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Rhynchophylline antagonizes Parkinson’s disease through alleviating neuroinflammation and regulating metabolic disorders.

The Au@POM nanoparticles were facilely synthesized using a one-step method. The as-prepared Au@POMs have excellent GOx-like and HRP-like activities, allowing for fast cascade reactions and sensitive bacterial detections.

Short half-life is one of the main causes of drug attrition in clinical development, which also leads to the failure of many leading compounds and hits to become drug candidates. Nowadays, nanomaterials have been applied to drug development to address this problem. In fact, the clinical application of nanoparticles (NPs) is severely limited due to their rapid elimination by the reticuloendothelial system (RES) in vivo. In this paper, we aim to summarize representative strategies on prolonging the circulation time for bridging the gap between excellent pharmaceutics and proper half-life and encourage clinical translation.

Five novel formyl-phloroglucinol-β-caryophyllene meroterpenoids, namely littordials A–E (1–5), were isolated from the leaves of Psidium littorale. Their structures were established by spectroscopic data and computational methods, and the structure of 1 was confirmed by X-ray crystallography. Littordials A–E feature unusual acyl phloroglucinol units, and 5 possesses a rare 6/7/9/4-fused tetracyclic ring system. Compounds 2, 3 and 5 exhibited cytotoxic activities on two cancer cell lines (MDA-MB-231 and B16) with IC50 values from 6.6 ± 1.5 to 9.2 ± 1.7 μM.

A facile and efficient approach to synthesize a series of new N-fused benzimidazoles in good yield is reported for the first time using the [4 + 2] cascade cycloaddition of 2-substituted benzimidazole derivatives and a bromoethylsulfonium salt, which is easily prepared on a large scale and is stably crystalline, under mild reaction conditions.

Gambogic acid (GA) is a natural antitumor drug candidate with advantages of broad-spectrum activity, low toxicity and multiple mechanisms. Its clinical application is hindered, however, by low aqueous solubility, instability and poor pharmacokinetic properties. In this research, core-shell hybrid nanoparticles have been developed to improve the druggability of GA. The nanoparticles are composed of a benzylamidated poly(γ-glutamic acid) (BzPGA) derivative as a core material and an amphiphilic hyaluronic acid derivative grafted with all-trans retinoic acid (HA-C6-ATRA) as a shell material. Through π-π stacking interactions, GA is encapsulated into BzPGA to form the "core" of the hybrid nanoparticle and the "shell" is formed by HA-C6-ATRA with a π-π stacking mediated "molecular fence". The nanovehicle, with sub 100 nm size, provides almost 100% encapsulation efficiency, a good protective effect and a sustained release profile for GA. A series of evaluations suggest that the core-shell nanoparticles provide a stable aqueous injection formulation (I), improved stability (II), prolonged circulation time and conferred tumor targeting properties (III) for GA. As a result, the anti-tumor activity of GA is significantly enhanced without causing higher toxicity, indicating that the designed nanoplatform dramatically improves the druggability of GA. This study may also provide inspiration for drug development research.

Phenylhydrazines, which are important intermediates in pharmaceutical synthesis, are known as genotoxic or mutagenic impurities. They are only allowed to be present at trace levels in drug products and therefore their control is critical in pharmaceutical development. A conventional high-performance liquid chromatograph with an ultraviolet (UV) detector is always used for the test of phenylhydrazines in drugs, but the similar maximum UV absorption wavelengths of phenylhydrazines and the drug matrix or related substances make the method lack specificity. In this paper, a simple pre-column derivatization approach was applied to selectively move the maximum absorption wavelengths of residual phenylhydrazines in drug substances to the visible region, in which most drugs have little absorption. Phenylhydrazine was chosen as the model analyte for the establishment and validation of the method. Different derivatization reagents were systematically compared, and 4-nitrobenzaldehyde was finally selected as the most suitable choice. This was because the maximum absorption wavelength of its derivative had the largest redshift to 416 nm with a strong absorption intensity, which could not only reduce the matrix interference from drug substances and related substances, but also largely minimize the interference of the derivatization reagent itself. After optimizing the reaction conditions, the limits of detection and quantification were 0.008 μg mL−1 and 0.02 μg mL−1, respectively. This method was successfully applied for the determination of residual phenylhydrazine in antipyrine and indapamide, and 4-hydrazinylbenzenesulfonamide in celecoxib.

