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In transdermal drug delivery system (TDDS) patches, achieving prolonged adhesion, high drug loading, and rapid drug release simultaneously presented a significant challenge. In this study, a PHT-SP-Cu2+ adhesive was synthesized using polyethylene glycol (PEG), hexamethylene diisocyanate (HDI), trimethylolpropane (TMP), and silk protein (SP) as functional monomers which were combined with Cu2+ to improve the adhesion, drug loading, and drug release of the patch. The structure of the adhesion chains and the formation of Cu2+-p-π conjugated network in PHT-SP-Cu2+ were characterized and elucidated using different characterization methods including FT-IR, 13C NMR, XPS, SEM imaging and thermodynamic evaluation. The formulation of pressure-sensitive adhesive (PSA) was optimized through comprehensive research on adhesion, mechanics, rheology, and surface energy. The formulation of 3 wt.% SP and 3 wt.% Cu2+ provided superior adhesion properties compared to commercial standards. Subsequently, the peel strength of PHT-SP-Cu2+ was 7.6 times higher than that of the commercially available adhesive DURO-TAK® 87–4098 in the porcine skin peel test. The adhesion test on human skin confirmed that PHT-SP-Cu2+ could adhere to the human body for more than six days. Moreover, the drug loading, in vitro release test and skin permeation test were investigated using ketoprofen as a model drug, and the results showed that PHT-SP-Cu2+ had the efficacy of improving drug compatibility, promoting drug release and enhancing skin permeation as a TDDS. Among them, the drug loading of PHT-SP-Cu2+ was increased by 6.25-fold compared with PHT, and in the in vivo pharmacokinetic analysis, the AUC was similarly increased by 19.22-fold. The mechanism of α-helix facilitated drug release was demonstrated by Flori-Hawkins interaction parameters, molecular dynamics simulations and FT-IR. Biosafety evaluations highlighted the superior skin cytocompatibility and safety of PHT-SP-Cu2+ for transdermal applications. These results would contribute to the development of TDDS patch adhesives with outstanding adhesion, drug loading and release efficiency. A new adhesive, PHT-SP-Cu2+, was created for transdermal drug delivery patches. Polyethylene glycol, hexamethylene diisocyanate, trimethylolpropane, silk protein, and Cu2+ were used in synthesis. Characterization techniques confirmed the structure and Cu2+-p-π conjugated networks. Optimal formulation included 3 wt.% SP and 3 wt.% Cu2+, exhibiting superior adhesion. PHT-SP-Cu2+ showed 7.6 times higher peel strength than DURO-TAK® 87–4098 on porcine skin and adhered to human skin for over six days. It demonstrated a 6.25-fold increase in drug loading compared to PHT, with 19.22-fold higher AUC in vivo studies. α-helix facilitated drug release, proven by various analyses. PHT-SP-Cu2+ showed excellent cytocompatibility and safety for transdermal applications. This study contributes to developing efficient TDDS patches. [Display omitted] [ABSTRACT FROM AUTHOR]

