Semisynthetic routes to PF1022H—A precursor for new derivatives of the anthelmintic cyclooctadepsipeptide PF1022A

The cyclooctadepsipeptide PF1022A and its semisynthetic, commercial analogue emodepside show excellent anthelmintic properties. Bis-hydroxy PF1022 (PF1022H), a minor fermentative side-product represents an interesting precursor for new PF1022 related anthelmintics. We report herein two complementary routes which allow a highly efficient conversion of PF1022A to a regioisomeric mixture consisting mainly of the bis-para isomer PF1022H and the meta–para analogue.     

Identification,characterization, kinetics,and molecular docking of flavonoid constituents from Archidendron clypearia (Jack.) Nielsen leaves and twigs

In our search for natural soluble epoxide hydrolase (sEH) inhibitors from plants, we found that the methanolic extract of the leaves and twigs of Archidendron clypearia (Jack.) Nielsen (Fabaceae) significantly inhibits sEH in vitro. In a phytochemical investigation of the water layer of A. clypearia, we isolated two new chalcones, clypesides A–B (1–2), 13 flavonoid derivatives (3–15) and established their structures based on an extensive 1D and 2D NMR, CD data, and MS analysis. All of the flavonoid derivatives inhibited sEH enzymatic activity in a dose-dependent manner, with IC₅₀ values ranging from 10.0 ± 0.4 to 30.1 ± 2.1 μM. A kinetic analysis of compounds 4, 8–10, 12, 13, and 15 revealed that the compounds 8–10 were non-competitive, 4, 13, and 15 were mixed-type, and 12 was competitive inhibitors. Additionally, molecular docking increased our understanding of their receptor-ligand binding. These results demonstrated that flavonoid derivatives from A. clypearia are potential sEH inhibitors.     

Structure–activity relationships of dibenzoylhydrazines for the inhibition of P-glycoprotein-mediated quinidine transport

We previously demonstrated that dibenzoylhydrazines (DBHs) are not only P-glycoprotein (P-gp) substrates, but also inhibitors. In the present study, we evaluated the inhibition of P-gp-mediated quinidine transport by two series of DBHs and performed a classical QSAR analysis and docking simulation in order to investigate the mechanisms underlying P-gp substrate/inhibitor recognition. The results of the QSAR analysis identified the hydrophobic factor as the most important for inhibitory activities, while electronic and steric effects also influenced the activities. The different substituent effects observed in each series suggested the different binding modes of each series of DBHs, which was supported by the results of the docking simulation.     

4H-Chromene-based anticancer agents towards multi-drug resistant HL60/MX2 human leukemia: SAR at the 4th and 6th positions

4H-Chromene-based compounds, for example, CXL017, CXL035, and CXL055, have a unique anticancer potential that they selectively kill multi-drug resistant cancer cells. Reported herein is the extended structure–activity relationship (SAR) study, focusing on the ester functional group at the 4th position and the conformation at the 6th position. Sharp SARs were observed at both positions with respect to cellular cytotoxic potency and selectivity between the parental HL60 and the multi-drug resistant HL60/MX2 cells. These results provide critical guidance for future medicinal optimization.     

Comparative pharmacokinetics of a proliposome formulation of Ginkgo biloba extract and Ginaton in rats by a sensitive ultra performance liquid chromatography–tandem mass spectrometry method

As a novel oral drug delivery system, proliposome was applied to improve the solubility of active components of Ginkgo biloba extract (GbE). There are currently few reports focusing on the pharmacokinetic characteristics of proliposome of GbE (GbP). A rapid and sensitive ultra performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method for the simultaneous quantification of active components of GbP and a commercial tablet product (Ginaton) in rat plasma was developed and successfully validated. The method was applied to the comparative pharmacokinetic evaluation of GbP and Ginaton in rat plasma. The results indicated that GbP has a significant effect on absorption, elimination and bioavailability of flavonoids and terpenoid lactones in comparison with Ginaton. The obtained results would be helpful for evaluating the absorption mechanism in the gastrointestinal tract in pharmacokinetic level and guiding the development of the novel oral drug delivery system.     

