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A series of 3-aminopropyloxy derivatives of chalcone were synthesised and evaluated for their antiproliferative activity against liver, gastric and neuroendocrine cancer cell lines. Most of the synthesised compounds exhibited moderate to good activity against all three cancer cell lines, but in particular, a 3-(pyrrolidin-1-yl)propyloxy chalcone containing a 3,4,5-trimethoxyphenyl group showed the highest antiproliferative activity with an IC50 value of 2.74 μM against liver cancer cells. [ABSTRACT FROM AUTHOR]

Nine chalcone derivatives containing an N-heterocyclic compound attached by its nitrogen atom to one of the benzene rings were prepared and evaluated for their antiproliferative activity against liver, gastric and neuroendocrine cancer cell lines. Most of the synthesised compounds exhibited moderate to good activity against all three cancer cell lines, but in particular, a chalcone containing a 4-(imidazol1yl)phenyl group and a 3,4,5-trimethoxyphenyl group showed the highest antiproliferative activity with an IC50 value of 5.39 μM against liver cancer cells. [ABSTRACT FROM AUTHOR]

A series of novel dithiocarbamate–chalcone derivates were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell lines (EC-109, SK-N-SH and MGC-803). Majority of the synthesized compounds exhibited moderate to potent activity against all the cancer cell lines assayed. Particularly, compounds II2 and II5 exhibited the excellent growth inhibition against SK-N-SH with IC 50 values of 2.03 μM and 2.46 μM, respectively. Further mechanism studies revealed that compound II2 could obviously inhibit the proliferation of SK-N-SH cells by inducing apoptosis and arresting the cell cycle at G0/G1 phase. [ABSTRACT FROM AUTHOR]

A series of novel coumarin derivatives were synthesized from commercially available chemical agents. All prepared compounds were evaluated for their in vitro antiproliferative activity against five selected human cancer cell lines (EC109, MGC-803, PC-3, MCF-7, and EC9706) and their in vitro antimicrobial activity against E. coli and M. albicans. 4-(3-Bromopropoxy)-2 H-chromen-2-one exhibited the highest growth inhibition against MGC-803 cell line (IC 47.7 μM) and 7-(2-bromoethoxy)-2 H-chromen-2-one exhibited the highest growth inhibition against MCF-7 cell line (IC 48.3 μM). The latter compound was also the most active against E. coli (MIC 0.27 μg/ml). [ABSTRACT FROM AUTHOR]

A series of novel chalcone-1,2,3-triazole-azole hybrids were designed, synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (SK-N-SH, EC-109 and MGC-803). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Particularly, compound I-21 showed the most excellent antiproliferative activity with an IC50 value of 1.52 μM against SK-N-SH cancer cells. Further mechanism studies revealed that compound I-21 induced morphological changes of SK-N-SH cancer cells possibly by inducing apoptosis. Novel chalcone-1,2,3-triazole-azole derivatives in this work might be a series of promising lead compounds to develop anticancer agents for treating neuroblastoma. [ABSTRACT FROM AUTHOR]

A new C18-diterpenoid alkaloid, kirinenine A (1), was isolated from the root of Aconitum kirinense, along with eight known diterpenoid alkaloids. The structures of all compounds were characterized on the basis of extensive NMR and MS analyses and by comparison with literature values, and the new one was further confirmed by X-ray crystallographic diffraction. All the compounds were isolated from the title plant for the first time. [ABSTRACT FROM AUTHOR]

Abstract: Two benzophenone glucopyranosides have been isolated from the nut shell part of Mahkota Dewa. The structures were identified as 2,4′,6-trihydroxy-4-methoxy-benzophenone-2-O-β-d-glucoside (Mahkoside A) and 2,4′,6-trihydroxy-4-methoxy-6″-acetyl-benzophenone-2-O-β-d-glucoside (Mahkoside B). Mahkoside B was recognized as a novel compound. Furthermore, a series of benzophenone glucopyranoside derivatives (compounds 3–18) were synthesized and their bioactivities were characterized. Our results demonstrated that compound 18 has significant cytotoxicity against two esophageal cancer cell lines, stomach cancer cell line and prostate cancer cell line, with IC50 less than 10μM, indicating its potential activity against cancer cells. [Copyright &y& Elsevier]