Poor skin adhesion and mechanical properties are common problems of pressure-sensitive adhesive (PSA) in transdermal drug delivery system (TDDS). Its poor water compatibility also causes the patch to fall off after sweating or soaking in the application site. To solve this problem, poly (2-Ethylhexyl acrylate- co - N -Vinyl-2-pyrrolidone- co - N -(2-Hydroxyethyl)acrylamide) (PENH), a cross-linked pyrrolidone polyacrylate PSA, was designed to improve the adhesion and water resistance of PSA through electrostatic force and hydrogen bonding system. The structure of PENH was characterized by 1H NMR, FTIR, DSC, and other methods. The mechanism was studied by FTIR, rheological test, and molecular simulation. The results showed that the PENH patch could adhere to human skin for more than 10 days without cold flow, and it could still adhere after sweating or water contact. In contrast, the commercial PSA Duro-Tak® 87-4098 and Duro-Tak® 87-2852 fell off completely on the 3rd and 6th day, respectively, and Duro-Tak® 87-2510 showed a significant dark ring on the second day. Mechanism studies have shown that the hydrogen bond formed by 2-ethylhexyl acrylate (2-EHA), N-vinyl-2-pyrrolidinone (NVP), and N -(2-Hydroxyethyl)acrylamide (HEAA) enhances cohesion, the interaction with skin improves skin adhesion, and the electrostatic interaction with water or drug molecules enhances the ability of water absorption and drug loading. Due to the synergistic effect of hydrogen bonds and electrostatic force, PENH can maintain high cohesion after drug loading or water absorption. PENH provides a choice for the development of water-compatible patches with long-lasting adhesion. Based on the synergistic effect of hydrogen bonding and electrostatic force, a hydrogen-bonded, cross-linked pyrrolidone acrylate pressure-sensitive adhesive for transdermal drug delivery was designed and synthesized, which has high adhesion and cohesive strength and is non-irritating to the skin. The patch can be applied on the skin surface continuously for more than 10 days without the phenomenon of "dark ring", and the patch can remain adherent after the patient sweats or bathes. This provides a good strategy for choosing a matrix for patches that require prolonged administration. [Display omitted] [ABSTRACT FROM AUTHOR]

Pressure-sensitive adhesives are critical to the product's safety, efficacy, and quality in transdermal drug delivery systems. However, many defects of transdermal patches (e.g. , insufficient adhesion, patch displacement, and "dark ring" phenomenon) remain. Herein, the N -[tris(hydroxymethyl)methyl]acrylamide (NAT)-modified acrylic pressure-sensitive adhesive coordinated with Fe(III) (AA-NAT/Fe3+) was creatively proposed. Results demonstrated that the adhesiveness and cohesiveness of the optimized AA-NAT/Fe3+ were higher by 1.8- and 9.7-fold, respectively, than those of commercially available DURO-TAK® 87-4098 due to the hydrogen bonding interaction of NAT-skin interface and coordination of NAT-Fe3+. Moreover, compared with that of DURO-TAK® 87-4098, the adhesion time of AA-NAT/Fe3+ on the human forearm was remarkably prolonged, and no "dark ring" phenomenon was observed for AA-NAT/Fe3+ after removal. After clonidine (CLO) was loaded into AA-NAT/Fe3+, controlled drug release and a drug transdermal behavior were endowed for CLO@AA-NAT/Fe3+ in vitro and in vivo. AA-NAT/Fe3+ still maintained superiority in adhesion and cohesion properties after CLO loading. These observations would contribute to the development of pressure-sensitive adhesives with outstanding adhesion and cohesion for transdermal patches. This N -[tris(hydroxymethyl)methyl]acrylamide-modified acrylic pressure-sensitive adhesive coordinated with Fe(III) has enhanced adhesion and cohesion properties, which provide a simple but effective strategy to solve the problems (e.g. , insufficient adhesion, patch displacement, and "dark ring" phenomenon) in existing transdermal patches. [Display omitted] [ABSTRACT FROM AUTHOR]

• First-year students' evolving habitus in a hybrid higher education field. • The influence of individual capital (linguistic and social) and competence (proactivity, adaptability, and inclusivity). • The interpenetrated and counteractive global-oriented logic and local-informed logic of Sino-foreign cooperative university. Transition to higher education (HE) is fraught with challenges, particularly for first-year students navigating an academic and social landscape that is often unfamiliar. Based on Bourdieu's theory of habitus, field, and capital, this qualitative study delves into the complex interplay between traditional (i.e., non-working-class, rural or international) students and the hybrid field of Sino-foreign cooperative university (SFCU). Drawing on a case study of 24 first-year traditional students, we uncover the dynamic evolvement of their habitus in response to the frictions encountered during their transition. The findings reveal three distinct patterns of evolving habitus: aligning, transforming, and alternating. These patterns are influenced by students' linguistic and social capital, as well as their demonstrated competencies in proactivity, adaptability, and inclusivity. Furthermore, the global-oriented logic of the SFCU fosters habitus evolvement, encouraging students to embrace new academic and social paradigms. Conversely, the local-informed logic can lead to habitus hysteresis among certain students. It reveals the often-overlooked side of HE internationalization, where local practices persist despite being overshadowed by the dominant global discourse and can sometimes counteract the prevailing narrative. This study contributes to the literature on student transition by providing a nuanced lens through which to view the evolving habitus of first-year traditional students in a hybrid HE field. It offers insights for HE institutions on harmonizing competing logics and supporting student transitions more effectively through targeted capital provision and competence development. [ABSTRACT FROM AUTHOR]

