1313605-21-8Relevant articles and documents
Design and synthesis of novel meta-linked phenylglycine macrocyclic FVIIa inhibitors
Richter, Jeremy M.,Cheney, Daniel L.,Bates, J. Alex,Wei, Anzhi,Luettgen, Joseph M.,Rendina, Alan R.,Harper, Timothy M.,Narayanan, Rangaraj,Wong, Pancras C.,Seiffert, Dietmar,Wexler, Ruth R.,Priestley, E. Scott
supporting information, p. 67 - 72 (2017/12/12)
Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/ FVIIa Ki was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.
Molecular editing and assessment of the cytotoxic properties of iejimalide and progeny
Gagnepain, Julien,Moulin, Emilie,Nevado, Cristina,Waser, Mario,Maier, Armin,Kelter, Gerhard,Fiebig, Heinz-Herbert,Fuerstner, Alois
supporting information; experimental part, p. 6973 - 6984 (2011/07/30)
Systematic variation of all substructures embedded into the framework of iejimalide B (2) led to a panel of synthetic analogues of this polyunsaturated macrolide, featuring structural modifications that are not accessible by derivatization of the natural lead compound itself. The assessment of the cytotoxicity of these compounds with the aid of a monolayer proliferation assay (12 human tumor cell lines in vitro) as well as a colony formation assay (24 human tumor xenografts ex vivo) revealed the exceptional potency of 2 and several of its synthetic congeners, with IC50 values in the picomolar range for the most sensitive cell lines. Whereas structural modifications of the macrocycle or of the side chain generally lead to a decrease in activity, changes of the peptidic terminus are not only well accommodated but engender increased tumor selectivity as well. 2 and two of the most promising analogues were selected for in vivo studies in mice, in which their activity against human tumor xenografts of breast cancer (MAXF 401) and prostate cancer (PRXF PC-3M) was tested. In contrast to a previous report in the literature however, which had claimed in vivo activity for the parent iejimalides, these tests did not show a significant therapeutic effect against the chosen solid tumors upon intraperitoneal administration. Copyright
