- PHOTORESPONSIVE NUTLIN DERIVATIVES AND USES THEREOF
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The invention relates to the field of medicine and medicinal chemistry, more in particular to the design, manufacture and use of anti-cancer drugs that can be activated by an external stimulus that can be applied in a spatiotemporal fashion. Provided herein is a compound having the chemical structure or a pharmaceutically acceptable salt thereof.
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Page/Page column 19; 24-25
(2020/05/15)
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- Photoactivation of MDM2 Inhibitors: Controlling Protein-Protein Interaction with Light
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Selectivity remains a major challenge in anticancer therapy, which potentially can be overcome by local activation of a cytotoxic drug. Such triggered activation can be obtained through modification of a drug with a photoremovable protecting group (PPG), and subsequent irradiation in the chosen place and time. Herein, the design, synthesis and biological evaluation is described of a photoactivatable MDM2 inhibitor, PPG-idasanutlin, which exerts no functional effect on cellular outgrowth, but allows for the selective, noninvasive activation of antitumor properties upon irradiation visible light, demonstrating activation with micrometer, single cell precision. The generality of this method has been demonstrated by growth inhibition of multiple cancer cell lines showing p53 stabilization and subsequent growth inhibition effects upon irradiation. Light activation to regulate protein-protein interactions between MDM2 and p53 offers exciting opportunities to control a multitude of biological processes and has the potential to circumvent common selectivity issues in antitumor drug development.
- Hansen, Mickel J.,Feringa, Femke M.,Kobauri, Piermichele,Szymanski, Wiktor,Medema, René H.,Feringa, Ben L.
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p. 13136 - 13141
(2018/10/20)
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- Practical Synthesis of MDM2 Antagonist RG7388. Part 2: Development of the Cu(I) Catalyzed [3 + 2] Asymmetric Cycloaddition Process for the Manufacture of Idasanutlin
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A concise catalytic asymmetric synthesis of idasanutlin (1) was developed in which the key pyrrolidine core, containing four contiguous stereocenters, was constructed via a Ag/MeOBIPHEP promoted [3 + 2] cycloaddition reaction. Further development of the [
- Rimmler, G?sta,Alker, Andre,Bosco, Marcello,Diodone, Ralph,Fishlock, Dan,Hildbrand, Stefan,Kuhn, Bernd,Moessner, Christian,Peters, Carsten,Rege, Pankaj D.,Schantz, Markus
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p. 2057 - 2066
(2016/12/26)
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- ASYMMETRIC SYNTHESIS OF A SUBSTITUTED PYRROLIDINE-2-CARBOXAMIDE
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The present invention provides an improved method for the large scale production of the compound 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic a
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Page/Page column 14; 15; 27
(2014/09/03)
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- Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development
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Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of s
- Ding, Qingjie,Zhang, Zhuming,Liu, Jin-Jun,Jiang, Nan,Zhang, Jing,Ross, Tina M.,Chu, Xin-Jie,Bartkovitz, David,Podlaski, Frank,Janson, Cheryl,Tovar, Christian,Filipovic, Zoran M.,Higgins, Brian,Glenn, Kelli,Packman, Kathryn,Vassilev, Lyubomir T.,Graves, Bradford
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p. 5979 - 5983
(2013/08/23)
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