Abstract
The synthesis and antiproliferative activities of analogues of 2-substituted estradiol-3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent confirm that an H-bond acceptor is essential for high activity; its optimal linkage to C-17 and the local environment in which it resides are defined. In the non-sulfamoylated series 17β-acyl substitution delivers 48b, the most potent compound identified to date. In the sulfamate series a number of permutations of linker and H-bond acceptor deliver excellent activity, with 55, 61, 65, 49a, and 49b proving especially promising. The in vivo potential of these compounds was explored in the NCI hollow fiber assay and also in a mouse Matrigel model of antiangiogenesis in which 49 and 55 show significant inhibitory activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / chemical synthesis
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Angiogenesis Inhibitors / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Collagen
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Drug Combinations
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Drug Screening Assays, Antitumor
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Estradiol / analogs & derivatives*
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Estradiol / chemical synthesis*
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Estradiol / pharmacology
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Female
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Humans
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Laminin
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Mice
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Mice, Inbred C57BL
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Neovascularization, Physiologic / drug effects
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Nitriles / chemical synthesis
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Nitriles / pharmacology
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Proteoglycans
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Structure-Activity Relationship
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Sulfonic Acids / chemical synthesis*
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Sulfonic Acids / pharmacology
Substances
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Angiogenesis Inhibitors
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Antineoplastic Agents
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Drug Combinations
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Laminin
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Nitriles
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Proteoglycans
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Sulfonic Acids
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matrigel
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Estradiol
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Collagen
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sulfamic acid