Cover Image,Volume 69, Issue 3

The cover image is based on the Mini‐Review Well‐defined, environment‐friendly synthesis of polypeptides based on phosgene‐free transformation of amino acids into urethane derivatives and their applications by Takeshi Endo et al., https://doi.org/10.1002/pi.5952 . Cover image © Takeshi Endo Images.

     

Novel hepatitis C virus protease inhibitors: thiazolidine derivatives

This study evaluated the inhibitory effects of thiazolidine derivatives on hepatitis C virus (HCV) protease and other human serine proteases. The inhibition efficacy was tested with a reversed-phase high-performance liquid chromatography (HPLC) assay system using a NS3-NS4A fusion protein as the HCV protease and a synthetic peptide substrate that mimics the NS5A-5B junction. Nine thiazolidine derivatives showed more than 50% inhibition at 50 microg/ml. The most potent derivative was RD4-6250, with 50% inhibition at a concentration of 2.3 microg/ml; this concentration was lower than those of other protease inhibitors reported previously. The most selective derivative was RD4-6205, with 50% inhibition at a concentration of 6.4 microg/ml, a lower concentration than those on other serine proteases (chymotrypsin, trypsin, plasmin, and elastase). These results suggest that the RD4-6205 skeleton is an important structure for inhibitory activity on the HCV protease NS3-NS4A.     

Well‐defined,environment‐friendly synthesis of polypeptides based on phosgene‐free transformation of amino acids into urethane derivatives and their applications

In this study, both naturally occurring and artificial amino acids were successfully transformed into the corresponding urethane derivatives using diphenyl carbonate. The urethanes thus prepared could be efficiently cyclized into amino acid N‐carboxyanhydrides (NCAs) without the requirement of phosgene. In addition, the presence of primary amines converted the urethane derivatives into NCAs and initiated the ring‐opening polymerization of the in situ formed NCAs, allowing for the well‐defined synthesis of polypeptides. These polypeptides contained initiating ends functionalized by an amine‐derived residue and propagating ends bearing the reactive amino group. By precise control of the structures of the polypeptides, various polypeptide conjugates such as block copolymers and graft copolymers were successfully synthesized as designed, and their applications in antifouling coatings against proteins, drug delivery systems and biosensors were demonstrated. © 2019 Society of Chemical Industry     

A two-way coupled multiscale model for predicting damage-associated performance of asphaltic roadways

This paper presents a quasi-static multiscale computational model with its verification and rational applications to mechanical behavior predictions of asphaltic roadways that are subject to viscoelastic deformation and fracture damage. The multiscale model is based on continuum thermo-mechanics and is implemented using a finite element formulation. Two length scales (global and local) are two-way coupled in the model framework by linking a homogenized global scale to a heterogeneous local scale representative volume element. With the unique multiscaling and the use of the finite element technique, it is possible to take into account the effect of material heterogeneity, viscoelasticity, and anisotropic damage accumulation in the small scale on the overall performance of larger scale structures. Along with the theoretical model formulation, two example problems are shown: one to verify the model and its computational benefits through comparisons with analytical solutions and single-scale simulation results, and the other to demonstrate the applicability of the approach to model general roadway structures where material viscoelasticity and cohesive zone fracture are involved.     

Elevation of plasma levels of L-dopa in transdermal administration of L-dopa-butylester in rats

To increase delivery of L-dopa in its transdermal absorption, a new lipophilic derivative of L-dopa, L-dopa-butylester, was synthesized. An in-vitro study employing two-chamber diffusion cells, in which the excised rat abdominal skin was mounted, revealed that, in the presence of L-menthol and ethanol, L-dopa-butylester penetrated in its original form more effectively than L-dopa. L-Dopa-butylester sheets were made by immersing wiper sheets in methanol containing the compound, and then evaporating the methanol. An extraction study of the compound from the sheets revealed that its stability was maintained for at least 12 weeks. In an in-vivo cutaneous absorption study, an L-dopa-butylester sheet was attached to the shaved rat abdominal skin. A hydrogel containing L-menthol and ethanol was spread on vinyl tape, and this sheet was placed over it. In plasma, the L-dopa level rose linearly between 30 and 180 min after the cutaneous application; L-dopa-butylester was not detected. The L-dopa level was higher than that in which L-dopa was applied. These findings indicated that the lipophilic nature of L-dopa-butylester further increased its penetration through the skin, and that L-dopa-butylester that was taken up into the general circulation system was rapidly converted to L-dopa by hydrolysis in the body.     

Rupture of the aortic arch due to bacterial aortitis--a case report of a patient undergoing successful surgical therapy

A 59-year-old man came to our hospital because of hoarseness and chest pain. On initial examination, a chest roentgenogram showed no abnormality. Three weeks later, while the patient was waiting to undergo a computed tomographic (CT) scan, shock suddenly developed. A chest roentgenogram revealed an extremely wide mediastinal shadow. A CT scan revealed rupture of the aortic arch near the base of the left subclavian artery, although there was no aneurysm. An emergency operation was performed. The ruptured aortic arch was replaced with an artificial graft during cardiopulmonary bypass with selective cerebral perfusion. A diagnosis of infectious aortitis was not made until a pathologist discovered colonies of gram-positive cocci in the resected specimen of the aortic arch. Postoperatively, antibiotics were administered for only four days. The patient is well about two years after the operation. Infectious aortitis had a very low prevalence and rarely involves the thoracic aorta. However, we should be aware of that it may cause aortic rupture even in the absence of aneurysmal dilatation.     

Involvement of neutrophil elastase in crescentic glomerulonephritis

To elucidate the role of neutrophils in the tissue damage of crescentic glomerulonephritis (GN), we examined neutrophils infiltrated in renal tissues and the localization of neutrophil elastase (NE), as a neutrophil-derived tissue destructive mediator, using an immunohistochemical technique with antibodies specific for neutrophils and neutrophil elastase; the enzyme histochemical technique (chloroesterase staining) also was used to detect neutrophils. In normal controls, neutrophil infiltration was scarce, and NE was localized in neutrophil cytoplasm. Neutrophils were abundant in crescentic GN and infiltrated in the glomerulus and interstitium; the infiltrating neutrophils were often aggregated. NE was localized in the cytoplasm of neutrophils and also appeared extracellularly (in granular or diffuse patterns) in glomerular necrotizing lesions, crescents, ruptured portions of Bowman's capsules, and in periglomerular and perivascular sites of the interstitium. Moreover, urinary concentration of NE measured by enzyme-linked immunosorbent assay (ELISA) in crescentic GN patients was significantly higher than in normals (93.6 +/- 13.3 v 1.4 +/- 0.5 microg/g x Cr, respectively; P < .001). These data suggest that NE plays a significant role in renal tissue damage, especially in the formation of glomerular necrotizing and crescentic lesions and in periglomerular interstitial lesions of crescentic GN.