Late-Stage Derivatization of Oleanolic Acid-Based Anti-HIV-1 Compounds.

A 12-keto-type oleanolic acid derivative (4) has been identified as a potent anti-human immunodeficiency virus type-1 (HIV-1) compound that demonstrates synergistic effects with several types of HIV-1 neutralizing antibodies. In the present study, we used a common key synthetic intermediate to carry out the late-stage derivatization of an anti-HIV compound based on the chemical structure of a 12-keto-type oleanolic acid derivative. To execute this strategy, we designed a diketo-type oleanolic acid derivative (5) for chemoselective transformation, targeting the carboxy group and the hydroxyl group on the statine unit, as well as the 3-carbonyl group on the oleanolic acid unit, as orthogonal synthetic handles. We carried out four types of chemoselective transformations, leading to identification of the indole-type derivative (16) as a novel potent anti-HIV compound. In addition, further optimization of the ß-hydroxyl group on the statine unit provided the R-4-isobutyl γ-amino acid-type derivative (6), which exhibited potent anti-HIV activity comparable to that of 4 but with reduced cytotoxicity.

Synthesis and Structural Characterization of ß-Turn Mimics Containing (Z)-Chloroalkene Dipeptide Isosteres.

Described here is the synthetic, spectroscopic, crystallographic, and computational analysis of a series of peptidomimetics containing l-Xaa-d-Yaa-type (Z)-chloroalkene dipeptide isosteres (CADIs) that were measured in an investigation of the ß-turn mimicry of this peptide bond surrogate. We found that the 1,3-allylic strain across the chloroalkene moiety engenders the hyperconjugative interactions between the chloroalkene moiety and the C-H bonding or antibonding orbitals of the C-H bonds in allylic positions. These effects contribute significantly to the stabilization of ß-turn structures.

Design, synthesis, and bio-evaluation of novel triterpenoid derivatives as anti-HIV-1 compounds.

Two betulinic acid derivatives, RPR103611 (2) and IC9564 (3) were previously reported to be potent HIV-1 entry inhibitors. In this current study, a SAR study of the triterpenoid moiety of 2 and 3 has been performed and an oleanolic acid derivative (4) was identified as a novel HIV-1 entry inhibitor. In addition, the combination of 4 with several-type of HIV-1 neutralizing antibodies provided significant synergistic effects. The synthetic utility of the CC double bond in the C-ring of 4 was also demonstrated to develop the 12-keto-type oleanolic acid derivative (5) as a potent anti-HIV compound. This simple transformation led to a significantly increased anti-HIV activity and a reduced cytotoxicity of the compound.

Amide-to-chloroalkene substitution for overcoming intramolecular acyl transfer challenges in hexapeptidic neuromedin U receptor 2 agonists.

CPN-116 is a peptidic agonist that activates human neuromedin U receptor type 2 (NMUR2) but suffers from chemical instability due to inherent backbone isomerization on the Dap residue. To address this, a Leu-Dap-type (Z)-chloroalkene dipeptide isostere was synthesized diastereoselectively as a surrogate of the Leu-Dap peptide bond to develop a (Z)-chloroalkene analogue of CPN-116. The synthesized CPN-116 analogue is stable in 1.0 M phosphate buffer (pH 7.4) without backbone isomerization and can activate NMUR2 with similar potency to CPN-116 at nM concentrations (EC50 = 1.0 nM).

Stereoselective synthesis of highly functionalized (Z)-chloroalkene dipeptide isosteres containing an α,α-disubstituted amino acid.

Described here is the first stereoselective synthesis of highly functionalized chloroalkene dipeptide isosteres containing an α,α-disubstituted amino acid (ααAA). This synthesis requires the construction of a quaternary carbon center, and this challenge was overcome by the Aza-Darzens condensation of ketimine with α,α-dichloroenolate, producing 2-chloroaziridines with quaternary carbon centers including spirocyclic motifs, which are valuable for the previously elusive synthesis of various ααAA-containing chloroalkene isosteres.

The influence of the combination of visiting frequency of family caregivers and pre-admission frailty status on dependency after discharge among hospitalized older patients: a clinically-based prospective study.