In this work, a series of novel arylamide derivatives containing piperazine moiety were designed and synthesised as tubulin polymerisation inhibitors. Among 25 target compounds, compound 16f (MY-1121) exhibited low nanomolar IC50 values ranging from 0.089 to 0.238 μM against nine human cancer cells. Its inhibitory effects on liver cancer cells were particularly evident with IC50 values of 89.42 and 91.62 nM for SMMC-7721 and HuH-7 cells, respectively. Further mechanism studies demonstrated that compound 16f (MY-1121) could bind to the colchicine binding site of β-tubulin and directly act on β-tubulin, thus inhibiting tubulin polymerisation. Additionally, compound 16f (MY-1121) could inhibit colony forming ability, cause morphological changes, block cell cycle arrest at the G2 phase, induce cell apoptosis, and regulate the expression of cell cycle and cell apoptosis related proteins in liver cancer cells. Overall, the promising bioactivities of compound 16f (MY-1121) make the novel arylamide derivatives have the value for further development as tubulin polymerisation inhibitors with potent anticancer activities. [ABSTRACT FROM AUTHOR]

Neuroblastoma has obvious heterogeneity. It is one of the few undifferentiated malignant tumors that can spontaneously degenerate into completely benign tumors. However, for its high-risk type, even with various intensive treatment options, the prognosis is still unsatisfactory. At the same time, a large number of research data show that the abnormal amplification and high-level expression of the MYCN gene are positively correlated with the malignant progression, poor prognosis, and mortality of neuroblastoma. In this context, this article explores the role of the N-Myc, MYCN gene expression product on its target genes related to the cell cycle and reveals its regulatory network in promoting tumor proliferation and malignant progression. We hope it can provide ideas and direction for the research and development of drugs targeting N-Myc and its downstream target genes. [ABSTRACT FROM AUTHOR]

Mahkoside A (Ia) and B (Ib) are isolated from the nut shell part of Mahkota Dewa. [ABSTRACT FROM AUTHOR]

[1,2,4]Triazolo[1,5-a]pyrimidine and indole skeletons are widely used to design anticancer agents. Therefore, in this work, a series of [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives were designed and synthesized by the molecular hybridization strategy. The antiproliferative activities of the target compounds H1–H18 against three human cancer cell lines, MGC-803, HCT-116 and MCF-7, were tested. Among them, compound H12 exhibited the most active antiproliferative activities against MGC-803, HCT-116 and MCF-7 cells, with IC50 values of 9.47, 9.58 and 13.1 μM, respectively, which were more potent than that of the positive drug 5-Fu. In addition, compound H12 could dose-dependently inhibit the growth and colony formation of MGC-803 cells. Compound H12 exhibited significant inhibitory effects on the ERK signaling pathway, resulting in the decreased phosphorylation levels of ERK1/2, c-Raf, MEK1/2 and AKT. Furthermore, compound 12 induced cell apoptosis and G2/M phase arrest, and regulated cell cycle-related and apoptosis-related proteins in MGC-803 cells. Taken together, we report here that [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives, used as anticancer agents via the suppression of ERK signaling pathway and the most active compound, H12, might be a valuable hit compound for the development of anticancer agents. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel honokiol thioethers bearing a 1,3,4-oxadiazole moiety were prepared. • Honokiol derivative 3k exhibited the best anti-proliferative activity against HCT116 cells. • 3k can arrest HCT116 cells in G1 phase and induce HCT116 cell death. • 3k directly inhibits the transcription and expression of YAP protein without activating the Hippo signaling pathway. Honokiol, derived from Magnolia officinalis (a traditional Chinese medicine), has been reported to have anticancer activity. Here, a series of novel honokiol thioethers bearing a 1,3,4-oxadiazole moiety were prepared and evaluated for their anticancer activities against three types of digestive system tumor cells. Biological evaluation showed that honokiol derivative 3k exhibited the best antiproliferative activity against HCT116 cells with an IC 50 value of 6.1 μmol/L, superior to the reference drug 5-fluorouracil (IC 50 : 9.63 ± 0.27 µmol/L). The structure–activity relationships (SARs) indicated that the introduction of –(4-NO 2)Ph, 3-pyridyl, –(2-F)Ph, –(4-F)Ph, –(3-F)Ph, –(4-Cl)Ph, and –(3-Cl)Ph groups was favorable for enhancing the anticancer activity of the title honokiol thioethers. Further study revealed that honokiol thioether 3k can well inhibit the proliferation of colon cancer cells HCT116, arresting the cells in G1 phase and inducing cell death. Moreover, a preliminary mechanism study indicated that 3k directly inhibits the transcription and expression of YAP protein without activating the Hippo signaling pathway. Thus, honokiol thioether 3k could be deeply developed for the development of honokiol-based anticancer candidates. [ABSTRACT FROM AUTHOR]