Highlights • Joint effects of perception and engagement on learning outcomes were found. • Engagement mediated the relationship between course experience and generic skills. • Cocurricular experience positively predicted learning satisfaction. • First semester GPA positively predicted cumulative university GPA. • National College Entrance Examination scores did not correlate with any factor. Abstract The study examined the relationships among students' perceptions of the learning environment, prior academic achievement, engagement, and learning outcomes (cumulative university GPA, generic skills development, and learning satisfaction) with a sample of 2,616 seniors from a full-time research-oriented university in Mainland China. The results supported a model which showed that students' perceptions of the learning environment and prior academic achievement had direct effects on learning outcomes, and indirect effects via their engagement. The effects, however, varied depending on the type of the outcome in question: (1) Student engagement mediated the relationship between course experience and generic skills development, (2) cocurricular experience positively predicted learning satisfaction, (3) first semester GPA positively predicted cumulative university GPA, and (4) National College Entrance Examination scores did not correlate with any other factor. A major proportion of the variance in the three types of learning outcomes was accounted for by the model, showing its effectiveness in predicting university students' learning. Implications for improving undergraduate education in China are provided. [ABSTRACT FROM AUTHOR]

Persistent activated STAT3 has a striking correlation with cancer development and inhibition of STAT3 signaling pathway is a novel therapeutic way for human cancers. Among STAT family, STAT1 and STAT3 play opposite roles in tumorigenesis. However, the discovery of selective STAT3 inhibitors is still challenging to date. In this study, a series of small-molecular (MW < 500) benzensulfanilamide derivatives were designed to selectively suppress STAT3 activation for anti-cancer treatment. The most potent compound 11 inhibited both overexpressed and IL-6 induced STAT3 phosphorylation, whereas 11 displayed little effect on the phosphorylation of other STAT isoforms STAT1, STAT5, demonstrating 11 was a selective STAT3 inhibitor. Meanwhile, 11 dismissed STAT3 DNA binding activity and colony formation. In addition, 11 elevated the ROS level and induced apoptosis of cancer cells. Furthermore, 11 effectively suppressed tumor growth in an in vivo mouse-xenograft model. [ABSTRACT FROM AUTHOR]

This study examined the relationship between students’ perceptions of the learning environment, high school performance, approaches to learning, and learning outcomes (generic skills development and course satisfaction). A sample of 74,687 undergraduates from 39 full-time regular universities in China responded to a questionnaire comprising four self-constructed scales. The results supported the reliability and validity of the instruments. A structural equation model showed that approaches to learning mediated the relationship between perceptions of the learning environment and learning outcomes. Specifically, deep approach was found to positively predict learning outcomes. Good teaching positively predicted deep and surface approaches, as well as learning outcomes. Student-faculty and peer interactions were strong predictors of learning approaches and learning outcomes. High school performance had weak effects on learning approaches and learning outcomes. These findings highlight the need of developing new instruments for assessing Chinese undergraduate students’ learning and have implications for improving undergraduate teaching in China. [ABSTRACT FROM AUTHOR]

