Anti-gastric Cancer Activity Research Articles

Structural Optimization and Structure-Activity Relationship of 1H-Pyrazole-4-carboxylic Acid Derivatives as DNA 6mA Demethylase ALKBH1 Inhibitors and Their Antigastric Cancer Activity.

DNA N6-methyladenine (6mA) demethylase ALKBH1 plays an important role in various cellular processes. Dysregulation of ALKBH1 is associated with the development of some cancer types, including gastric cancer, implicating a potential therapeutic target. However, there is still a lack of potent ALKBH1 inhibitors. Herein, we report the discovery of a highly potent ALKBH1 inhibitor, 1H-pyrazole-4-carboxylic acid derivative 29. The structure-activity relationship of this series of compounds was also discussed. Because of the poor cell membrane permeability of 29, we prepared a prodrug of 29 (29E), which showed excellent cellular activities. In gastric cancer cell lines HGC27 and AGS, 29E treatment significantly increased the abundance of 6mA, inhibited cell viability, and upregulated the AMP-activated protein kinase (AMPK) signaling pathway. In addition, the hydrolysis product 29 showed high exposure in mice after administration of 29E. Collectively, this research provides a new potent ALKBH1 inhibitor, which could serve as a lead compound for subsequent drug development.

Experimental and computational study on anti-gastric cancer activity and mechanism of evodiamine derivatives.

Introduction: Human topoisomerase 1 (TOP1) is an important target of various anticancer compounds. The design and discovery of inhibitors targeting TOP1 are of great significance for the development of anticancer drugs. Evodiamine and thieno [2,3-d] pyridine hybrids show potential antitumor activity. Herein, the anti-gastric cancer activities of these hybrids were investigated. Methods: The inhibitory effects of different concentrations of ten evodiamine derivatives on the gastric cancer cell line SGC-7901 were assessed using a methyl thiazolyl tetrazolium assay. Compounds EVO-1 and EVO-6 strongly inhibited gastric cancer cell proliferation, with inhibition rates of 81.17% ± 5.08% and 80.92% ± 2.75%, respectively. To discover the relationship between the structure and activity of these two derivatives, density functional theory was used to investigate their optimized geometries, natural population charges, frontier molecular orbitals, and molecular electrostatic potentials. To clarify their anti-gastric cancer mechanisms, molecular docking, molecular dynamics simulations, and binding free energy calculations were performed against TOP1. Results: The results demonstrated that these compounds could intercalate into the cleaved DNA-binding site to form a TOP1-DNA-ligand ternary complex, and the ligand remained secure at the cleaved DNA-binding site to form a stable ternary complex. As the binding free energy of compound EVO-1 with TOP1 (-38.33kcal·mol-1) was lower than that of compound EVO-6 (-33.25kcal·mol-1), compound EVO-1 could be a more potent anti-gastric cancer agent than compound EVO-6. Discussion: Thus, compound EVO-1 could be a promising anti-gastric cancer drug candidate. This study may facilitate the design and development of novel TOP1 inhibitors.

Extraction and Isolation of Two Polysaccharides from Chloranthus japonicus Sieb. and Evaluation of Their Anti-Gastric Cancer Activities.

Two unreported heteropolysaccharides, denoted as YCJP-1 and YCJP-2, were isolated from the herbs of Chloranthus japonicus. YCJP-1 was a heteropolysaccharide composed of glucose, galactose, arabinose, mannose, rhamnose, and a minor proportion of uronic acids, with the molecular weight mainly distributed in the 74,475-228,443 Da range. YCJP-2 was mainly composed of glucose, mannose, and galactose, with the molecular weights ranging from 848 to 5810 Da. To further evaluate the anti-gastric cancer effects of C. japonicus, the inhibitory effects of the crude polysaccharide (YCJP) and the purified polysaccharides (YCJP-1 and YCJP-2) were determined using a CCK-8 assay and colon-forming assay on MGC-803 and AGS gastric cancer cell lines. Our results showed that YCJP, YCJP-1, and YCJP-2 possess prominent inhibitory effects on the proliferation of MGC-803 and AGS cells, and the AGS cell was more sensitive to YCJP, YCJP-1, and YCJP-2. Moreover, YCJP-2 demonstrated superior anti-gastric cancer effects compared to YCJP-1. This could potentially be attributed to YCJP-2's higher glucose content and narrower molecular weight distribution.

