RESULTS Structure Table 1. (Fig. 3). Degradation of cIAP1 and XIAP by SNIPER(ER)s.As observed in studies of many IAP antagonists, SNIPERs in our study rapidly ( Fig. 2a and 3b), consistent with their increased binding affinities for cIAP1 (Table 1). Further, these SNIPER(ER)s reduced XIAP expression in MCF-7 cells after 48 h in a more potent fashion than SNIPER(ER)-87( Fig. 2a). The reduction of XIAP by SNIPER(ER)s was prominent in T47D cells after 48 h, but was weak after 4 h of exposure (Fig. 3b). The difference in the degradation pattern between cIAP1 and XIAP suggests that these IAPs are degraded through a different mechanism, as discussed below. XIAP is required for the ERα degradation by SNIPER(ER)s.We previously reported that XIAP is In vivo protein knockdown activities and antitumor activities of SNIPER(ER)sWe measured the metabolic stabilities of Development of potent SNIPER derivatives against ERα 9MCF-7 cells, but not in T47D cells (Fig. 6).The role of IAPs in cancer cell survival has been suggested in many papers (32,(42)(43)(44)(45)58 Measurement of binding affinities of ERα and IAPsThe bindings between test compounds and cIAP1, cIAP2 or XIAP were determined by
A catalytic enantioselective desymmetrization of meso-N-p-nitrobenzoylaziridines with TMSCN was developed using a chiral gadolinium catalyst generated from Gd(OiPr)3 and d-glucose-derived ligand 1. In this reaction, the addition of a catalytic amount of trifluoroacetic acid (TFA) improved enantioselectivity. High enantioselectivity was obtained from a range of meso-aziridines at 0-60 degrees C. The product could be easily transformed into beta-amino acids. Thus, the developed catalytic enantioselective desymmetrization reaction allowed for efficient catalytic synthesis of chiral cyclic beta-amino acids. The incorporation of TFA into the catalyst complex was observed using ESI-MS. Generation of this new complex might be the origin of the improved enantioselectivity.
New chiral ligands for asymmetric polymetallic catalysts were designed on the basis of the assumption that the higher-order assembly structure is stabilized by modifying the modular unit. The designed ligands 6 and 7 contained a scaffolding cyclohexane ring with a Lewis base phosphine oxide directly attached to the scaffold. A module in the polymetallic complex contains two metals per ligand, and a stable 6-, 5-, 5-membered fused chelation ring system should be generated. Synthesis of these ligands is simple and high yielding, using a catalytic dynamic kinetic resolution promoted by the Trost catalyst as a key step. Ligand function was assessed in a catalytic asymmetric ring-opening reaction of meso-aziridines with TMSCN, a useful reaction for the synthesis of optically active beta-amino acids. The Gd complex generated from Gd(OiPr)3 and the ligand was a highly active and enantioselective catalyst in this reaction. Enantioselectivity was reversed compared to the previously reported d-glucose-derived catalyst containing the same chirality of the individual module. ESI-MS analysis and X-ray crystallographic studies indicate that the assembly state of the modules in the polymetallic catalysts differs depending on the chiral ligand. The difference in the higher-order structure stems from a subtle change (one carbon) in the position of the Lewis base relative to the Gd metal. The change in the higher-order structure of the polymetallic complex led to a dramatic reversal of the enantioselectivity and increased catalyst activity.
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