PURPOSE: This study aims to determine whether the combination of visiting frequency of the family caregiver and frailty status has an additive effect on the incidence of dependency among hospitalized older patients. METHODS: We analyzed the prospective cohort data of hospitalized older patients (65 years and older) with internal medical problems. The main outcome showed patients' dependency from admission to a month after discharge. We investigated the visiting frequency of family caregivers and the frailty status and categorized respondents into 4 groups: group 1, visiting frequency 3-7 times a week and non-frailty; group 2, visiting frequency 0-2 times a week and non-frailty; group 3, visiting frequency 3-7 times a week and frailty; or group 4, visiting frequency 0-2 times a week and frailty. We used the Cox proportional hazards regression to estimate the hazard ratios (HR) and confidence intervals (95% CI) of relationships between the combination of visiting frequency and frailty status, and dependency. RESULTS: A total of 182 participants who completed the follow-up were analyzed. During the follow-up period, 45 participants (24.7%) showed some dependency. The hazards regression showed that the low visiting frequency group with presence of frailty had the most increased dependency, compared to other groups (adjusted HR 8.61 [95% CI 3.38-21.98]). CONCLUSIONS: The coexistence of low visiting frequency and the presence of frailty influenced dependency more strongly than each factor alone. These findings suggest that the combination of visiting frequency and frailty status is a useful predictor for future dependency.

Supramolecular Light-Harvesting Antennas of Metal-Coordinated Bis(8-Hydroxyquinoline)-Substituted Porphyrin Networks.

Artificial antenna complexes of metal-coordinated bis(8-hydroxyquinoline)-substituted porphyrin networks that mimic antenna chromophores in plants were organized on titanium dioxide electrodes in photoelectrochemical cells. The generated photocurrents can be optimized according to the two ways of porphyrin self-assembly due to the "antenna effect": changing the number of assembled porphyrin monolayers and the number of generations of the metal-coordinated porphyrin networks.

A case grafted with polyglycolic acid sheets and fibrin glue for protection after temporary resection of a metastatic cervical skin tumor.

The aim of this case report was to evaluate the usefulness of a grafting with polyglycolic acid sheet and a fibrin glue spray (PGA sheet grafting) after resection of a cervical skin tumor. A 61-year-old woman presented with left cervical skin tumor resistance to chemo-radiotherapy. She had been undergoing multimodal therapy for ovarian serous papillary adenocarcinoma for the previous six years. Although she had a poor general condition and a cervical skin tumor of 9cm in diameter, which was painful and easy bleeding, had offensive smell, she hoped to return to her job. Under local anesthesia, resection was performed, and PGA sheet grafting were used to shield the skin defect. After resection, she was relieved from pain, and could stay home without daily wound treatment. One and half months after resection, the wound was almost epithelialized. The PGA sheets consist of soft, elastic, nonwoven fabric made of PGA. In recent years, PGA sheet grafting has been widely used in the reconstruction and was chosen to shield the skin defect for this case. PGA sheet grafting after resection of cervical skin tumor can be an acceptable method for palliative care to relieve pain, bleeding, offensive smell, and ugly appearance.

Preadmission frailty status as a powerful predictor of dependency after discharge among hospitalized older patients: A clinical-based prospective study.

AIM: Frailty is a predictor of several adverse health outcomes in older adults. However, the relationship between preadmission frailty status and the incidence of dependency after discharge in hospitalized older patients remains unclear. The aim of the present study was to determine whether preadmission frailty status can predict dependency after discharge among hospitalized older patients. METHODS: We analyzed the cohort data for hospitalized older patients (aged ≥65 years) with internal medical problems obtained from a prospective study. The main outcome was the incidence of dependency from admission to a month after discharge. The frailty status was assessed using the Kihon Checklist. We defined scores of ≥8 as frail, 4-7 as pre-frail and 0-3 as robust. The Cox proportional hazards regression model was used to estimate the hazard ratios and confidence intervals of the relationships between preadmission frailty status and the incidence of dependency. RESULTS: A total of 151 participants who completed follow ups were analyzed (mean age 77.2 years [SD 6.9 years]). The prevalence of frailty, pre-frailty and robust was 22.5%, 37.8% and 39.7%, respectively. During the follow-up period, 39 participants (25.8%) had an incidence of dependency. Participants with frailty (adjusted hazard ratio 4.29, 95% confidence interval 1.72-10.69) had a significantly elevated incidence of dependency compared with that of robust participants. Participants with pre-frailty (adjusted hazard ratio 1.27, 95% confidence interval 0.51-10.69) had no significantly elevated incidence of dependency compared with robust participants. CONCLUSIONS: The preadmission frailty status using the Kihon Checklist can predict the incidence of dependency after discharge among hospitalized older patients. Geriatr Gerontol Int 2018; 18: 1609-1613.

