Application of Band-Selective HSQC NMR in Species Discrimination and Adulteration Identification of Panax Linn.

The quality of Panax Linn products available in the market is threatened by adulteration with different Panax species, such as Panax quinquefolium (PQ), Panax ginseng (PG), and Panax notoginseng (PN). In this paper, we established a 2D band-selective heteronuclear single quantum coherence (bs-HSQC) NMR method to discriminate species and detect adulteration of Panax Linn. The method involves selective excitation of the anomeric carbon resonance region of saponins and non-uniform sampling (NUS) to obtain high-resolution spectra in less than 10 min. The combined strategy overcomes the signal overlap limitation in 1H NMR and the long acquisition time in traditional HSQC. The present results showed that twelve well-separated resonance peaks can be assigned in the bs-HSQC spectra, which are of high resolution, good repeatability, and precision. Notably, the identification accuracy of species was found to be 100% for all tests conducted in the present study. Furthermore, in combination with multivariate statistical methods, the proposed method can effectively determine the composition proportion of adulterants (from 10% to 90%). Based on the PLS-DA models, the identification accuracy was greater than 80% when composition proportion of adulterants was 10%. Thus, the proposed method may provide a fast, practical, and effective analysis technique for food quality control or authenticity identification.

Synthesis and Cytotoxicity Assessment against Human Colorectal Cancer Cell Lines of Quaternary 8-Dichloromethyl Protoberberine Alkaloids.

Twenty-two quaternary 8-dichloromethylprotoberberine alkaloids were synthesized from unmodified quaternary protoberberine alkaloids (QPAs) to improve their physical and chemical properties and to obtain selectively anticancer derivatives. The synthesized derivatives showed more appropriate octanol/water partition coefficients by up to values 3-4 compared to unmodified QPA substrates. In addition, these compounds exhibited significant antiproliferative activity against colorectal cancer cells and lower toxicity on normal cells, resulting in more significant selectivity indices than unmodified QPA compounds in vitro. The IC50 values of antiproliferative activity of quaternary 8-dichloromethyl-pseudoberberine 4-chlorobenzenesulfonate and quaternary 8-dichloromethyl-pseudopalmatine methanesulfonate against colorectal cancer cells are 0.31 µM and 0.41 µM, respectively, significantly stronger than those of other compounds and positive control 5-fluorouracil. These findings suggest that 8-dichloromethylation can be used as one of the modification strategies to guide the structural modification and subsequent investigation of anticancer drugs for CRC based on QPAs.

Chemoproteomics Reveals That Quaternary Protoberberine Alkaloids Inhibit Telomerase Activity Oncologically by Binding to PES1.

Natural QPAs have anti-cancer property. The prodrugs of QPAs synthesized in our work with significantly improved solubility showed significantly stronger activity in animal experiments. Nevertheless, the mechanism of action of QPAs for treating cancers remains poorly understood. Here, a chemoproteomic study reveals that QPAs non-covalently and multivalently bind to PES1 in CRC cells, which impinges on the direct interaction between hTERT and hTR in the assembly of the telomerase complex, downregulates telomerase activity, and so promotes the aging process of CRC cells. This study is beneficial for us to conduct extensively the pharmaceutical chemistry research of QPAs.

Study on the Application of Sediment-Based Embankment Building and Ultra-High-Performance Concrete (UHPC) Preparation in the Resource Utilization of Yellow River Sediment.

The Yellow River is difficult to control. Little water and a large amount of sediment results in sediment accumulation in its lower reaches as sediment inflow exceeds transport capacity. Reducing this sediment deposition is essential for harnessing the Yellow River. Included in this process is the rational use of the sediment. Many researchers have investigated usage of Yellow River sediment as an aggregate material for concrete production, but there are still some problems (e.g., low resource utilization and low strength of the concrete made from Yellow River sediment). To make up the deficiency in the existing research, this study proposes two methods of sediment utilization. One is to use Yellow River sediment to build embankments, and the other is to use ultra-fine Yellow River sand to prepare ultra-high-performance concrete (UHPC). Test results reveal that the prepared high-strength concrete performs well in each test, including: fluidity, mechanical properties, pore structure, ecological evaluation, microscopic measurement of the interface transition zone, and economic analysis.

