30932-85-5Relevant academic research and scientific papers
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.
Copper-catalyzed intermolecular chloro- and bromotrifluoromethylation of alkenes
Fu, Mingyang,Chen, Long,Jiang, Yongpeng,Jiang, Zhong-Xing,Yang, Zhigang
, p. 348 - 351 (2016/02/19)
A highly practical copper-catalyzed intermolecular halotrifluoromethylation of alkenes has been developed under mild reaction conditions. A variety of Cl/Br-containing trifluoromethyl derivatives were directly synthesized from a wide range of alkenes, including electron-deficient and unactivated alkenes.
Novel spiroheterocycles by aziridination of α-methylene-γ- and -δ-lactams
Loreto, M. Antonietta,Migliorini, Antonella,Tardella, P. Antonio,Gambacorta, Augusto
, p. 2365 - 2371 (2008/02/08)
New potentially bioactive α-spiroaziridino-γ- and -δ-lactams have been prepared by treatment of α-methylene-γ- and -δ-lactams with ethyl N-([(4-nitrophenyl)sulfonyl]oxy)-carbamate (NsONHCO2Et) in the presence of CaO. These compounds, through reductive aziridine ring opening, can be intermediates for the synthesis of α- and β-aminolactams, which are useful as conformational constraints in peptides. The above procedure has been successfully extended to one α-methyleneoxindole to obtain a new spirooxindole derivative, a potential precursor of natural alkaloids. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
Carbamoyloxy derivatives of mutiline and their use as antibacterials
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, (2008/06/13)
PCT No. PCT/EP96/05874 Sec. 371 Date Dec. 4, 1998 Sec. 102(e) Date Dec. 4, 1998 PCT Filed Dec. 19, 1996 PCT Pub. No. WO97/25309 PCT Pub. Date Jul. 17, 1997Derivatives of mutiline of formula (1A) and pharmaceutically acceptable salts and derivatives thereof, in which R1 is ethyl or vinyl, Y is a carbamoyloxy group, in which the N-atom is unsubstituted, or mono- or di-substituted, are useful in the treatment of bacterial infections.
