2gd8
Crystal structure analysis of the human carbonic anhydrase II in complex with a 2-substituted estradiol bis-sulfamate
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OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[611492]
About this StructureAbout this Structure
2GD8 is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Active as Carbonate dehydratase, with EC number 4.2.1.1 Full crystallographic information is available from OCA.
ReferenceReference
2-substituted estradiol bis-sulfamates, multitargeted antitumor agents: synthesis, in vitro SAR, protein crystallography, and in vivo activity., Leese MP, Leblond B, Smith A, Newman SP, Di Fiore A, De Simone G, Supuran CT, Purohit A, Reed MJ, Potter BV, J Med Chem. 2006 Dec 28;49(26):7683-96. PMID:17181151
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