Trifluoromethylation of dihydrocoptisines and the effect on structural stability and XBP1-activating activity.

In order to obtain new dihydrocoptisine-type compounds with stable structure and activating XBP1 transcriptional activity, (±)-8-trifluoromethyldihydrocoptisine derivatives as target compounds were synthesized from quaternary ammonium chlorides of coptisine alkaloids as starting materials by a one-step reaction. The structures of the synthesized compounds were confirmed by 1H-, 13C-, and 19F-NMR as well as HRESIMS methods. These compounds showed more significant structural stability and activating XBP1 transcription activity in vitro than dihydrocoptisine as positive control. No obvious cytotoxicity on normal cell in vitro was observed with (±)-8-trifluoromethyldihydrocoptisines. Trifluoromethylation can be used as one of the fluorine modification strategies for dihydrocoptisines to guide follow-up studies on structural modification of coptisine-type alkaloids and on anti-Ulcerative colitis drugs with coptisines.

A unified total synthesis of benzo[d][1,3]dioxole-type benzylisoquinoline alkaloids of aporphines, coptisines, and dibenzopyrrocolines.

The first total synthesis of (S)-(+)-ovigerine, (S)-(+)-N-formylovigerine, and (6aS,6a'S)-(+)-ovigeridimerine of aporphine alkaloids with a benzo[d][1,3]dioxole structure feature was established. The strategy was based upon the well-known Pd-catalyzed arylation to set the aporphine framework, and Noyori asymmetric hydrogenation followed by diastereoselective resolution to achieve excellent enantioselectivity. By slightly modifying the total synthetic route and strategically combining it with a aza-Michael addition, Bischler-Napieralski reaction and N-arylation, this methodology was also applied to the total syntheses of benzo[d][1,3]dioxole-type benzylisoquinoline alkaloids of coptisines and dibenzopyrrocolines, including two impatiens, tetrahydrocoptisine, and quaternary coptisine bromide of coptisines and two dibenzopyrrocoline analogues, with the syntheses of all of these target compounds being efficient. Among the nine synthesized compounds, the total syntheses of the three aporphines and the two impatiens, all with ee values of greater than 99%, were reported for the first time. This work also represents the first unification of synthetic routes for the total synthesis of benzo[d][1,3]dioxole-type aporphines, coptisines, and dibenzopyrrocolines.

HLJ2 Effectively Ameliorates Colitis-Associated Cancer via Inhibition of NF-κB and Epithelial-Mesenchymal Transition.

INTRODUCTION: Colitis-associated cancer (CAC) accounts for approximately 15% of IBD patient mortalities. However, currently available anti-CAC drugs possess many disadvantages including safety, specificity and side effects. Therefore, the development of novel anti-CAC compounds is imperative. HLJ2 was a monomeric compound synthesized by our institute and reported to have an effect on ulcer colitis. METHODS: In vivo the AOM/DSS-induced CAC model was used to evaluate the effects of HLJ2 on ameliorating CAC symptoms, immunohistochemical analysis was used to analyze the pathological damage to colons and epithelial-mesenchymal transition was for changes of cytokines. In vitro, flow cytometric analysis, immunofluorescence and Western blot were used to detect the inhibition effect of HLJ2 on nuclear factor-κB and epithelial-mesenchymal transition in TGF-ß1-stimulated SW480 cells. RESULTS: In the AOM/DSS animal model, HLJ2 was demonstrated to inhibit the secretion of inflammatory cytokines and nuclear factor-κB, levels of tumorigenesis-related proteins including snail, and finally inhibited a key step in metastasis, epithelial-mesenchymal transition. In vitro, HLJ2 was also shown to inhibit nuclear factor-κB and epithelial-mesenchymal transition in TGF-ß1-stimulated SW480 cells in accordance with in vivo results. Meanwhile, the nuclear factor-κB inhibitor could interrupt the effect of HLJ2 on epithelial-mesenchymal transition. DISCUSSION: HLJ2 may ameliorate CAC through inhibiting nuclear factor-κB and then downstream epithelial-mesenchymal transition. The combination of the obvious improvement in effects on CAC without obvious side effects suggests that HLJ2 could be developed as a potential CAC therapeutic candidate.