Abstract: In this paper we discussed the penetration effects of common interplanetary magnetic cloud (MC) structures like sheath region, both sheath and magnetic cloud boundary layer (MCBL), MC body, and shock-running into a preceding MC on the equatorial ionosphere during intense (SYM-H ≤−100nT) geomagnetic storms. Using solar wind data obtained from the ACE and WIND spacecraft, we have identified these four types of MC structures responsible for the electric field penetration events detected by Jicamarca incoherent scatter radar. After elimination of the propagation delay, the observations show that the equatorial electric field (EEF) was changed immediately following the arrival of solar wind disturbance. Moreover, the duration of EEF corresponded well with that of the corresponding MC structure interval. We suggest that identifying the solar wind structures associated with penetration electric field may shed light on the understanding of the penetration processes and further help exploring their effects on the ionospheric plasma. [ABSTRACT FROM AUTHOR]

[Display omitted] The aim of this study was to develop a long-acting transdermal patch of levamlodipine (LAM) using an ion-pair strategy to reduce the skin irritation induced by topical application of LAM and explore the mechanism underlying the improvement of skin irritation. The formulation was optimized through porcine in vitro transdermal experiments and rabbit in vivo skin irritation tests. The obtained formulation consisted of poly (2-Ethylhexyl acrylate-co-N-Vinyl-2-pyrrolidone-co-N-(2-Hydroxyethyl) acrylamide) (PENH) as the adhesive matrix, 13.00 % levamlodipine-sorbic acid ion-pair complex (LAM-SA) (w/w), and 10 % isopropyl myristate (IPM) (w/w), with a patch thickness of 70 μm, achieving an erythema index of 188 for rabbit skin and 117–187 for human skin (264 for rabbit skin and 110–260 for human skin in the absence of sorbic acid (SA)). In vivo rabbit and human skin erythema analysis and H&E staining verified that the optimized ion-pair patch effectively reduced skin irritation. Drug distribution experiments in the skin, ATR-FTIR, and molecular simulation were used to characterize the mechanism by which the ion-pair reduced skin irritation. Excessive accumulation of LAM in the epidermis induced secondary structural changes in keratin, resulting in skin barrier damage and inflammatory response. The formation of the LAM-SA ion pair altered physicochemical properties of LAM, reducing drug retention in the epidermis and, thereby, reducing skin irritation. This study demonstrated the potential of the ion-pair strategy to improve the safety of transdermal drug delivery system (TDDS) and provided a means for reducing skin irritation caused by the active pharmaceutical ingredient (API) itself. [ABSTRACT FROM AUTHOR]

• A cross-sectional survey on 1,150 Chinese college students. • Structural equation modeling (SEM) was used. • Academic involution atmosphere significantly impacts students' mental exhaustion. • Relative deprivation and perception of academic pressure mediate the relationship. • Relative deprivation and perception of academic pressure also play a chain effect. With the increasing intensity of social competition and the continuous changes in the educational environment, the phenomenon of academic involution in colleges and universities has become increasingly serious, and the problem of mental exhaustion among college students has become increasingly prominent. A convenient sampling method was used to survey 1150 college students in China. The structural equation model (SEM) was employed to analyze the relationships among the variables. Specifically, this study constructed a model with academic involution atmosphere as the independent variable, mental exhaustion as the dependent variable, and relative deprivation and perception of academic pressure as mediators. The bias-corrected bootstrap method was used to test the significance of the mediation effects. This study elucidates the mechanisms through which the academic involution atmosphere influences college students' mental wellbeing, uncovering its origins and pathways. These insights offer valuable guidance for educators in implementing targeted and effective mental health interventions. [ABSTRACT FROM AUTHOR]