Three new cardiac glycosides strophanthidin-3-O-α-L-rhamnopyranosyl-(1→4)-6-deoxy-β-D-allopyranoside (1), 5βH-16β-acetylkamaloside (2), and mansonin-19-carboxylic acid (3) along with seven known steroids including five cardiac glycosides were isolated from the methanol extracts of Streblus asper Lour. roots. The structures of these compounds were established by spectroscopic analyses. The cytotoxicities of crude extracts and all the isolated compounds were evaluated against four human cancer cell lines (HL60, A549, AZ521, and SKBR3). Furthermore, the selective index (SI) of each compound was measured by the ratio of cytotoxic effect on a normal cell line (WI38) to the cytotoxic effect on cancer cell line (A549). The results suggested that cardiac glycosides (2, 4, and 6–8) exhibited significant cytotoxicities with IC50 values from 0.01 to 3.77 μM as well as high selective index for WI38/A549 (SI 1.50–24.26), and they displayed superior selectivities when compared with the reference cisplatin (SI 1.09). Preliminary structure–activity relationships (SARs) were also discussed regarding the type of C-10 group in the cardiac glycosides being a crucial factor in determining the cytotoxic activities and regarding the sugar moieties having much less of an active role than the type of C-10 group. In addition, the melanogenesis-inhibitory abilities of these compounds were also evaluated. Cardiac glycosides (3 and 6–8) displayed moderate inhibition effects on melanogenesis with melanin content (MC) of 26.22–74.90% at a concentration of 100 μM, thus showing high cell viability (CV: 77.94–111.70%) compared with that of the reference arbutin (MC: 82.50% and CV: 107.60%). Furthermore, western blot analysis of melanogenesis-related proteins suggested that 3 could inhibit melanogenesis by suppressing the protein expressions of TRP-2 and tyrosinase.

A series of 4-O-substituted chrysotoxine (CTX) derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro assays indicated that four ring substituted compounds (2a, 2b, 3i and 3j) exhibited significant neuroprotective effects against Aβ25–35-induced toxicity in PC12 cells. The four compounds also inhibited self- and Cu2+-induced Aβ1–42 aggregation and acted as biometal chelators. In particular, compound 2a was a potential lead compound for AD treatment (cell viability up to 100.78% at 50 µM in Aβ25–35-treated PC12 cells, 51.88% and 58.03% inhibition at 25 µM for self- and Cu2+-induced Aβ1–42 aggregation, respectively). A metal chelating experiment showed that compound 2a had a moderate interaction with Cu2+ and Al3+. Moreover, western blot analysis showed that compound 2a attenuated Aβ-induced tau protein hyperphosphorylation at Ser199/202 and Ser396 sites. Furthermore, compound 2a could efficiently cross the blood-brain barrier (BBB) by a parallel artificial membrane permeability assay (PAMPA). In summary, these results suggested that compound 2a was a promising multifunctional compound for AD therapy.

Angiogenesis plays an important role in the development of inflammatory diseases, including cancer, psoriasis and rheumatoid arthritis. In this paper, we conducted a zebrafish bioassay-guided fractionation of Picrasma quassioides and identified twenty alkaloids from the anti-angiogenic fraction, including four new ones (1–4). In addition, in vivo relationship analyses of the structure and anti-angiogenic activity/toxicity led to the conclusion that the skeleton of alkaloids as well as the positions and properties of the substituents are pivotal to their activity and toxicity. Furancanthin (1) is the first-reported furan-fused canthin-6-one with an unprecedented highly-conjugated pentacyclic skeleton. 1-Hydroxymethyl-8-hydroxy-β-carboline (3) was found to have the most potent anti-angiogenic activity and the lowest toxicity in vivo, whose anti-angiogenic activity was also confirmed in vitro. Further qRT-PCR analysis revealed that the kdr, kdrl signaling axle in the VEGF–VEGFR pathway and the angpt2b, tek in the ANGPT–TEK pathway seemed to be involved in the anti-angiogenic activity of compound 3.

Polydiacetylene (PDA) is a promising membrane-screening tool because lipid constituents can be incorporated into the PDA framework to form lipid/PDA vesicles used as lipid bilayers. Previous reports have shown that the colorimetric signals of PDA could be utilized for the measurement of drug–lipid membrane interactions. In this study, the fluorescence signals of PDA vesicles were investigated for the measurement of lipid membrane affinity. Based on the fluorescence response of PDA vesicles (excitation wavelength 485 nm, emission wavelength 560 nm), the half maximal response concentration (EC50) was introduced for the evaluation of drug–membrane interactions. In order to validate this method, local anesthetics and flavonoids were selected as the reference compounds and their log(EC50) values correlated well with other lipid membrane affinity constants. Then the influence of buffer pH conditions and lipid constituents on the membrane affinity were investigated to show the wide application of this method using tetracaine hydrochloride as the reference compound. The particle size of vesicles before and after addition of tetracaine hydrochloride was determined to observe the extent of vesicle binding of the tested compound. The zeta potential results showed that the electrostatic interaction had less effect on the change of lipid membrane affinity at different pH value. Therefore, the hydrophobic interaction was assumed to play the most important role in the increase in lipid membrane affinity of tetracaine hydrochloride as the buffer pH value increased. The ratio of Chol in the lipid constituents affected the affinity of tetracaine hydrochloride less, but significantly weakened the sensitivity of PDA-based fluorescence signals. In summary, this work provides a simple, sensitive and reproducible PDA-based fluorescent method for the rapid measurement of lipid membrane affinity.