Syntheses and Structure-Activity Relationships in Antibacterial Activity against Clostridium difficile and XBP1 Activation Property of 13-[(N-Alkylamino)methyl]-8-oxodihydrocoptisines.

13-[(N-Alkylamino)methyl]-8-oxodihydrocoptisines were synthesized to evaluate antibacterial activity against Clostridium difficile and activating x-box-binding protein 1 (XBP1) activity, biological properties both associated with ulcerative colitis. Improving structural stability and ameliorating biological activity were major concerns. Different substituents on the structural modification site were involved to explore the influence of diverse structures on the bioactivities. The target compounds exhibited the desired activities with definite structure-activity relationship. In the series of 13-[(N-n-alkylamino)methyl]-8-oxodihydrocoptisines, the length of n-alkyl groups has a definite effect on the bioactivity, elongation of the length increasing the antibacterial activity. The synthesized compounds were determined to display strong or weak XBP1-activating activity in vitro. The preliminary results of this study warrant further medicinal chemistry studies on these synthesized compounds.

Syntheses and Structure-Activity Relationships in Growth Inhibition Activity against Human Cancer Cell Lines of 12 Substituted Berberine Derivatives.

In this study, quaternary berberine chloride is used as a lead compound to design and synthesize a series of berberine-12-amine derivatives to evaluate the growth inhibition activity against human cancer cell lines. Forty-two compounds of several series were obtained. The quaternary berberine-12-N,N-di-n-alkylamine chlorides showed the targeted activities with the IC50 values of most active compounds being dozens of times those of the positive control. A significant structure-activity relationship (SAR) was observed. The activities of quaternary berberine-12-N,N-di-n-alkylamine chlorides are significantly stronger than those of the reduced counterparts. In the range of about 6-8 carbon atoms, the activities increase with the elongation of n-alkyl carbon chain of 12-N,N-di-n-alkylamino, and when the carbon atom numbers are more than 6-8, the activities decrease with the elongation of n-alkyl carbon chain. The activities of the tertiary amine structure are significantly higher than that of the secondary amine structure.

Racemic 3,4-dihydro-4-naphthyl-naphthalen-1(2H)-ones from Juglans regia flowers.

Three previously undescribed (±)-3,4-dihydro-4-naphthyl-naphthalen-1(2H)-one derivatives were isolated from Juglans regia flowers. Elucidation of the 2D structures of these first-reported compounds was completed via regular spectroscopic methods. The assignment of racemic nature of these compounds was achieved using the examination of their chiral HPLC profiles. (±)-2,3-Dihydro-4',8,8'-trihydroxy-(1,1'-binaphthalen)-4(1H)-one, (±)-2,3-dihydro-4',5,8,8'-tetrahydroxy-(1,1'-binaphthalen)-4(1H)-one, and (±)-2,3-dihydro-1',5,5',8-tetrahydroxy-(1,2'-binaphthalen)-4(1H)-one were the structures of these racemic compounds, all taking on central chirality. The resolution of all the racemic compounds was conducted and achieved using a chiral HPLC procedure. The absolute configurations of the three isolated pairs of enantiomers were assigned via time-dependent density functional theory calculations from the electronic circular dichroism data. The findings in this paper demonstrated that the relevant biochemical reactions for the construction of these 3,4-dihydro-4-naphthyl-naphthalen-1(2H)-one derivatives in the test plant are nonselective. The (±)-2,3-dihydro-4',8,8'-trihydroxy-(1,1'-binaphthalen)-4(1H)-one showed selective inhibitory activity on tumor cells growth, preliminarily supporting the application of Juglans regia flowers to protect against cancers in a few Chinese folk areas.

Butyric Acid Increases the Therapeutic Effect of EHLJ7 on Ulcerative Colitis by Inhibiting JAK2/STAT3/SOCS1 Signaling Pathway.

Ulcerative colitis (UC) is a refractory chronic disease characterized by bloody diarrhea and mucosal or submucosal ulcers. There is an urgent need of new drugs for the treatment of ulcerative colitis. EHLJ7 is a quaternary coptisine derivative. Herein, we explored the therapeutic effect of EHLJ7 on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) in mice. Results showed that EHLJ7 have good effects on DSS-induced colitis. EHLJ7 significantly improved symptoms induced by DSS including of weight loss, colon contracture, disease activity index (DAI), inflammatory infiltration, and so on. Furthermore, results showed that EHLJ7 could enhance short-chain fatty acids (SCFAs) production especially butyric acid, suggesting that EHLJ7 could improve the metabolic disorder of intestinal flora to a certain extent. Further study indicated that EHLJ7 could cooperate with butyrate to exert its anti-ulcerative colitis effect by inhibiting the activation of janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3)/suppressor of cytokine signaling 1 (SOCS1) pathway. Therefore, EHLJ7 has a potential to be developed as a candidate for the treatment of colitis.