Following nearly two decades of development, significant advancements have been achieved in PROTAC technology. As of the end of 2022, more than 20 drugs have entered clinical trials, with ARV-471 targeting estrogen receptor (ER) showing remarkable progress by entering phase III clinical studies. In 2022, significant progress has been made on multiple targets. The first reversible covalent degrader designed to target the KRASG12C mutant protein, based on cyclopropionamide, has been reported. Additionally, the activity HDCA1 degrader surpassed submicromolar levels during the same year. A novel FEM1B covalent ligand called EN106 was also discovered, expanding the range of available ligands. Furthermore, the first PROTAC drug targeting SOS1 was reported. Additionally, the first-in-class degraders that specifically target BRD4 isoforms (BRD4 L and BRD4 S) have recently been reported, providing a valuable tool for further investigating the biological functions of these isoforms. Lastly, a breakthrough was also achieved with the first degrader targeting both CDK9 and Cyclin T1. In this review, we aimed to update the PROTAC degraders as potential anticancer agents covering articles published in 2022. The design strategies, degradation effects, and anticancer activities were highlighted, which might provide an updated sight to develop novel PROTAC degraders with great potential as anticancer agents as well as favorable drug-like properties. [Display omitted] • PROTAC degraders exhibit great potential for cancer treatment. • The discovery and development of PROTAC degraders in 2022 are comprehensively reviewed. • The first reversible KRASG12C covalent degrader was reported in 2022. • A breakthrough was achieved with the first degrader targeting both CDK9 and Cyclin T1 in 2022. [ABSTRACT FROM AUTHOR]

In this work, we utilized the molecular hybridization strategy to design and synthesize novel 1,2,3-triazole benzothiazole derivatives K1-26. The antiproliferative activities against MGC-803, Kyse30 and HCT-116 cells were explored, and their structure-activity relationship were preliminarily conducted and summarized. Among them, compound K18 , exhibited the strongest proliferation inhibitory activity, with esophageal cancer cells Kyse30 and EC-109 being the most sensitive to its effects (IC 50 values were 0.042 and 0.038 μM, respectively). Compound K18 effectively inhibited tubulin polymerization (IC 50 = 0.446 μM), thereby hindering tubulin polymerize into filamentous microtubules in Kyse30 and EC-109 cells. Additionally, compound K18 induced the degradation of oncogenic protein YAP via the UPS pathway. Based on these dual molecular-level effects, compound K18 could induce G2/M phase arrest and cell apoptosis in Kyse30 and EC-109 cells, as well as regulate the expression levels of cell cycle and apoptosis-related proteins. In summary, our findings highlight a novel 1,2,3-triazole benzothiazole derivative K18 , which possesses significant potential for treating esophageal cancers. [Display omitted] • Compound K18 showed low nanomolar IC 50 values of 0.042 and 0.038 μM against Kyse30 and EC-109 cells. • Compound K18 inhibited tubulin polymerization (EC 50 = 0.445 μM). • Compound K18 induced YAP degradation. • Compound K18 induced the G2/M phase arrest and apoptosis in Kyse30 and EC-109 cells. [ABSTRACT FROM AUTHOR]

