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Design of a carbonic anhydrase IX active-site mimic to screen inhibitors for possible anticancer properties.

ABSTRACT: Recently, a convincing body of evidence has accumulated suggesting that the overexpression of carbonic anhydrase isozyme IX (CA IX) in some cancers contributes to the acidification of the extracellular matrix, which in turn promotes the growth and metastasis of the tumor. These observations have made CA IX an attractive drug target for the selective treatment of certain cancers. Currently, there is no available X-ray crystal structure of CA IX, and this lack of availability has hampered the rational design of selective CA IX inhibitors. In light of these observations and on the basis of structural alignment homology, using the crystal structure of carbonic anhydrase II (CA II) and the sequence of CA IX, a double mutant of CA II with Ala65 replaced by Ser and Asn67 replaced by Gln has been constructed to resemble the active site of CA IX. This CA IX mimic has been characterized kinetically using (18)O-exchange and structurally using X-ray crystallography, alone and in complex with five CA sulfonamide-based inhibitors (acetazolamide, benzolamide, chlorzolamide, ethoxzolamide, and methazolamide), and compared to CA II. This structural information has been evaluated by both inhibition studies and in vitro cytotoxicity assays and shows a correlated structure-activity relationship. Kinetic and structural studies of CA II and CA IX mimic reveal chlorzolamide to be a more potent inhibitor of CA IX, inducing an active-site conformational change upon binding. Additionally, chlorzolamide appears to be cytotoxic to prostate cancer cells. This preliminary study demonstrates that the CA IX mimic may provide a useful model to design more isozyme-specific CA IX inhibitors, which may lead to development of new therapeutic treatments of some cancers.

SUBMITTER: Genis C

PROVIDER: S-EPMC2713499 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Design of a carbonic anhydrase IX active-site mimic to screen inhibitors for possible anticancer properties.

Genis Caroli C Sippel Katherine H KH Case Nicolette N Cao Wengang W Avvaru Balendu Sankara BS Tartaglia Lawrence J LJ Govindasamy Lakshmanan L Tu Chingkuang C Agbandje-McKenna Mavis M Silverman David N DN Rosser Charles J CJ McKenna Robert R

Biochemistry 20090201 6

Recently, a convincing body of evidence has accumulated suggesting that the overexpression of carbonic anhydrase isozyme IX (CA IX) in some cancers contributes to the acidification of the extracellular matrix, which in turn promotes the growth and metastasis of the tumor. These observations have made CA IX an attractive drug target for the selective treatment of certain cancers. Currently, there is no available X-ray crystal structure of CA IX, and this lack of availability has hampered the rati ...[more]

PMID: 19170619

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Project description:Changes in gene expression cause uncontrolled cell proliferation and consequently tumor hypoxia. The tumor cells shift their metabolism to anaerobic glycolysis with a significant modification in pH. Therefore, an over expression of carbonic anhydrase IX (CA IX) genes was detected in many solid tumors. Accordingly, selective inhibition of CA IX can be a useful target for discovering novel antiproliferative agents. The present study described the synthesis of new aryl thiazolone-benzenesulfonamides 4a-j as well as their carbonic anhydrase IX inhibitory effect. All the designed derivatives were evaluated for their anti-proliferative activity against triple-negative breast cancer cell line (as MDA-MB-231) and another breast cancer cell line (MCF-7) in addition to normal breast cell line MCF-10A. Compounds 4b-c, 4e, 4g-h showed significant inhibitory effect against both cancer cell lines at concentration ranges from 1.52-6.31 μM, with a high selectivity against breast cancer cell lines ranges from 5.5 to 17.5 times. Moreover, three sulfonamides derivatives 4e, 4g and 4h showed excellent enzyme inhibition against CA IX with IC50 10.93-25.06 nM and against CA II with IC50 1.55-3.92 μM that revealed their remarkable selectivity for CA IX over CA II. Additionally, 4e was able to induce apoptosis in MDA-MB-231 with a significant increase in the annexin V-FITC percent by 22 fold as compared with control. Cellular uptake on MDA-MB-231 cell lines were carried out using HPLC method on the three active compounds (4e, 4g and 4h). On the other hand inhibition of one or more CAs present in bacteria was reported to interfere with bacterial growth. So, the new benzenesulfonamides were evaluated against their antibacterial and anti-biofilm activities. Analogues 4e, 4g and 4h exhibited significant inhibition at 50 μg mL-1 concentration with 80.69%, 69.74% and 68.30% against S. aureus compared to the positive control CIP which was 99.2%, while compounds 4g and 4h showed potential anti-biofilm inhibition 79.46% and 77.52% against K. pneumonia. Furthermore, the designed compounds were docked into CA IX (human) protein (PDB ID: 5FL6) and molecular modeling studies revealed favorable binding interactions for the active inhibitors. Finally, the predictive ADMET studies showed that, compounds 4e, 4g and 4h possessed promising pharmacokinetic properties.

Dataset Information

Design of a carbonic anhydrase IX active-site mimic to screen inhibitors for possible anticancer properties.

Publications

Design of a carbonic anhydrase IX active-site mimic to screen inhibitors for possible anticancer properties.

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