Re-engineering and synthesis of cytotoxic 2,3:7,8-di(alkylenedioxy)-extended analogs of quaternary sanguinarine chloride.

A method was developed to synthesize 2,3:7,8-di(alkylenedioxy)-extended analogs of quaternary sanguinarine chloride. 1-Bromo-2-bromomethyl-3,4-alkylenedioxy benzenes and 6,7-alkylenedioxynaphthalen-1-amines were synthesized first. Reactions to construct the target compounds with these two series of synthons involved alterations on a published method for synthesizing 2,3,7,8-tetraoxygenated derivatives of benzo[c]phenanthridinium, substituting benzyl bromides for benzoic aldehydes, prolonging the radical annulation time, and conducting N-methylation with formic acid and NaBH4. All the target compounds showed the same or better in vitro growth inhibitory activities against cancer cell lines compared with the positive compound. The structure activity relationship relevant to cytotoxicity and lipophilicity of the target compounds was produced.

Syntheses and structure-activity relationships on antibacterial and anti-ulcerative colitis properties of quaternary 13-substituted palmatines and 8-oxo-13-substituted dihydropalmatines.

In this study, quaternary palmatine is used as a lead compound to design and synthesize derivatives to evaluate bioactivities, with twenty-seven compounds of four series being obtained. Antibacterial activity was examined by determining the minimal inhibitory concentration (MIC) values on Staphylococcus aureus, Escherichia coli, and Candida albicans, three series of derivatives being found to exhibit activity in vitro with significant structure-activity relationship (SAR). Elongating the carbon chain led to the antibacterial activity increased, with quaternary 13-hexanoylpalmatine chloride, quaternary 13-(ω-ethoxycarbonyl)heptylpalmatine chloride, and 8-oxo-13-(N-n-nonyl)aminomethyldihydropalmatine, all of which possess the longest aliphatic carbon chain in the corresponding series of derivatives, showing the MIC values of 62.5, 7.81, and 15.63 µg/ml against S. aureus, respectively. The property of anti-ulcerative colitis (anti-UC) was assessed at the levels of both in vitro and in vivo, with X-box-binding protein 1 (XBP1) being targeted in vitro. Seven compounds were found not only to be hypocytotoxic toward intestinal epithelial cells, but also to exhibit activity of activating the transcription of XBP1 in vitro. Five compounds were found to possess significant dose-effect relationship with EC50 values at a level of 10-7 µM in vitro. 8-Oxo-13-formyldihydropalmatine as an intermediate was found to display significant curative effect on UC in vivo based on the biomarkers of body weight change, colon length change, and calculated values of disease activity index and colon macroscopic damage index of the experimental animals, as well as the examination into the pathological changes of the colon tissue of the modeled animals.

Colitis Is Effectively Ameliorated by (±)-8-Acetonyl-dihydrocoptisine via the XBP1-NF-κB Pathway.

Ulcerative colitis (UC) is a recurrent, chronic intestinal disease. Available treatments for UC are poor effective and/or cause severe adverse events. X-box binding protein 1 (XBP1) and nuclear factor-κB (NF-κB) have been reported to play important roles in UC. Specifically, deletion or downregulation of XBP1 leads to spontaneous enteritis and results in imbalanced secretion of NF-κB and other proinflammatory cytokines. (±)-8-acetonyl-dihydrocoptisine, i.e., (±)-8-ADC, is a monomer semi-synthesized from coptisine. In vitro, (±)-8-ADC activated the transcriptional activity of XBP1, inhibited expression of NF-κB, and reduced production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß), in lipopolysaccharide-stimulated IEC6 cells. Therefore, silencing XBP1 would reduce the inhibition effect of (±)-8-ADC on NF-κB expression and the cytokines secretion in vitro. In a dextran sulfate sodium-induced colitis mouse model, oral administration of (±)-8-ADC ameliorated weight loss and colon contracture, and decreased the average disease activity index score and pathological damage. Simultaneously, (±)-8-ADC also increased XBP1 expression, and decreased NF-κB expression and secretion of myeloperoxidase, TNF-α, IL-6 and IL-1ß in the colon. Therefore, (±)-8-ADC may ameliorate UC via the XBP1-NF-κB pathway and should be considered as a therapeutic candidate for UC.