Trace elements (TEs) are essential for the treatment of rheumatoid arthritis (RA). This study aimed to prepare a TEs solution enriched with various organic states to evaluate its preventive, therapeutic effects, and mechanism of action in RA and to provide a treatment method for RA treatment. The TEs in natural ore were extracted and added to 0.5% (W/V) L-alanyl-L-glutamine (LG) to obtain a TEs solution (LG-WLYS), which was examined for its concentration and quality. The antioxidant properties and effects of LG-WLYS on cell behavior were evaluated at the cellular level. The preventive and therapeutic effects and mechanism of action of LG-WLYS in rats with RA were explored. The LG-WLYS solution was clear, free from visible foreign matter, and had a pH of 5.33 and an osmolality of 305.67 mOsmol/kg. LG-WLYS inhibited cell migration and angiogenesis. LG-WLYS solution induced macrophages to change from M1-type to M2-type, increased the content of antioxidant enzymes (glutathione, superoxide dismutase, and IL-10), decreased the levels of nitric oxide, malondialdehyde, TNF-α, IL-1β, IL-6, COX-2, and iNOs, scavenging reactive oxygen species from the lesion site, inhibiting the apoptosis of chondrocytes, regulating inflammatory microenvironment, and decreasing inflammation response to exert the therapeutic effect for RA. In conclusion, LG-WLYS has outstanding therapeutic and preventive effects against RA and has enormous potential for further development. [Display omitted] • An organic state trace element solution (LG-WLYS) was successfully prepared. • The LG-WLYS exerts an anti-inflammatory effect by scavenging reactive oxygen species. • The LG-WLYS treats rheumatoid arthritis by modulating macrophage phenotype. • The LG-WLYS can prevent the development of inflammatory diseases. [ABSTRACT FROM AUTHOR]

STAT3 has been extensively studied as a potential antitumor target. Though studies on regulating STAT3 mainly focus on the inhibition of STAT3 phosphorylation at Tyr705 residue, the phosphorylation at Ser727 residue of STAT3 protein is also closely associated with the mitochondrial import of STAT3 protein. N , N -diethyl-7-aminocoumarin is a fluorescent mitochondria-targeting probe. In this study, a series of STAT3 inhibitors were developed by connecting N , N -diethyl-7-aminocoumarin fluorophore with benzo [ b ]thiophene 1, 1-dioxide moiety. All designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 7a was mainly accumulated in mitochondria visualized by its fluorescence. STAT3 phosphorylation was inhibited by compound 7a at both Tyr705 and Ser727 residues. Compound 7a inhibited STAT3 phosphorylation whereas had no influence on the phosphorylation levels of STAT1, JAK2, Src and Erk1/2, indicating good selectivity of compound 7a. Moreover, compound 7a down-regulated the expression of STAT3 target genes Bcl-2 and Cyclin D1, increased ROS production and remarkably reduced the mitochondrial membrane potential to induce mitochondrial apoptotic pathway. Furthermore, compound 7a in vivo suppressed breast cancer 4T1 implanted tumor growth. Taken together, these results highlighted that compound 7a might be a promising mitochondria-targeting STAT3 inhibitor for cancer therapy. Compound 7a acted as a mitochondria-targeting STAT3 inhibitor to exert antitumor activities in vitro and in vivo. Image 1 • Fluorescent coumarin-BTP conjugates were discovered as mitochondria-targeting STAT3 inhibitors. • Compound 7a was mainly accumulated in mitochondria. • Compound 7a inhibited STAT3 phosphorylation at both Tyr705 and Ser727 residues. • Compound 7a exhibited potent antitumor activity in vitro. • Compound 7a arrested tumor growth in vivo. [ABSTRACT FROM AUTHOR]

STAT3 is an attractive therapeutic target for cancer therapy. However, due to low potency or poor druggability, none of its inhibitors are clinically available. Herein, a series of aminobenzo[ b ]thiophene 1, 1-dioxides with good drug-likeness properties were designed, synthesized and evaluated as STAT3 inhibitors. Most of them exhibited higher antitumor activity than the small-molecule STAT3 inhibitor, Stattic. Compound 15 was the most potent and had an IC 50 range in 0.33–0.75 μM in various cancer cell lines. The overexpressed and IL-6 induced phosphorylation levels of STAT3 were both inhibited by 15 without influencing the phosphorylation levels of the upstream kinases Src and Jak2. 15 also suppressed the expressions of STAT3 downstream gene, Bcl-2. 15 effectively increased the ROS levels of cancer cells, induced cancer cell apoptosis and abolished the colony formation ability of cancer cells without affecting bypass kinase p-Erk. Furthermore, 15 in vivo induced significant antitumor responses, and exhibited less toxicity than Doxorubicin. Together, this study described a class of new STAT3 inhibitors as antitumor agents. [ABSTRACT FROM AUTHOR]