Retraction Note to: Synthesis, Crystal Structure, and Anti-Gastric Cancer Activity of a Heterometallic Coordination Polymer Based on Flexible 6,6-Dithiodinicotinic Acid

Retraction Note to: Synthesis, Crystal Structure, and Anti-Gastric Cancer Activity of a Heterometallic Coordination Polymer Based on Flexible 6,6-Dithiodinicotinic Acid

Discovery of cinnamylaldehyde-derived mono-carbonyl curcumin analogs as anti-gastric cancer agents via suppression of STAT3 and AKT pathway

The structural modification of curcumin has always been a hotspot in drug development. In this paper, a class of cinnamylaldehyde-derived mono-carbonyl curcumin analogs (MCAs) with 7-carbon-links were designed and synthesized and their anticancer properties were evaluated. Through screening anti-gastric cancer activity of these compounds, H1 exhibited the strongest cytotoxic activity by inhibiting cell viability and colony formation, inducing cell cycle G2/M phase arrest in vitro (SGC-7901 and AGS gastric cancer cells). Moreover, the SGC-7901 subcutaneous tumor-bearing mice studies revealed that H1 significantly inhibited the tumor growth of gastric cancer. We explored the possible potential targets of H1 through network pharmacology. Mechanistically, our results demonstrated that H1 showed potential anti-gastric cancer activity through suppression of the STAT3 and AKT signaling pathway in vitro and in vivo, which was validated by molecular docking. Overall, our results indicate the potential of H1 as a potent chemotherapeutic drug against gastric cancer.

In vitro anti-Helicobacter pylori, anti-urease and anti-gastric cancer activities of novel hydrazones

In this study, new hydrazone derivatives were synthesized by taking into account the virulence factor of the urease in the urease-positive microorganism H. pylori. The structure of synthesized compounds 3a-3j was confirmed using 1H NMR, 13C NMR and elemental analyses. After structure confirmations all compounds were evaluated for in vitro urease inhibitory and anti-H. pylori activities. Furthermore, since H. pylori infection is associated with gastric cancer, the effects of the synthesized compounds against two different gastric cancer cell lines (SNU1 and AGS) were also evaluated. Amongst the series, two compounds 3c and 3j were found to be excellent inhibitors of urease, having IC50 values of 9.813 ± 0.403 µM and 11.407 ± 0.393 µM, better than the standard thiourea (IC50 = 13.428 ± 0.587 µM), whereas the remaining compounds displayed moderate activity. Compounds 3c and 3d were found to be the most active in the series against H. pylori with MIC values 4 µg/mL and 5 µg/mL. Next, compounds were evaluated as anti-gastric cancer activity and the compounds 3c and 3j were more potent than reference drug cisplatin against SNU1 and AGS. The docking study was executed to analyzed the interaction between the active site of the urease and the compounds 3c and 3j. When the all activities (anti-H. pylori, anti-urease and anti-gastric cancer activities) examined, it was found that the presence of the nitro group, which is an electron withdrawing group, in the 5th position of the thiophene ring (compound 3c) increased all activities. From the structure-activity relationship, it has been observed that the compound 3c showed excellent potential for anti-H. pylori, anti-gastric cancer and can be alternative therapy in the future.

Retraction Note to: Crystal Structure and Evaluation of the Anti-Gastric Cancer Activity of a New Sr(II)-Based Coordination Polymer

Retraction Note to: Crystal Structure and Evaluation of the Anti-Gastric Cancer Activity of a New Sr(II)-Based Coordination Polymer

Design, synthesis, and evaluation of cyclic C7-bridged monocarbonyl curcumin analogs containing an o-methoxy phenyl group as potential agents against gastric cancer