Six scalemic mixtures of 6-monosubstituted dihydrobenzophenanthridine alkaloids from Chelidonium majus and optically active structures of enantiomers.

Six pairs of previously undescribed 6-monosubstituted dihydrobenzophenanthridine alkaloids were separated as corresponding six scalemic mixtures from the aerial part of Chelidonium majus. The elucidation for the 2D structures of these alkaloids was achieved using regular spectroscopic and chemical methods. The assignment of scalemic-mixture nature was achieved using combined examinations of their NMR data, CD spectra, calculation of specific rotations, and chiral HPLC profiles. The identification for the relative configurations of alkaloids possessing two asymmetric carbons directly connected up by a rotatable sp3-sp3 carbon-carbon single bond was significantly facilitated by discussing the erythro and threo relative configurations defined by the mutuality of the orders of decreasing steric hindrances between the two sets of ligands linked to the two chiral centers. Two scalemic mixtures were assigned as (1'R,6R/1'S,6S)- and (1'S,6R/1'R,6S)-1-(dihydrochelerythrine-6-yl)ethanols, two as (1'R,6R)/(1'S,6S)- and (1'S,6R)/(1'R,6S)-1-(dihydrosanguinarine-6-yl)ethanols, one as (±)-ethyl 2-(dihydrosanguinarine-6-yl)acetate, and one as (±)-ethyl dihydrosanguinarine-6-carboxylate, respectively. The resolution of three scalemic mixtures was achieved and the absolute configurations of the three pairs of enantiomers were assigned via time-dependent Density Functional Theory calculations of electronic circular dichroism (ECD) data. The assignment for the absolute configurations of the other three scalemic mixtures was achieved via a chiral HPLC-UV/CD method plus analyzing their ECD data. The findings of this paper demonstrated that the relevant biochemical reactions concerning the construction of these 6-monosubstituted dihydrobenzophenanthridine alkaloids in the test plant are very nonselective. Scalemic mixture of (1'R,6R)/(1'S,6S)-1-(dihydrosanguinarine-6-yl)ethanol exhibited biological activity. It inhibited the growth of human MDA-MB-231 cell line at a moderate level with IC50 value of 5.12 µM.

Development of an XBP1 agonist, HLJ2, as a potential therapeutic agent for ulcerative colitis.

There is a severe lack of effective treatments for ulcerative colitis (UC), a recurrent and intractable inflammatory bowel disease. The identification of valid targets and new drugs is an urgent need. In this study, we identified the XBP-1 agonist HLJ2 as a promising treatment candidate. In an in vivo mouse model of DSS-induced colitis, HLJ2 decreased weight loss, colon contracture, disease activity index (DAI), colon mucosa damage index (CMDI) and histopathological index (HI). HLJ2 also decreased myeloperoxidase (MPO) activity and reduced production of the inflammatory cytokines TNF-α, IL-1ß, and IL-6. HLJ2 improved intestinal mucosa damage induced by dextran sodium sulfate (DSS) and increased the expression of ZO-1 and claudin-1. Fecal 16s rRNA high-throughput sequencing demonstrated a significant improvement in UC intestinal dysbacteriosis in mice treated with HLJ2, including increased abundance of probiotics such as Lachnospiraceae, Prevotellaceae, and Lactobacillaceae. At the same time there was a reduction in the abundance of pathogenic or conditional pathogenic microorganisms such as Bacteroidaceae, Porphyromonadaceae, Deferribacteraceae, and Pseudomonadaceae in HLJ2-treated mice compared with untreated mice. Our results demonstrated that the XBP1 agonist HLJ2 inhibits inflammation, regulates the intestinal flora, and protects the intestinal mucosa. It is thus a potential therapeutic agent for ulcerative colitis.

