Characterization of Carbonic Anhydrase Isozyme Specific Inhibition by Sulfamated 2-Ethylestra Compounds

Katherine      H. Sippel; Andre      Stander; Chingkuang      Tu; Balasubramanian      Venkatakrishnan; Arthur      H. Robbins; Mavis      Agbandje-McKenna; Fourie      Joubert; Annie      M. Joubert; Robert      McKenna

Abstract

Sulfamated 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.

Keywords: Carbonic anhydrase, Isozyme specific, Structure based drug design, 2-Ethylestra compounds, Anti-cancer therapy, Steroid sulfatase inhibitors, Sulfamated 2-ethylestra compounds, erythrocytes, liver metabolism, estrogen, colchicine binding site, apoptosis, anti-angiogenic, PISA server, CA isoforms, cancer