Synthesis and characterisation of tetranuclear ruthenium polyhydrido clusters with pseudo-tetrahedral geometry.

Dicationic tetranuclear ruthenium octahydride [(Cp*Ru)4H8]2+ (5) with tetrahedral geometry was obtained by reaction of dinuclear ruthenium tetrahydride (Cp*Ru)2(µ-H)4 (1) with an excess of Brønsted acids, such as HBF4·OEt2, in toluene. Monocationic tetraruthenium heptahydride [(Cp*Ru)4H7]+ (7) was obtained by dropwise addition of a diluted acid to a rigorously stirred solution of 1 at ambient temperature. Dication 5 was converted into monocationic heptahydrido complex 7 in high yield by treatment with sodium methoxide or sodium hydride. The direct conversion of 5 into neutral hexahydrido complex (Cp*Ru)4H6 (8) was achieved in a highly efficient manner by treating 5 with LiAlH4 in tetrahydrofuran (THF). The conversion of 5 into 8 was reversible, and the addition of a Brønsted acid to 8 gave 5via the formation of 7 as an intermediate. Tetranuclear complex 8 was directly obtained from 1 by heating it in THF at 70 °C. Complex 8' and tetraruthenium tetrahydride (CpEtRu)4H4 (10'), where 8' and 10' possessed η5-C5EtMe4 ligands instead of Cp* ligands, were mutually related by the elimination/addition of dihydrogen. The structures of 5, 7, 8, and 10' were determined by X-ray diffraction, and the Ru4 core structure and the coordination mode of hydrido ligands were discussed based on density functional theory (DFT) calculations for model compounds where the methyl groups of Cp* ligands were replaced with hydrogen atoms.

Differential Characteristics of Skeletal Muscle in Community-Dwelling Older Adults.

BACKGROUND: Sarcopenia is diagnosed on the basis of skeletal muscle mass and muscle strength/function. However, more simple and accurate measures for muscle mass and muscle strength/function should be explored. OBJECTIVE: The aim of this study was to compare the skeletal muscle characteristics at each stage of sarcopenia (normal, presarcopenia, dynapenia, and sarcopenia) via ultrasonography, multifrequency bioelectrical impedance analysis (BIA), and physical assessment batteries in community-dwelling older adults. By evaluating the relationship between muscle quality/quantity indicators and muscle mass/muscle function, we attempted to identify better muscle quantity and quality indicators for the diagnosis of sarcopenia. SETTING AND SUBJECTS: Community-dwelling older men (n = 100, 81.6 ± 7.4 years) and women (n = 247, 79.7 ± 6.9 years) participated in this study. MEASUREMENTS: Skeletal muscle quantity and quality were measured by ultrasonography and multifrequency BIA. Ultrasonographic (thickness and echo intensity) and multifrequency BIA (volume and density) indicators, as well as physical assessment measures, were compared among each stage of sarcopenia. In addition, receiver-operating characteristic analysis was used to assess the sensitivity and specificity of each indicator. RESULTS: Most of the muscle quantity indicators were lower in the sarcopenia and presarcopenia groups than in the other groups, whereas most of the muscle quality indicators were lower in the sarcopenia and dynapenia groups than in the other groups. According to the receiver-operating characteristic analysis, quadriceps muscle thickness and thigh muscle volume were better indicators of muscle mass, whereas the quadriceps muscle echo intensity and thigh muscle density were more robust indicators of muscle function. CONCLUSIONS: In this study, we found potential muscle quality and quantity indicators for sarcopenia diagnosis by ultrasonography and multifrequency BIA. Future longitudinal studies are warranted to define the role of these indicators for the diagnosis of sarcopenia.