Characterization of carbonic anhydrase isozyme specific inhibition by sulfamated 2-ethylestra compounds

dc.contributor.authorSippel, Katherine H.
dc.contributor.authorStander, Andre
dc.contributor.authorTu, Chingkuang
dc.contributor.authorVenkatakrishnan, Balasubramanian
dc.contributor.authorRobbins, Arthur H.
dc.contributor.authorAgbandje-McKenna, Mavis
dc.contributor.authorJoubert, Fourie
dc.contributor.authorJoubert, Annie M.
dc.contributor.authorMcKenna, Robert
dc.date.accessioned2012-02-27T07:10:38Z
dc.date.available2012-10-31T00:20:03Z
dc.date.issued2011-10
dc.description.abstractSulfamated 2-ethylestra compounds have demonstrated strong anticancer activity, high bioavailability and an ability to bypass liver metabolism by reversibly binding carbonic anhydrase (CA) II in erythrocytes. Another CA isoform, CA IX, is overexpressed in many cancers. The CA domain of CA IX is oriented extracellularly, which may permit targeting inhibitors to tumors. Presented here is the characterization of three 2-ethylestra compounds bound to both CA II and a CA IX mimic protein. Inhibition by 18O exchange showed that compound 16 demonstrated an approximately 12-fold higher affinity for CA II over CA IX mimic. Structurally, compounds 15 and 16 showed alternate binding modes between CA II and CA IX mimic, apparently due to a water-mediated hydrogen bond to the isozyme-specific residue 67. Though the specificity was demonstrated for CA II over CA IX, this study reveals insights that may be key to developing isozyme specific CA inhibitors for novel anticancer therapies.en
dc.description.librariannf2012en
dc.description.sponsorshipThis work was supported by NIH Grant GM25154 and by grants from the Medical Research Council of South Africa (AG374, AK076), the Cancer Association of South Africa (AK246), the Struwig-Germeshuysen Cancer Research Trust of South Africa (AJ038) and RESCOM University of Pretoria (A0R984).en_US
dc.description.urihttp://www.benthamscience.com/lddd/en_US
dc.identifier.citationSippel, KH, Stander, A, Tu, C, Venkatakrishnan, B, Robbins, AH, Agbandje-McKenna, M, Joubert, F, Joubert, AM & McKenna, R 2011, 'Characterization of carbonic anhydrase isozyme specific inhibition by sulfamated 2-ethylestra compounds', Letters in Drug Design & Discovery, vol. 8, no. 8, pp. 678-684.en
dc.identifier.issn1570-1808
dc.identifier.other10.2174/157018011796576105
dc.identifier.urihttp://hdl.handle.net/2263/18239
dc.language.isoenen_US
dc.publisherBentham Scienceen_US
dc.rightsBentham Science. This article is embargoed by the publisher until October 2012.en
dc.subjectStructure based drug designen
dc.subject2-Ethylestra compoundsen
dc.subjectAnticancer therapyen
dc.subjectSteroid sulfatase inhibitorsen
dc.subjectSulfamated 2-ethylestra compoundsen
dc.subjectLiver metabolismen
dc.subjectColchicine binding siteen
dc.subjectAnti-angiogenicen
dc.subjectPISA serveren
dc.subjectCA isoformsen
dc.subject.lcshCarbonic anhydraseen
dc.subject.lcshIsoenzymesen
dc.subject.lcshDrugs -- Designen
dc.subject.lcshErythrocytesen
dc.subject.lcshEstrogenen
dc.subject.lcshApoptosisen
dc.subject.lcshCancer -- Treatmenten
dc.titleCharacterization of carbonic anhydrase isozyme specific inhibition by sulfamated 2-ethylestra compoundsen
dc.typePostprint Articleen

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