1370018-07-7Relevant 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)
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.
Copper-catalysed approach to spirocyclic oxindoles via a direct C-H, Ar-H functionalisation
Moody, Catherine L.,Franckevi?ius, Vilius,Drouhin, Pauline,Klein, Johannes E.M.N.,Taylor, Richard J.K.
supporting information; experimental part, p. 1897 - 1899 (2012/05/31)
A practical and efficient entry to spirocyclic oxindoles from readily accessible anilide precursors, using only catalytic amounts of an inexpensive copper salt together with air as the sole re-oxidant, is described. In addition to providing access to a br