Isolation by zinc-affinity chromatography of the histidine–proline-rich-glycoprotein molecule associated with rabbit skeletal muscle AMP deaminase: Evidence that the formation of a protein–protein complex between the catalytic subunit and the novel component is critical for the stability of the enzyme

The histidine–proline-rich glycoprotein (HPRG) component of rabbit skeletal muscle AMP deaminase under denaturing and reducing conditions specifically binds to a Zn²⁺-charged affinity column and is only eluted with an EDTA-containing buffer that strips Zn²⁺ from the gel. The isolated protein is homogeneous showing an apparent molecular weight (MW) of 95 000 and the N-terminal sequence L-T-P-T-D-X-K-T-T-K-P-L-A-E-K-A-L-D-L-I, corresponding to that of rabbit plasma HPRG. The incubation with peptide-N-glycosidase F promotes the reduction of the apparent MW of isolated HPRG to 70 000, characterizing it as a N-glycosylated protein. The separation from AMP deaminase of an 85-kDa component with a blocked N terminus is observed when the enzyme is applied to the Zn-charged column under nondenaturing conditions. On storage under reducing conditions, this component undergoes an 85- to 95-kDa transition yielding a L-T-P-T-D-X-K-T-T-K-P-L N-terminal sequence, suggesting that the shift in the migration on SDS/PAGE as well as the truncation of the protein at its N terminus are promoted by the reduction of a disulfide bond present in freshly isolated HPRG. The separation of HPRG induces a marked reduction in the solubility of AMP deaminase, strongly suggesting a role of HPRG in assuring the molecular integrity of the enzyme.     

Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity

Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR–TK inhibitory activity. Especially, N⁶-((5-bromothiophen-2-yl)methyl)-N⁴-(3-chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC₅₀ = 3.11 μM for Hep G2, IC₅₀ = 0.82 μM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells.     

Mammal decline in the Middle America

The Middle America is located in the Nearctic–Neotropical boundary. The combination of temperate and tropical biota of these two biogeographic regions, plus an area of biotic overlap propitiates unusually high species diversity and endemism. We present the first general assessment based on the IUCN Red List of Threatened Species that provides evidence of widespread decline in the conservation status of land mammals from southern U.S.A. to Panama. One in every three species considered in our study (n = 273) is classified as threatened, and the rate of biodiversity loss increased 0.64% between 2008 and 2012. Endangered species of the Middle America represents 11.8% of the global endangered mammal species, and 7.9% of the threatened species. Habitat loss and the introduction of alien species are the major threats; however, the relative impact of these threats varies among habitats. For continental species, habitat loss is prevalent, while for insular species the introduction of alien species has devastating effects. Our results suggest that if no integral multi-species conservation actions are applied in the short-term, more than 20% of the extant mammal species in the region could become extinct in the near future (10–50 years).     

Enrichment in a stoichiometric model of two producers and one consumer

We consider a stoichiometric population model of two producers and one consumer. Stoichiometry can be thought of as the tracking of food quality in addition to food quantity. Our model assumes a reduced rate of conversion of biomass from producer to consumer when food quality is low. The model is open for carbon but closed for nutrient. The introduction of the second producer, which competes with the first, leads to new equilibria, new limit cycles, and new bifurcations. The focus of this paper is on the bifurcations which are the result of enrichment. The primary parameters we vary are the growth rates of both producers. Secondary variable parameters are the total nutrients in the system, and the producer nutrient uptake rates. The possible equilibria are: no-life, one-producer, coexistence of both producers, the consumer coexisting with either producer, and the consumer coexisting with both producers. We observe limit cycles in the latter three coexistence combinations. Bifurcation diagrams along with corresponding representative time series summarize the behaviours observed for this model.     

A nonparametric method for classification trees using grouped covariates

A group of variables are commonly seen in diagnostic medicine when multiple prognostic factors are aggregated into a composite score to represent the risk profile. A model selection method considers these covariates as all-in or all-out types. Model selection procedures for grouped covariates and their applications have thrived in recent years, in part because of the development of genetic research in which gene–gene or gene–environment interactions and regulatory network pathways are considered groups of individual variables. However, little has been discussed on how to utilize grouped covariates to grow a classification tree. In this paper, we propose a nonparametric method to address the selection of split variables for grouped covariates and their following selection of split points. Comprehensive simulations were implemented to show the superiority of our procedures compared to a commonly used recursive partition algorithm. The practical use of our method is demonstrated through a real data analysis that uses a group of prognostic factors to classify the successful mobilization of peripheral blood stem cells.