2GD8

Crystal structure analysis of the human carbonic anhydrase II in complex with a 2-substituted estradiol bis-sulfamate

Summary for 2GD8

• Entry DOI: 10.2210/pdb2gd8/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: protein-inhibitor complexes, lyase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00918
• Total number of polymer chains: 1
• Total formula weight: 30501.56

Authors

De Simone, G.,Di Fiore, A. (deposition date: 2006-03-15, release date: 2007-02-06, Last modification date: 2023-08-30)

Primary citation

Leese, M.P.,Leblond, B.,Smith, A.,Newman, S.P.,Di Fiore, A.,De Simone, G.,Supuran, C.T.,Purohit, A.,Reed, M.J.,Potter, B.V.
2-substituted estradiol bis-sulfamates, multitargeted antitumor agents: synthesis, in vitro SAR, protein crystallography, and in vivo activity.
J.Med.Chem., 49:7683-7696, 2006

PubMed Abstract: The anticancer activities and SARs of estradiol-17-O-sulfamates and estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) as steroid sulfatase (STS) inhibitors and antiproliferative agents are discussed. Estradiol 3,17-O,O-bis-sulfamates 20 and 21, in contrast to the 17-O-monosulfamate 11, proved to be excellent STS inhibitors. 2-Substituted E2bisMATEs 21 and 23 additionally exhibited potent antiproliferative activity with mean graph midpoint values of 18-87 nM in the NCI 60-cell-line panel. 21 Exhibited antiangiogenic in vitro and in vivo activity in an early-stage Lewis lung model, and 23 dosed p.o. caused marked growth inhibition in a nude mouse xenograft tumor model. Modeling studies suggest that the E2bisMATEs and 2-MeOE2 share a common mode of binding to tubulin, though COMPARE analysis of activity profiles was negative. 21 was cocrystallized with carbonic anhydrase II, and X-ray crystallography revealed unexpected coordination of the 17-O-sulfamate of 21 to the active site zinc and a probable additional lower affinity binding site. 2-Substituted E2bisMATEs are attractive candidates for further development as multitargeted anticancer agents.

PubMed: 17181151
DOI: 10.1021/jm060705x

Experimental method

X-RAY DIFFRACTION (1.46 Å)