- Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold
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Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure-activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm.
- Crowley, Vincent M.,Khandelwal, Anuj,Mishra, Sanket,Stothert, Andrew R.,Huard, Dustin J. E.,Zhao, Jinbo,Muth, Aaron,Duerfeldt, Adam S.,Kizziah, James L.,Lieberman, Raquel L.,Dickey, Chad A.,Blagg, Brian S. J.
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p. 3471 - 3488
(2016/05/19)
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- The Generation and Chemistry of Dianions derived from Furancarboxylic Acids
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Methods for the generation of the dianionic species lithium 5-lithiofuran-2-carboxylate (5) and lithium 2-lithiofuran-3-carboxylate (21) from furan-2- and furan-3-carboxylic acids recpectively are described.The reactions of (5) and (21) with a range of electrophiles have been examined; in general these are very efficient with aldehydes and ketones but not as satisfactory with alkyl halides and epoxides.The dianions do not couple with allylic or benzylic halides, nor with nitriles or orthoesters.The generation of lithium-5-lithio-3-methylfuran-2-carboxylate (15) from 3-methyl furan-2-carboxylic acid is also described; the chemistry of (15) is very similar to (5) derived from furan-2-carboxylic acid.
- Knight, David W.,Nott, Andrew P.
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p. 1125 - 1131
(2007/10/02)
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