The structure-activity relationship (SAR) between toxicity and the types of linking ketones of C7 bridged monocarbonyl curcumin analogs (MCAs) was not clear yet. In the pursuit of effective and less cytotoxic chemotherapeutics, we conducted a SAR analysis using various diketene skeletons of C7-bridged MCAs, synthesized cyclic C7-bridged MCAs containing the identified low-toxicity cyclopentanone scaffold and an o-methoxy phenyl group, and assessed their anti-gastric cancer activity and safety profile. Most compounds exhibited potent cytotoxic activities against gastric cancer cells. We developed a quantitative structure-activity relationship model (R 2 > 0.82) by random Forest method, providing important information for optimizing structure. An optimized compound 2 exhibited in vitro and in vivo anti-gastric cancer activity partly through inhibiting the AKT and STAT3 pathways, and displayed a favorable in vivo safety profile. In summary, this paper provided a promising class of MCAs and a potential compound for the development of chemotherapeutic drugs.

Retraction Note: Bifunctional (3,6)-Connected Gd(III) Metal–Organic Framework Material with Catalytic Properties for the Cyanosilylation Reaction and Anti-gastric Cancer Activity

Retraction Note: Bifunctional (3,6)-Connected Gd(III) Metal–Organic Framework Material with Catalytic Properties for the Cyanosilylation Reaction and Anti-gastric Cancer Activity

Design, synthesis, and evaluation of (1E,4E,6E)-1,7-diphenyl hepta-1,4,6-trien-3-one analogues-inspired o-methoxy phenyl group as potential anti–gastric cancer agents.

292 Background: Gastric cancer (GC) is a major global malignancy causing significant mortality. Most diagnoses occur at advanced stages. Current treatments involve surgery, chemotherapy, and targeted therapies. Targeted drugs face resistance and side effects. Curcumin, derived from Curcuma longa, shows promise against GC. Improved analogs addressing bioavailability have been developed. Some curcumin-based compounds with o-methoxy phenyl groups exhibit enhanced anticancer activity. We designed and synthesized (1E,4E,6E)-1,7-diphenyl hepta-1,4,6-trien-3-one analogs inspired by o-methoxy phenyl for anti-gastric cancer evaluation in vitro and in vivo. Methods: We designed and synthesized a series of analogs named (1E,4E,6E)-1,7-diphenyl hepta-1,4,6-trien-3-one analogues inspired by the o-methoxy phenyl group based on association theory. Anti-tumor activity was evaluated in vitro using gastric cancer cell lines BGC-823 and SGC-7901. Compound 2 was selected as a prime candidate based on its potency. Results: Compound 2 demonstrated potent anti-tumor effects in vitro by suppressing growth, migration, and invasion of SGC-7901 and BGC-823 cells. Impressively, it prompted cell cycle arrest at the G2/M phase and initiated apoptosis through Bax activation and caspase 3 inhibition. Moreover, in vivo trials on xenograft model nude mice validated the compound's substantial anti-gastric cancer potential while maintaining a favorable safety profile. Conclusions: A group of curcumin analogs exhibiting strong anti-gastric cancer activity was developed. The active compound 2 is capable of inhibiting the growth, colony formation, migration, and invasion of gastric cancer cells. It also arrests the cell cycle at the G2/M phase and stimulates the expression of apoptosis-related proteins, showcasing a powerful anti-gastric cancer effect in vitro. Furthermore, it demonstrates significant anti-gastric cancer activity in vivo while maintaining a favorable safety profile. Our research underscores the potential of (1E, 4E, 6E)-1,7-diphenylheptyl-1,4,6-trien-3-one analogs with o-methoxyphenyl in combatting tumors and highlights their promise as a secure anti-tumor candidate drug.

Ligand-Based Design of Novel Quinoline Derivatives as Potential Anticancer Agents: An In-Silico Virtual Screening Approach.