We synthesized a series of novel pyromeconic acid-styrene hybrid compounds and measured their activities in inhibiting Aβ 1-42 self-aggregation and promoting disaggregation, and their anti-inflammatory and antioxidant properties. The most potent compound, compound 30 , had IC 50 values of 11.15 μM and 6.87 μM for inhibition of fibril aggregation and promotion of fibril disaggregation, respectively. Because of its redox metal chelating property, 30 also inhibited Cu2+-induced Aβ 1-42 fibril aggregation and promoted fibril disaggregation with IC 50 of 3.69 μM and 3.35 μM, respectively. Molecular docking demonstrated that 30 interacted with key amino acids of Aβ 1-42 , and the reliability of the complex was confirmed by molecular dynamics. In addition, 30 displayed excellent antioxidative activity (oxygen radical absorbance capacity = 2.65 Trolox equivalents) and moderate anti-inflammatory activity and neuroprotection in cell culture assays. Compound 30 was safe in acute toxicity test in mice, and it exhibited favorable pharmacokinetic properties, particularly, accumulation in the hippocampus (maximum ratio of hippocampus to plasma = 7.12). Compound 30 alleviated cognitive deficits in scopolamine-induced amnesia mice; this property may have been attributed to reducing neuroinflammation by inhibiting ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein expression and reducing oxidative stress by activating the Nrf2/HO-1 signaling pathway. In view of its many properties, we envision that 30 is a promising lead for the treatment of Alzheimer's disease. [Display omitted] • Thirty hybrids synthesized by merging pyromeconic acid with styrene scaffolds. • Hybrid 30 had anti-Aβ, metal chelation, and neuroprotection properties. • 30 accumulated in hippocampus and had favorable pharmacokinetic parameters. • 30 had good safety and alleviated cognitive deficits in scopolamine-induced AD mice. [ABSTRACT FROM AUTHOR]

Constitutive activation of STAT3 has been found in a wide variety of cancers and demonstrated as a very attractive therapeutic target. Disrupting both acetylation and phosphorylation of STAT3 protein was hypothesized to greatly deactivate STAT3, therefore, treating cancers. To demonstrate the hypothesis, two series of novel resveratrol-caffeic acid hybrids were designed aiming to regulate both acetylation and phosphorylation of STAT3 protein, which is also the first report of the synthetic inhibitors simultaneously regulating two biological reactions of STAT3 to our knowledge. Most of these compounds were demonstrated with preferential antitumor activity with low IC 50 values against two cancer cell lines. Particularly, compound 7d was found as an excellent STAT3 inhibitor with over 50-fold better potency than resveratrol and caffeic acid. Meanwhile, the novel derivatives significantly inhibited the proliferation and induced the apoptosis of tumor cells. Molecular docking further disclosed the binding modes of STAT3 with the inhibitors. In addition, compound 7d orally and significantly suppressed breast cancer 4T1 xenograft tumor growth in vivo , indicating its great potential as an efficacious drug candidate for human cancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Hollow mesoporous silica nanoparticles-loaded ion-crosslinked bilayer films (CCS-PVA-TPP-FSM@HMSNs) were prepared for buccal delivery of furosemide. • CCS-PVA-TPP-FSM@HMSNs films exhibited outstanding mechanical properties and excellent bioadhesion. • CCS-PVA-TPP-FSM@HMSNs films achieved great acceptance among volunteers. • In pharmacokinetic study with golden hamster models, the relative bioavailability was increased by 191.54%. Mucoadhesive buccal films (MBFs) become the most promising buccal mucosal delivery system duo to its advantageous properties, including simple preparation technique and better patient compliance. The mechanical properties and mucoadhesion of MBFs are crucial in their successful performance as well as manufacturing and administration. In this study, we prepared hollow mesoporous silica nanoparticles-loaded ion-crosslinked bilayer films (CCS-PVA-TPP-FSM@HMSNs) using carboxymethyl chitosan (CCS) and polyvinyl alcohol (PVA) for buccal delivery of furosemide (FSM). The FSM-loaded hollow mesoporous silica nanoparticles (FSM@HMSNs) were firstly characterized by SEM, TEM, and nitrogen adsorption/desorption. Then, we constructed an ion-crosslinked network using CCS and PVA employed with the solution casting method, and sodium tripolyphosphate (TPP) was used as a hydrogen bond crosslinking agent. The formulation was optimized through Box-Behnken design, where the impact of the proportion of the ingredients on the quality of the films was evaluated entirely. Herein, folding endurance, swelling, tensile strength, and adhesion force were selected as response variables. Morphology, mechanical, spectroscopic, thermal, and safety of CCS-PVA-TPP-FSM@HMSNs films were also investigated. The release and permeability behaviors of CCS-PVA-TPP-FSM@HMSNs films were evaluated by in vitro drug release, across isolated porcine buccal and TR146 cell model. The CCS-PVA-TPP-FSM@HMSNs films showed outstanding mechanical properties, suitable bioadhesion, high drug loading, significant sustained-release properties, and improved permeability. In pharmacokinetic study with golden hamster models, the relative bioavailability was increased by 191.54%, and the absolute bioavailability was 82.20%. In summary, this study provides evidence that this innovative CCS-PVA-TPP-FSM@HMSNs films could be a promising and industrialized buccal drug delivery system. [ABSTRACT FROM AUTHOR]

