Hypoxia-targeting carbonic anhydrase IX inhibitors by a new series of nitroimidazole-sulfonamides/sulfamides/sulfamates.

A series of nitroimidazoles incorporating sulfonamide/sulfamide/sulfamate moieties were designed and synthesized as radio/chemosensitizing agent targeting the tumor-associated carbonic anhydrase (CA) isoforms IX and XII. Most of the new compounds were nanomolar inhibitors of these isoforms. Crystallographic studies on the complex of hCA II with the lead sulfamide derivative of this series clarified the binding mode of this type of inhibitors in the enzyme active site cavity. Some of the best nitroimidazole CA IX inhibitors showed significant activity in vitro by reducing hypoxia-induced extracellular acidosis in HT-29 and HeLa cell lines. In vivo testing of the lead molecule in the sulfamide series, in cotreatment with doxorubicin, demonstrated a chemosensitization of CA IX containing tumors. Such CA inhibitors, specifically targeting the tumor-associated isoforms, are candidates for novel treatment strategies against hypoxic tumors overexpressing extracellular CA isozymes.

[1]  P. Lambin,et al.  Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: a new concept of dual targeting drugs. , 2013, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[2]  C. Supuran,et al.  Exploiting the hydrophobic and hydrophilic binding sites for designing carbonic anhydrase inhibitors , 2013, Expert opinion on drug discovery.

[3]  C. Supuran,et al.  Development of potent carbonic anhydrase inhibitors incorporating both sulfonamide and sulfamide groups. , 2012, Journal of medicinal chemistry.

[4]  C. Supuran,et al.  Ureido-substituted sulfamates show potent carbonic anhydrase IX inhibitory and antiproliferative activities against breast cancer cell lines. , 2012, Bioorganic & medicinal chemistry letters.

[5]  C. Supuran,et al.  Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts. , 2012, Journal of medicinal chemistry.

[6]  Claudiu T. Supuran,et al.  Recent Developments in Targeting Carbonic Anhydrase IX for Cancer Therapeutics , 2012, Oncotarget.

[7]  S. Dedhar,et al.  Targeting hypoxic tumour cells to overcome metastasis , 2011, BMC Cancer.

[8]  C. Supuran,et al.  Glycosyl coumarin carbonic anhydrase IX and XII inhibitors strongly attenuate the growth of primary breast tumors. , 2011, Journal of medicinal chemistry.

[9]  Claudiu T. Supuran,et al.  Interfering with pH regulation in tumours as a therapeutic strategy , 2011, Nature Reviews Drug Discovery.

[10]  Kai Liu,et al.  Nitroimidazoles as anti-tumor agents. , 2011, Anti-cancer agents in medicinal chemistry.

[11]  W. Wilson,et al.  Targeting hypoxia in cancer therapy , 2011, Nature Reviews Cancer.

[12]  P. Lambin,et al.  Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[13]  S. Leung,et al.  Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. , 2011, Cancer research.

[14]  C. Supuran,et al.  Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. , 2011, Journal of medicinal chemistry.

[15]  P. Lambin,et al.  Carbonic anhydrase inhibitors: Gd(III) complexes of DOTA- and TETA-sulfonamide conjugates targeting the tumor associated carbonic anhydrase isozymes IX and XII , 2010 .

[16]  D. Lee,et al.  Synthesis and characterization of nitroimidazole derivatives for 68Ga-labeling and testing in tumor xenografted mice. , 2010, Journal of medicinal chemistry.

[17]  C. Supuran,et al.  Carbonic anhydrase inhibitors: crystallographic and solution binding studies for the interaction of a boron-containing aromatic sulfamide with mammalian isoforms I-XV. , 2010, Bioorganic & medicinal chemistry letters.

[18]  C. Supuran,et al.  Carbonic Anhydrase Inhibitors: Design of Membrane‐Impermeant Copper(II) Complexes of DTPA‐, DOTA‐, and TETA‐Tailed Sulfonamides Targeting the Tumor‐Associated Transmembrane Isoform IX , 2008, ChemMedChem.

[19]  C. Supuran,et al.  Carbonic anhydrase inhibitors: bioreductive nitro-containing sulfonamides with selectivity for targeting the tumor associated isoforms IX and XII. , 2008, Journal of medicinal chemistry.

[20]  Claudiu T. Supuran,et al.  Carbonic anhydrases: novel therapeutic applications for inhibitors and activators , 2008, Nature Reviews Drug Discovery.

[21]  P. Lambin,et al.  Imaging the hypoxia surrogate marker CA IX requires expression and catalytic activity for binding fluorescent sulfonamide inhibitors. , 2007, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[22]  C. Supuran,et al.  Carbonic anhydrase inhibitors: clash with Ala65 as a means for designing inhibitors with low affinity for the ubiquitous isozyme II, exemplified by the crystal structure of the topiramate sulfamide analogue. , 2006, Journal of medicinal chemistry.

[23]  F. Allen.  The Cambridge Structural Database: a quarter of a million crystal structures and rising. , 2002, Acta crystallographica. Section B, Structural science.

[24]  R J Read,et al.  Crystallography & NMR system: A new software suite for macromolecular structure determination. , 1998, Acta crystallographica. Section D, Biological crystallography.

[25]  J. Zou,et al.  Improved methods for building protein models in electron density maps and the location of errors in these models. , 1991, Acta crystallographica. Section A, Foundations of crystallography.

[26]  O. S. Nielsen,et al.  A comparative investigation of nimorazole and misonidazole as hypoxic radiosensitizers in a C3H mammary carcinoma in vivo. , 1982, British Journal of Cancer.

[27]  R. Khalifah,et al.  The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C. , 1971, The Journal of biological chemistry.

[28]  Z. Otwinowski,et al.  Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[29]  T A Jones,et al.  Refined structure of human carbonic anhydrase II at 2.0 Å resolution , 1988, Proteins.