In this study, using the Comparative Molecular Field Analysis (CoMFA) approach, the structure-activity relationship of 33 small quinoline-based compounds with biological anti-gastric cancer activity in vitro was analyzed in 3D space. Once the 3D geometric and energy structure of the target chemical library has been optimized and their steric and electrostatic molecular field descriptions computed, the ideal 3D-QSAR model is generated and matched using the Partial Least Squares regression (PLS) algorithm. The accuracy, statistical precision, and predictive power of the developed 3D-QSAR model were confirmed by a range of internal and external validations, which were interpreted by robust correlation coefficients (RTrain2=0.931; Qcv2=0.625; RTest2=0.875). After carefully analyzing the contour maps produced by the trained 3D-QSAR model, it was discovered that certain structural characteristics are beneficial for enhancing the anti-gastric cancer properties of Quinoline derivatives. Based on this information, a total of five new quinoline compounds were developed, with their biological activity improved and their drug-like bioavailability measured using POM calculations. To further explore the potential of these compounds, molecular docking and molecular dynamics simulations were performed in an aqueous environment for 100 nanoseconds, specifically targeting serine/threonine protein kinase. Overall, the new findings of this study can serve as a starting point for further experiments with a view to the identification and design of a potential next-generation drug for target therapy against cancer.

Identification of the Mechanism of Action of the Index Components of Banxia Xiexin Decoction for Gastric Cancer through Network Pharmacology, Bioinformatics, and Molecular Docking Analysis

Banxia Xiexin decoction (BXD) is a traditional prescription widely used to treat gastrointestinal conditions, including gastric cancer. Through network pharmacology, bioinformatics, and molecular docking analysis, this study aimed to investigate the potential mechanism of the antigastric cancer effect of BXD and pave the way for future research. The network pharmacology analysis used BXD index components to improve reliability and validity. Prognosis-related genes identified through Lasso and Cox regression analysis were considered potential BXD core targets for gastric cancer. Functional enrichment analysis was conducted to uncover the potential mechanism of action of BXD in gastric cancer. In addition, molecular docking of the index components of BXD and the core targets was used to validate the results. The present study obtained six index components of BXD and 155 corresponding antigastric cancer targets. ANXA5, CYP19A1, FGF1, and F2 in the prognostic signature model were identified as core targets of the index components of BXD. Protein-protein interaction networks and functional enrichment analysis indicated that proteoglycans in cancer, PI3K-Akt, and other pathways were involved. According to molecular docking results, six index components showed good-to-strong binding affinities to the core targets. The results indicated that the index components of BXD act on multiple pathways and targets of gastric cancer. Our study paved the way for further investigation of the antigastric cancer activity and mechanisms of BXD.

Discovery of novel coumarin-based derivatives as inhibitors of tubulin polymerization targeting the colchicine binding site with potent anti-gastric cancer activities

In this work, a series of novel coumarin-based derivatives were designed and synthesized as tubulin polymerization inhibitors targeting the colchicine binding site, and their antiproliferative activities against MGC-803, HCT-116 and KYSE30 cells were evaluated. Among them, the compound I-3 (MY-1442) bearing a 6-methoxy-1,2,3,4-tetrahydroquinoline group exhibited most potent inhibitory activities on MGC-803 (IC50 = 0.034 μM), HCT-116 (IC50 = 0.081 μM) and KYSE30 cells (IC50 = 0.19 μM). Further mechanism studies demonstrated that compound I-3 (MY-1442) could directly bind to the colchicine binding site of β-tubulin to inhibit tubulin polymerization and microtubules at the cellular level. The results of molecular docking indicated there were well binding interactions between compound I-3 (MY-1442) and the colchicine binding site of β-tubulin. Compound I-3 (MY-1442) also exhibited effective anti-proliferation, pro-apoptosis, and anti-migration abilities against gastric cancer cells MGC-803. Additionally, compound I-3 (MY-1442) could regulate the expression of cell cycle- and apoptosis-related proteins. Importantly, compound I-3 (MY-1442) could significantly inhibit tumor growth in the MGC-803 xenograft tumor model with a TGI rate of 65.5 % at 30 mg/kg/day. Taken together, this work suggested that the coumarin skeleton exhibited great potential to be a key pharmacophore of tubulin polymerization inhibitors for the discovery of anticancer agents.

