2gd8: Difference between revisions
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==Overview== | ==Overview== | ||
The anticancer activities and SARs of estradiol-17-O-sulfamates and | 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. | ||
==Disease== | ==Disease== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Fiore, A | [[Category: Fiore, A Di.]] | ||
[[Category: Simone, G | [[Category: Simone, G De.]] | ||
[[Category: CL]] | [[Category: CL]] | ||
[[Category: MBO]] | [[Category: MBO]] | ||
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[[Category: protein-inhibitor complexes]] | [[Category: protein-inhibitor complexes]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:30:39 2008'' | ||
Revision as of 15:30, 21 February 2008
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Crystal structure analysis of the human carbonic anhydrase II in complex with a 2-substituted estradiol bis-sulfamate
Overview
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.
Disease
Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[611492]
About this Structure
2GD8 is a Single protein structure of sequence from Homo sapiens with ZN, CL, PO1 and MBO as ligands. Active as Carbonate dehydratase, with EC number 4.2.1.1 Full crystallographic information is available from OCA.
Reference
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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