30932-84-4Relevant articles and documents
Discovery and Structure-Based Optimization of Next-Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors
Heinrich, Timo,Seenisamy, Jeyaprakashnarayanan,Blume, Beatrix,Bomke, J?rg,Calderini, Michel,Eckert, Uwe,Friese-Hamim, Manja,Kohl, Rainer,Lehmann, Martin,Leuthner, Birgitta,Musil, Djordje,Rohdich, Felix,Zenke, Frank T.
, p. 5025 - 5039 (2019/05/22)
Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure-based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign 11a was discovered with an enzymatic IC50 of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC50 of 1.9 μM. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC50 of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.
DDQ-mediated direct Intramolecular-Dehydrogenative-Coupling (IDC): Expeditious approach to the tetracyclic core of ergot alkaloids
Bhunia, Subhajit,Ghosh, Santanu,Dey, Dhananjay,Bisai, Alakesh
supporting information, p. 2426 - 2429 (2013/06/27)
An efficient route to 2-oxindoles bearing an all-carbon quaternary center at the pseudobenzylic position has been developed via a DDQ-mediated Intramolecular-Dehydrogenative-Coupling (IDC). The methodology involves a one-pot C-alkylation of β-N-arylamido esters (7) concomitant with dehydrogenative-coupling in the presence of stoichiometric amount of DDQ. A tentative mechanistic route has been proposed for the oxidative coupling. The methodology provides a two-step entry to the ergoline structure of ergot alkaloids.
Heterobicyclic pyrazole compounds and methods of use
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Page/Page column 80, (2008/06/13)
Compounds of Formulas Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting receptor tyrosine kinases and for treating disorders mediated thereby. Methods of using compounds of Formula Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.