Azacyclo-indoles and Phenolics from the Flowers of Juglans regia.

Seven new azacyclo-indoles and phenolics and four known alkaloids were isolated from the flowers of Juglans regia. Spectroscopic and chromatographic data revealed that the structures of the new compounds are 5,6,11,12-tetrahydropyrrolo[1',2':1,2]azepino[4,5-b]indole-3-carbaldehyde (1), (±)-5,6,7,11c-tetrahydro-1H-indolizino[7,8-b]indol-3(2H)-one (2), (±)-9-hydroxy-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-2-carboxamide (3), 5-(ethoxymethyl)-1-(4-hydroxyphenethyl)-1H-pyrrole-2-carbaldehyde (4), (±)-5,8-dihydroxy-4-(1H-indol-3-yl)-3,4-dihydronaphthalen-1(2H)-one (5), (±)-4-(6-amino-9H-purin-9-yl)-5,8-dihydroxy-3,4-dihydronaphthalen-1(2H)-one (6), and (±)-4-(6-amino-9H-purin-9-yl)-5-hydroxy-3,4-dihydronaphthalen-1(2H)-one (7). The five pairs of enantiomers were resolved, and the absolute configurations of the enantiomers were assigned via electronic circular dichroism data. Compound 1 exhibited significant in vitro growth inhibition against the HCT-116, HepG2, BGC-823, NCI-H1650, and A2780 cancer cell lines, with IC50 values of 2.87, 1.87, 2.28, 2.86, and 0.96 µM, respectively, and low cytotoxicity toward normal IEC-6 cells, with a 79.6% survival rate at a 10 µM concentration.

14,15-Secopregnane-Type Glycosides with 5α:9α-Peroxy and Δ6,8(14)-diene Linkages from the Roots of Cynanchum stauntonii.

Three new 14,15-secopregnane-type glycosides, stauntosides UA, UA1, and UA2, were isolated from the roots of Cynanchum stauntonii. The three compounds share the first reported and same basic structural features of 3ß-hydroxy-14:16,15:20,18:20-triepoxy-5α:9α-peroxy-14,15-secopregnane-6,8(14)-diene named as stauntogenin G as the aglycones. The structures of the new compounds were characterized on the basis of extensive spectroscopic analyses, mainly 1D and 2D NMR and MS methods and chemical analysis. The isolation and identification of the new compounds graced the structural diversity of pregnane-type steroids from C. stauntonii.

Sugar-free pregnane-type steroids from the roots of Cynanchum stauntonii.

Two new sugar-free 14,15-secopregnane-type steroids, 14-O-methyl-3-epi-hirundigenin (1) and 2-deoxyamplexicogenin A (2), along with two known sugar-free pregnane-type steroids, were isolated from the 95% ethanol extract of the roots of Cynanchum stauntonii. The structures of the new compounds were characterized on the basis of extensive spectroscopic analyses, mainly 1D and 2D NMR methods, albeit the MS experiments did not display the molecular ion peaks. Compound 2 was the aglycones of stauntosides J and K, etc., previously isolated from C. stauntonii. The isolation and identification of the new compounds graced the structural diversity of pregnane-type steroids from C. stauntonii.

14,15-Secopregnane-type C21-steriosides from the roots of Cynanchum stauntonii.

Nine 14,15-secopregnane-type C21-steriosides, stauntosides U, V, V1-V3, W and C1-C3, as well as two known C21-steriosides, were isolated from the roots of Cynanchum stauntonii. Stauntosides U, V and V1-V3 share the same basic structural features of 8α:14α,14:16,15:20,18:20-tetraepoxy-14,15-secopregn-6-ene-3ß,5α,9α-triol, with the numbering system following that of C21-pregnanes. The aglycones of stauntosides U, V and V1-V3 are classified into two subcategories, the 5,9-dihydroxy groups and 5α:9α-peroxy bridge, according to the oxidative states of the two hydroxy groups at the C-5 and C-9 positions. The anti-inflammatory activity of the major compounds was assessed in an in vitro inflammatory model of mouse peritoneal macrophages using IC50 values of the inhibition of nitric oxide (NO) production as an indicator. Stauntosides V1 and V3 exhibited target activity with IC50 values of 9.3 µM and 12.4 µM, respectively, compared with dexamethasone, which was used as a positive control.