Chemical & pharmaceutical bulletin最新文献

Twisted intramolecular charge transfer (TICT) is a phenomenon involving intramolecular charge transfer together with intramolecular rotation upon photoexcitation, and in general this excited state of fluorescent dyes undergoes non-radiative decay (producing no fluorescence). We recently discovered that the magnitude of TICT in rhodamine derivatives could be regulated by altering the size of the substituents on the xanthene moiety, generating differing degrees of intramolecular steric repulsion. To further illustrate the usefulness and generality of this strategy, we describe here an application of quinone methide chemistry, which is widely used as a fluorescence off/on switching reaction for fluorescence probes detecting enzymatic activity, to construct a steric repulsion-induced (sr)-TICT-based fluorescence probe targeting nitroreductase (NTR) activity. The developed probe was almost non-fluorescent in phosphate-buffered saline (PBS) due to strong induction of the TICT state. On the other hand, when the probe was incubated with NTR and nicotinamide adenine dinucleotide (NADH), a large fluorescence increase was observed over time. We confirmed that the enzymatic reaction proceeded as expected, i.e., the nitro group of the probe was reduced to the corresponding amino group, followed by spontaneous elimination of iminoquinone methide. These results suggest that our simple design strategy based on the sr-TICT mechanism, i.e., controlling intramolecular steric repulsion, would be applicable to the development of fluorescence probes for a variety of enzymes.

Surugamides are a group of non-ribosomal peptides produced by Streptomyces spp. Several derivatives possess acyl groups, which are proposed to be attached to a lysine side chain after backbone-macrocyclization during biosynthesis. To date, five different acyl groups have been identified in nature, yet their impacts on biological activity remain underexplored. Here we synthesized surugamide B derivatives with varied acyl moieties. Biological evaluations revealed that larger hydrophobic acyl groups on lysine ε-NH₂ enhance cytotoxicity.

As an easy-to-handle reagent for the in situ generation of outstandingly electrophilic Tf₂C=CH₂ (Tf=CF₃SO₂), we have designed and synthesised a novel 4-substituted 2-fluoropyridinium zwitterion, in which a partially fluorinated alkyl group is attached to the pyridinium 4-position. Its zwitterionic nature has been well characterised by quantum chemical bonding analysis. By using this reagent, a wide variety of organic compounds, including commercial bioactive agents, were successfully decorated by the strongly acidic or ionic functionality. Remarkably, the 4-substituted 2-fluoropyridine derivative, which results from the zwitterion with the generation of Tf₂C=CH₂, can be rapidly separated and recovered from the reaction mixture appropriately using distillation, organic solvent extraction, or fluorous solid phase extraction techniques. Such multi-optionality for the purification methods favours in the isolation of the strongly acidic and/or ionic products.

Monoammonium glycyrrhizic acid (MAG), a glycyrrhizic acid monoammonium salt, is a naturally derived low-molecular-weight gelling agent with surface-active properties. It has the capacity to individually facilitate the preparation of gel-solubilized drugs. As MAG is an anionic surfactant with carboxyl groups, the addition of counterions may affect micelle formation and gelation. In this study, the solubilization and gelling properties of MAG were investigated following the addition of metal salts (NaCl and KCl). The addition of metal salts resulted in a decrease in the critical micelle concentration and an increase in gel hardness. Supersaturation of curcumin (CUR) was maintained by the addition of metal salts because of increased micelle number and viscosity. When the gel hardness was compared between formulations with and without CUR, a significant reduction in hardness was observed with the solubilization of CUR. The addition of KCl prevented the decrease in the hardness of gels containing CUR compared to the addition of NaCl. Put together, the addition of metal salts had a noteworthy impact on micelle and gel formation of MAG. In particular, the addition of KCl was more effective in the preparation of gel-solubilized CUR.

Five new viridogriseins B-F were isolated from Streptomyces niveoruber, along with viridogrisein and griseoviridin which belong to streptogramin family antibiotics. A combination of liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis and the advanced Marfey's method elucidated the structures of viridogriseins B-F, each featuring distinct constituent amino acids. Consistent with other streptogramin family antibiotics, these viridogrisein analogs exhibited potent antibacterial activity against Staphylococcus aureus. Furthermore, equimolar mixtures of each viridogrisein analog and griseoviridin inhibited the growth of S. aureus more potently than each analog treatment alone. Finally, an in vitro functional analysis of SgvY, encoded in the viridogrisein biosynthetic gene cluster, revealed that SgvY detoxifies viridogrisein against S. aureus by linearization. Considering that viridogrisein is not autotoxic to S. niveoruber, SgvY likely contributes to the self-resistance system against viridogrisein in S. niveoruber.

