A series of mono-or dialkyl/phenyl o-substituted phenoxy ligands in half-metallocene titanium-(IV) complexes was examined to determine the structure-catalytic activity relationship in high temperature olefin polymerization. Five different types of polymerization catalysts with different Cp/Cp* and mono-or disubstituted symmetric/asymmetric alkyl/phenyl phenoxide ancillary ligands were compared. This series was examined for ethylene homopolymerization after activation with Ph 3 CB(C 6 F 5 ) 4 and mMAO-7 at high temperatures (140 °C). Type 4 complexes of compounds 15-18 [33.0-39.0 kg/(mmol of Ti 3 h)] showed much higher catalytic activity than those found in types 1-3 and 5 [3.6-27.6 kg/(mmol of Ti 3 h)], and among the type 4 complexes, the Cp*/2-phenylphenoxy combination of compound 18 [39 kg/(mmol of Ti 3 h)] surpassed the Cp*/2-alkyl ligand systems of compounds 15-17 [33.0-36.0 kg/(mmol of Ti 3 h)]. The revolving nature of the phenoxy ligand around the Ti-O-C axis was identified by the NOSEY correlation peaks between the methyl protons of Cp* and protons of ancillary phenyl phenoxy ligand in compound 18. The conformational flexibility of the phenyl phenoxy ligand was further confirmed by a series of temperature-dependent ROSEY experiments based on the optimization of two conformational structures related by this rotation. Rotational barriers of 4.3 and 6.6 kcal/mol were estimated from theoretical DFT studies. DFT calculations of the transition states for ethylene insertion and termination were carried out for representative examples of types 4 (15, 16, 18), 3 (10, 12), and 1 (3) catalysts as well as the constrained geometry catalyst (CGC) as a reference. The preference for back-side insertion was a unique feature of the monosubstituted type 4 catalysts. The type 4 catalysts showed significant activities for ethylene/1-octene copolymerization affording high molecular weight poly(ethylene-co-1-octene)s (M w = 107 000 -164 000) with unimodal molecular weight distributions (M w /M n = 2.08-4.15). The activity increased in the order of type 3 [90-132 kg/(mmol of Ti 3 h), in toluene, ethylene 30 atm, 1-octene 8 mL, 140 °C, 10 min.] < CGC (222) < type 4 (228-354). Among the type 4 series, compound 18 showed the best performance, reaching an activity of 354 kg/(mmol of Ti 3 h). The polymer density of 0.9148 g/mL for compound 18 was lower than that found in CGC (0.9154 g/mL), indicating higher 1-octene incorporation, which was further confirmed by an analysis of the 13 C NMR spectra of the polymers (18, 2.73 mol % and CGC, 2.55 mol %).
While the bone morphogenetic protein‐7 (BMP‐7) is a well‐known therapeutic growth factor reverting many fibrotic diseases, including peritoneal fibrosis by peritoneal dialysis (PD), soluble growth factors are largely limited in clinical applications owing to their short half‐life in clinical settings. Recently, we developed a novel drug delivery model using protein transduction domains (PTD) overcoming limitation of soluble recombinant proteins, including bone morphogenetic protein‐7 (BMP‐7). This study aims at evaluating the therapeutic effects of PTD‐BMP‐7 consisted of PTD and full‐length BMP‐7 on epithelial‐mesenchymal transition (EMT)‐related fibrosis. Human peritoneal mesothelial cells (HPMCs) were then treated with TGF‐β1 or TGF‐β1 + PTD‐BMP‐7. Peritoneal dialysis (PD) catheters were inserted into Sprague‐Dawley rats, and these rats were infused intra‐peritoneally with saline, peritoneal dialysis fluid (PDF) or PDF + PTD‐BMP‐7. In vitro, TGF‐β1 treatment significantly increased fibronectin, type I collagen, α‐SMA and Snail expression, while reducing E‐cadherin expression in HPMCs (P < .001). PTD‐BMP‐7 treatment ameliorated TGF‐β1‐induced fibronectin, type I collagen, α‐SMA and Snail expression, and restored E‐cadherin expression in HPMCs (P < .001). In vivo, the expressions of EMT‐related molecules and the thickness of the sub‐mesothelial layer were significantly increased in the peritoneum of rats treated with PDF, and these changes were significantly abrogated by the intra‐peritoneal administration of PTD‐BMP‐7. PTD‐BMP‐7 treatment significantly inhibited the progression of established PD fibrosis. These findings suggest that PTD‐BMP‐7, as a prodrug of BMP‐7, can be an effective therapeutic agent for peritoneal fibrosis in PD patients.
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