- Chiral synthesis method for producing cis-imidazoline compounds for pharmaceutical use
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This invention provides a method for enantioselective synthesis of cis-imidazolines and related structures through chiral resolution. A chiral acid is used to separate enantiomeric precursors of the cis-imidazolines from a racemic mixture by selective cry
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- ARYL-SUBSTITUTED IMIDAZOLES AND METHODS OF MAKING AND USING SAME
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The compounds of the invention are antagonists of MDM2 and/or MDMX, with excellent specificity for MDM2 and/or MDMX over other proteins. Several analogs demonstrate selective binding affinity to MDMX over MDM2. The disclosed compounds can therefore regulate p53 activity and treat a variety of cancers. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
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Paragraph 00451
(2015/12/17)
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- Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis -stilbene diamines: A platform for the preparation of single-enantiomer cis -imidazolines for protein-protein inhibition
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The finding by scientists at Hoffmann-La Roche that cis-imidazolines could disrupt the protein-protein interaction between p53 and MDM2, thereby inducing apoptosis in cancer cells, raised considerable interest in this scaffold over the past decade. Initial routes to these small molecules (i.e., Nutlin-3) provided only the racemic form, with enantiomers being enriched by chromatographic separation using high-pressure liquid chromatography (HPLC) and a chiral stationary phase. Reported here is the first application of an enantioselective aza-Henry approach to nonsymmetric cis-stilbene diamines and cis-imidazolines. Two novel mono(amidine) organocatalysts (MAM) were discovered to provide high levels of enantioselection (>95% ee) across a broad range of substrate combinations. Furthermore, the versatility of the aza-Henry strategy for preparing nonsymmetric cis-imidazolines is illustrated by a comparison of the roles of aryl nitromethane and aryl aldimine in the key step, which revealed unique substrate electronic effects providing direction for aza-Henry substrate-catalyst matching. This method was used to prepare highly substituted cis-4,5-diaryl imidazolines that project unique aromatic rings, and these were evaluated for MDM2-p53 inhibition in a fluorescence polarization assay. The diversification of access to cis-stilbene diamine-derived imidazolines provided by this platform should streamline their further development as chemical tools for disrupting protein-protein interactions.
- Vara, Brandon A.,Mayasundari, Anand,Tellis, John C.,Danneman, Michael W.,Arredondo, Vanessa,Davis, Tyler A.,Min, Jaeki,Finch, Kristin,Guy, R. Kiplin,Johnston, Jeffrey N.
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p. 6913 - 6938
(2014/08/18)
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- Efficient reactivation of p53 in cancer cells by a dual MdmX/Mdm2 inhibitor
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The aberrant interaction between p53 and Mdm2/MdmX is an attractive target for cancer drug discovery because the overexpression of Mdm2 and/or MdmX ultimately impairs the function of p53 in approximately half of all human cancers. Recent studies have show
- Qin, Lingyun,Yang, Fei,Zhou, Cindy,Chen, Yao,Zhang, Huashan,Su, Zhengding
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p. 18023 - 18033
(2015/03/03)
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- Preparation of (-)-nutlin-3 using enantioselective organocatalysis at decagram scale
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Chiral nonracemic cis-4,5-bis(aryl)imidazolines have emerged as a powerful platform for the development of cancer chemotherapeutics, stimulated by the Hoffmann-La Roche discovery that Nutlin-3 can restore apoptosis in cells with wild-type p53. The lack of efficient methods for the enantioselective synthesis of cis-imidazolines, however, has limited their more general use. Our disclosure of the first enantioselective synthesis of (-)-Nutlin-3 provided a basis to prepare larger amounts of this tool used widely in cancer biology. Key to the decagram-scale synthesis described here was the discovery of a novel bis(amidine) organocatalyst that provides high enantioselectivity at warmer reaction temperature (-20 C) and low catalyst loadings. Further refinements to the procedure led to the synthesis of (-)-Nutlin-3 in a 17 g batch and elimination of all but three chromatographic purifications.
- Davis, Tyler A.,Vilgelm, Anna E.,Richmond, Ann,Johnston, Jeffrey N.
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p. 10605 - 10616
(2013/11/19)
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- STEREOSELECTIVE METHODS, CATALYSTS AND INTERMEDIATES FOR THE SYNTHESIS OF (-)-NUTLIN-3 AND RELATED COMPOUNDS
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The present invention provides methods and intermediates are provided for the preparation of (?)-Nutlin-3. Methods and intermediates are also provided for the enantioselective addition of aryl nitromethanes to aldimines. Bis(amidine) catalysts for the use
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Page/Page column 16
(2012/04/18)
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- NOVEL CIS-IMIDAZOLINES
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The present invention relates to compounds of the formula (I), and the pharmaceutically acceptable salts and esters thereof, a process for their manufacture, medicaments containing them as well as the use of these compounds as pharmaceutically active agen
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Page/Page column 15
(2010/02/15)
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- Cis-imidazolines
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The present invention provides compounds according to formula I and formula II and pharmaceutically acceptable salts and esters thereof, having the designations provided herein and which inhibit the interaction of MDM2 protein with a p53-like peptide and
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