Design, synthesis and biological evaluation of N-benzylaryl cinnamide derivatives as tubulin polymerization inhibitors capable of promoting YAP degradation with potent anti-gastric cancer activities

In this work, we utilized the N-benzylaryl derivative 9 as a lead compound and employed the molecular hybridization strategy by introducing cinnamoyl fragments to successfully design and synthesize 33 novel N-benzylaryl cinnamide derivatives 15a∼15 ag. The in vitro antiproliferative activities were explored, and the preliminary analysis and summary of their structure-activity relationship were conducted. The majority of the compounds demonstrated significant inhibitory potency on MGC-803, HCT-116 and KYSE450 cells with IC50 values below 0.5 μM. Among them, compound 15e (MY-1076) exhibited the most effective effect on the proliferative inhibition of MGC-803, SGC-7901, HCT-116 and KYSE450 cells with IC50 values of 0.019, 0.017, 0.020 and 0.044 μM, respectively, which is more potent than colchicine and the lead compound 9. Additionally, compound 15e (MY-1076) still exhibited significant inhibitory proliferation activity against 13 other types of tumor cells (IC50 values < 0.1 μM). Further studies revealed that compound 15e (MY-1076) could effectively inhibit tubulin polymerization by acting on the β-tubulin colchicine binding site, thereby disrupting microtubule network assembly and mitotic progression. Additionally, compound 15e (MY-1076) also demonstrated a notable inhibitory effect on the oncogenic protein YAP by inducing its degradation. Compound 15e (MY-1076) could dose-dependently induce G2/M phase arrest and cell apoptosis, effectively inhibit the colony formatting ability and cause morphological changes in MGC-803 and SGC-7901 cells. Compound 15e (MY-1076) exhibited significant regulatory effects on the expression levels of cell cycle and apoptosis-related proteins. Taken together, we here reported a novel N-benzylaryl cinnamide derivative 15e (MY-1076) as a tubulin polymerization inhibitor capable of promoting degradation of YAP, which held great potential as an anti-gastric cancer agent.

Design, synthesis and biological evaluation of novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors of FAK with potent anti-gastric cancer activities

In this study, twenty-one novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors targeting FAK were designed and synthesized based on the structure of TAE-226, and the inhibitory effects of these compounds on both the FAK enzyme and three cancer cell lines (MGC-803, HCT-116, and KYSE30) were investigated. Among them, compound 12s displayed potent inhibitory potency on FAK (IC50 = 47 nM), and demonstrated more significant antiproliferative activities in MGC-803, HCT-116 and KYSE30 cells (IC50 values were 0.24, 0.45 and 0.44 μM, respectively) compared to TAE-226. Furthermore, compound 12s significantly inhibited FAK activation leading to the negative regulation of FAK-related signaling pathways such as AKT/mTOR and MAPK signaling pathways. Molecular docking study suggested that compound 12s could well occupy the ATP-binding pocket site of FAK similar to TAE-226. In addition, compound 12s also efficiently inhibited the proliferation, induced apoptosis and cellular senescence in MGC-803 cells. In conclusion, compound 12s emerges a potent FAK inhibitor that could exert potent inhibitory activity against gastric cancer cells.

Identifying natural products for gastric cancer treatment through pharmacophore creation, 3D QSAR, virtual screening, and molecular dynamics studies.

Gastric cancer (GC) is known as the fourth leading cause of cancer-related death and the fifth major cancer in the world, and this is a serious threat to general health all over the world. The lack of early detection markers results in a belated diagnosis, i.e. the final stages, which could be associated with the ineffectiveness of the treatment strategies, and naturally, it leads to poor prognosis. Even though a variety of treatments have been developed, there is a trend of studying traditional medicinal plants, due to the worrying side effect of drugs available in the market. In this study, pharmacophore generation and 3D-QSAR model were created using 50 compounds with anti-gastric cancer activity (with IC50 had been reported in the previous studies). Based on three of the best pharmacophoric hypotheses, virtual screening was performed to discover the top anti-gastric cancer compounds from a database of 183,885 compounds. The selected compounds were used for molecular docking with three protein receptors 7BKG, 4F5B, and 4ZT1 to investigate the intermolecular interactions between these ligands and receptors. Finally, 21 lead compounds with the highest amount of docking score ranging from - 13.366 to -6.404kcal/mol were selected, and then the ADME/Tox properties of these compounds were calculated. All these compounds have a fitness score above 1.8, a molecular weight of less than 500g/mol, hydrogen bond donors up to 3, hydrogen bond acceptors up to 8.50, and logP of 1.013 to 4.174. Finally, molecular dynamic simulations for top-scoring ligand-receptor complexes were investigated. These selected lead compounds have the most anti-gastric cancer effects among the 183,885 compounds in the database. Therefore, lead compounds might be considered for gastric cancer therapy in future studies.