Auraptene (Aur) is a naturally occurring monoterpene coumarin ether that exhibits numerous therapeutic properties. Its high lipophilicity and low skin penetration, however, limit its potential application for local and transdermal delivery. Biocompatible non-ionic sugar esters (SEs) possess beneficial properties for the development of transdermal formulations in delivering pharmaceutically challenging molecules such as graphene and Aur. In the present study, we conducted a series of experiments to demonstrate the effect of several previously unstudied SEs on the skin permeation and distribution of Aur by preparing gel- and dispersion-type formulations. Skin permeation and deposition experiments were conducted using a Franz diffusion cell with rat skin as the membrane. The dispersion-type formulations prepared using SEs had higher entrapment efficiency, as well as better skin permeation and retention profiles. The dispersion-type formulation containing sucrose palmitate (sSP) exhibited the highest skin permeation over 8 h. Notably, the enhancement effects on Aur concentration in full-thickness skin after the application of the dispersion-type formulation was higher than those of the control formulation. These results indicated that the prepared formulation has potential for use in the transdermal delivery of Aur in pharmaceutical and cosmetic products.

Gout is the second largest metabolic disease worldwide after diabetes, with acute gouty arthritis as most common symptom. Xanthine oxidase (XOD) and the NOD like receptor-3 (NLRP3) inflammasome are the key targets for acute gout treatment. Chlorogenic acid has been reported with a good anti-inflammatory activity, and Apigenin showed an excellent potential in XOD inhibition. Therefore, a series of chlorogenic acid-apigenin (CA) conjugates with varying linkers were designed and synthesized as dual XOD/NLRP3 inhibitors, and their activities both in XOD and NLRP3 inhibition were evaluated. An in vitro study of XOD inhibitory activity revealed that the majority of CA conjugates exhibited favorable XOD inhibitory activity. Particularly, the effects of compounds 10c and 10d, with an alkyl linker on the apigenin moiety, were stronger than that of allopurinol. The selected CA conjugates also demonstrated a favorable anti-inflammatory activity in RAW264.7 cells. Furthermore, compound 10d, which showed the optimal activity both in XOD inhibition and anti-inflammatory, was chosen and its inhibitory ability on NLRP3 and related proinflammatory cytokines was further tested. Compound 10d effectively reduced NLRP3 expression and the secretion of interluekin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) with an activity stronger than the positive control isoliquiritigenin (ISL). Based on these findings, compound 10d exhibits dual XOD/NLRP3 inhibitory activity and, therefore, the therapeutic effects on acute gout is worthy of further study.

The development of polymeric nanoparticles (NPs) from preformed polymers usually requires the use of organic solvents and is more expensive. Hence, in this work, the development of polymeric nanoparticles by in situ aqueous dispersion polymerization from the monomers was set as an objective. Acrylonitrile monomer based polymeric NPs comprising Lamivudine (LMV) as a model drug were prepared using the aqueous dispersion polymerization technique. A quality by design approach was applied to optimise various formulation and process factors viz. monomer concentration, initiator concentration, stabilizer concentration and polymerization temperature. Polymerization time (PT), entrapment efficiency (EE), particle size (PS), and drug release rate constant (k) were taken as the responses to define the quality of the prepared NPs. Design of experiments analysis followed by optimization was performed to identify the optimized combination of the factors. Later, the optimized formulation was studied for the physical state of the LMV in the nanoparticles, surface morphology of the NPs and cytotoxicity studies. The optimized formulation was found to have 91.7 min. of PT, 81.4% of EE, 253 nm of PS and a k value of 0.262 h^-1 (18 h to release 99%). The cytotoxicity studies indicated that the NPs were highly safe to use. These results altogether inferred that LMV contained NPs were developed effectively from the acrylonitrile monomer by the aqueous dispersion polymerization method.

This study aims to design and synthesize a series of novel formononetin (FMN) derivatives and explore their protective effects on oxygen glucose deprivation/relapse (OGD/R) damage to H9C2 cells, along with their molecular regulatory mechanisms. The OGD/R model was established to simulate myocardial ischemia-reperfusion injury. The protective effects of these novel compounds on H9C2 cells were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, while the apoptosis rate, myocardial enzyme activity, and autophagy reaction post-compound treatment were assessed using kit-based methods. The formation of autophagosomes in H9C2 cells was observed via transmission electron microscopy, and the expression levels of autophagy-related proteins phosphatidylinositol 3-kinase (PI3K), Akt, Beclin-1, and P62 were determined using Western blotting. The experimental findings demonstrated that compounds 1-6 (C1-6) exhibited varying degrees of protective effects on damaged H9C2 cells, generally outperforming the parent compound FMN. Among these compounds, C4 demonstrated the most significant activity, even surpassing the positive control drug diltiazem. Further mechanistic investigations revealed that C4 could mitigate apoptosis rates, reduce the activity of myocardial enzyme (such as aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and CK), diminish the number of autophagic vesicles, and restore excessive autophagy. Additionally, C4 exerted its protective effects by downregulating the expression of autophagic proteins PI3K, Akt, Beclin-1, P62, LC3 and ATG12. These results indicated that C4 regulates autophagy through the PI3K/Akt/Beclin-1 signaling pathway, thereby exerting a protective effect on cardiomyocytes. Therefore, C4 emerges as a potential myocardial protective drug, offering a new research direction and strategy for the treatment of myocardial ischemia-reperfusion injury.