Compound 6 , a novel isoquinoline comprising two isoquinoline-3-carboxylic acids and a benzoic acid conjugated together using tris(2-aminoethyl)amine, was synthesized and tested for anti-tumor activity. In vivo evaluations found 6 to be well tolerated, of high therapeutic efficacy and of low systemic toxicity, at effective doses. The results suggest 6 to be a promising lead for future study, and the use of multiple isoquinoline-3-carboxylic acid moieties as pharmacophores in the same molecule to be a useful strategy for the design of anti-tumor drugs. [ABSTRACT FROM AUTHOR]

Deregulation of GP130 in signal transduction is involved in multiple types of human diseases, especially in cancers, indicating that GP130 is an attractive target for cancer therapy. However, GP130 was conventionally considered as an undruggable target thus the discovery of GP130 PPI inhibitors is extremely challenging. By the aid of structure-based drug design, in this study, two series of bazedoxifene based analogues were designed to target GP130 D1 domain and block the IL-6/GP130/STAT3 signaling pathway for antitumor treatment. Most of these designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 10a was demonstrated to directly bind to GP130 protein with an affinity (K D) value of 3.8 μM via both SPR and DARTS methods. Subsequently, molecular docking study predicted that 10a targeted D1 domain of GP130 and co-IP assay demonstrated that 10a did not inhibit IL-6R/GP130 interaction, which meant 10a did not bind to the D2 and D3 domains of GP130. Moreover, 10a selectively inhibited JAK2 and STAT3 phosphorylation as well as IL-6 induced STAT3 phosphorylation. 10a effectively inhibited tumor cell viability, migration and promoted apoptosis. Furthermore, 10a effectively suppressed xenograft model tumor growth in vivo. Taken together, this study described a new class of bazedoxifene derived GP130 inhibitors as antitumor agents. Compound 10a targets GP130 and inhibits the activation of JAK2/STAT3 pathway to exert antitumor activity. Image 1 • Novel bazedoxifene based analogues were designed as direct GP130 inhibitors for anti-cancer treatment. • 10a was indicated as a directly GP130 D1 domain inhibitor and blocked the IL-6/GP130/STAT3 signaling pathway. • 10a exhibited potent antitumor activity in vitro. • 10a arrested tumor growth in vivo. [ABSTRACT FROM AUTHOR]