester inhibitors should also be interesting candidates to pursue as inhibitors of CA isozymes that are over-expressed in human tumours.
authors.affiliation: Endocrinology and Metabolic Medicine and Sterix Ltd., Faculty of Medicine, Imperial College, St. Mary's Hospital, London W2 1NY, UK.
authors.forename: Y T
authors.initials: YT
authors.lastname: Ho
authors.forename: A
authors.initials: A
authors.lastname: Purohit
authors.forename: N
authors.initials: N
authors.lastname: Vicker
authors.forename: S P
authors.initials: SP
authors.lastname: Newman
authors.forename: J J
authors.initials: JJ
authors.lastname: Robinson
authors.forename: M P
authors.initials: MP
authors.lastname: Leese
authors.forename: D
authors.initials: D
authors.lastname: Ganeshapillai
authors.forename: L W L
authors.initials: LW
authors.lastname: Woo
authors.forename: B V L
authors.initials: BV
authors.lastname: Potter
authors.forename: M J
authors.initials: MJ
authors.lastname: Reed
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000737:chemistry / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D013256:Steroids; D013449:Sulfonamides; C088768:estrone-3-O-sulfamate; D004970:Estrone; D024402:Carbonic Anhydrase II