Statement of Retraction: A new Sr(II)-based coordination polymer: structural insight and anti-gastric cancer activity

Statement of Retraction: A new Sr(II)-based coordination polymer: structural insight and anti-gastric cancer activity

Statement of Retraction: Sonochemical synthesis and anti-gastric cancer activity of a Cu(II) coordination polymer

Statement of Retraction: Sonochemical synthesis and anti-gastric cancer activity of a Cu(II) coordination polymer

Discovery of a novel Coumarin-Dihydroquinoxalone derivative MY-673 as a tubulin polymerization inhibitor capable of inhibiting the ERK pathway with potent anti-gastric cancer activities

As a class of microtubule targeting agents, colchicine binding site inhibitors (CBSIs) are considered as promising drug candidates for cancer therapy. However, due to adverse reactions, there are currently no CBSIs approved by FDA for cancer treatment. Therefore, extensive efforts are still encouraged to find novel CBSIs with different chemical structures and better anticancer efficacies. In this work, we designed and synthesized a new coumarin-dihydroquinoxalone derivative, MY-673, and evaluated its anticancer potency in vitro and in vivo. We confirmed that MY-673 was a potent CBSI that it not only inhibited tubulin polymerization, but also exhibited significant inhibitory potency on the growth of 13 cancer cells with IC50 values from 11.7 nM to 395.9 nM. Based on the results of kinase panel screening, MY-673 could inhibit ERK (extracellular regulated protein kinases) pathways-related kinases. We further confirmed that MY-673 could inhibit ERK signaling pathway in MGC-803 and HGC-27 cells, and then affected the expression level of SMAD4 protein in TGF-β (transforming growth factor β) /SMAD (small mother against decapentaplegic) signaling pathway using the western blotting assay. In addition, compound MY-673 could effectively inhibit cell proliferation, migration and induce cell apoptosis. We also further confirmed the in vivo efficacy of MY-673 in inhibiting tumor growth using the MGC-803 xenograft tumor model. At 20 mg/kg, the TGI rate was 85.9%, and it did not cause obvious toxicity to the main organs of mice. Together, the results we report here indicated that MY-673 was a promising CBSI for cancer treatment, which was capable of inhibiting the ERK pathway with potent antiproliferative activities in vitro and in vivo.

CircSCUBE3 Reduces the Anti-gastric Cancer Activity of Anti-PD-L1.

The progression of gastric cancer (GC) is closely related to tumor immune escape. The research, therefore, studied the impact of possible circRNAs on the immune escape of GC tumors and the underlying mechanisms. Here, to explore circRNAs that may affect GC, the differential circRNAs in six normal gastric mucosal tissues and six GC samples (GSM2005868-GSM2005879) were analyzed through the bioinformatics website circmine, and hsa_circ_0076092 (circSCUBE3) was identified as the research object. In vitro assays revealed the functions of circSCUBE3 and its downstream miRNA/mRNA axis in GC cells. The effect of circSCUBE3 against PD-1 anti-tumor activity was evaluated in vivo. The relationship between circSCUBE3 and miR-744-5p, miR-744-5p, and SLC7A5 was identified by RNA immunoprecipitation and dual-luciferase reporter experiments. The effect of SLC7A5 on GC immune escape by regulating PD-L1 expression was assessed by co-culture system and flow cytometry. CircSCUBE3 was up-regulated in human GC tissues and GC cell lines. circSCUBE3 was associated with poor prognosis in GC patients. Functional experiments reported that circSCUBE3 knockdown could suppress GC immune escape. Mechanistically, circSCUBE3 bound to miR-744-5p, which further targeted SLC7A5, and SLC7A5 can affect GC immune escape by regulating PD-L1. Furthermore, in vivo assay manifested that circSCUBE3 attenuated the anti-tumor effect of PD-L1. Our study revealed the importance of the circSCUBE3/miR-744-5p/SLC7A5 axis in GC immune escape and anti-PD-1 resistance.