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 (IC 50 = 0.034 μM), HCT-116 (IC 50 = 0.081 μM) and KYSE30 cells (IC 50 = 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. [Display omitted] • A series of novel coumarin-based derivatives were designed and synthesized. • Compound I-3 (MY-1442) exhibited potent inhibitory activities. • Compound I-3 (MY-1442) could inhibit tubulin polymerization by binding to the colchicine binding site. • Compound I-3 (MY-1442) was effective in the inhibition of MGC-803 cells Xenograft Model. [ABSTRACT FROM AUTHOR]

Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative, compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC50 values of 0.36 μM (MGC-803 cells), 0.70 μM (HCT-116 cells), 1.04 μM (PC-3 cells), and 0.81 μM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo. Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP. [ABSTRACT FROM AUTHOR]

Background: The Hippo pathway is widely considered to inhibit cell growth and play an important role in regulating the size of organs. However, recent studies have shown that abnormal regulation of the Hippo pathway can also affect tumor invasion and metastasis. Therefore, finding out how the Hippo pathway promotes tumor development by regulating the expression of target genes provides new ideas for future research on targeted drugs that inhibit tumor progression. Methods: PubMed, Embase, Web of Science, and the Cochrane Library were systematically searched. Results: The search strategy identified 1892 hits and 196 publications were finally included in this review. As the core molecule of the Hippo pathway, YAP/TAZ are usually highly expressed in tumors that undergo invasion and migration and are accompanied by abnormally strong nuclear metastasis. Through its interaction with nuclear transcription factors TEADs, it directly or indirectly regulates and the expressions of target genes related to tumor metastasis and invasion. These target genes can induce the formation of invasive pseudopodia in tumor cells, reduce intercellular adhesion, degrade extracellular matrix (ECM), and cause epithelial-mesenchymal transition (EMT), or indirectly promote through other signaling pathways, such as mitogen-activated protein kinases (MAPK), TGF/Smad, etc, which facilitate the invasion and metastasis of tumors. Conclusion: This article mainly introduces the research progress of YAP/TAZ which are the core molecules of the Hippo pathway regulating related target genes to promote tumor invasion and metastasis. Focus on the target genes that affect tumor invasion and metastasis, providing the possibility for the selection of clinical drug treatment targets, to provide some help for a more in-depth study of tumor invasion and migration mechanism and the development of clinical drugs. [ABSTRACT FROM AUTHOR]

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 IC 50 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 IC 50 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 (IC 50 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. [Display omitted] • Compound 15e (MY-1076) showed low nanomolar IC 50 values of 0.017–0.098 μM against 17 cancer cells. • Compound 15e (MY-1076) inhibited tubulin polymerization by binding to the colchicine site. • Compound 15e (MY-1076) induced YAP degradation. • Compound 15e (MY-1076) induced G2/M phase arrest and apoptosis. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel 2,4-diaminopyrimidine cinnamyl derivatives were designed and synthesized. • Compound 12s displayed inhibition of FAK with an IC 50 value of 47 nM. • Compound 12s exhibited potent antiproliferative activities against MGC-803, HCT-116 and KYSE30 cells. • Compound 12s effectively inhibited the proliferation, induced apoptosis and induced cellular senescence in MGC-803 cells. 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 (IC 50 = 47 nM), and demonstrated more significant antiproliferative activities in MGC-803, HCT-116 and KYSE30 cells (IC 50 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. [ABSTRACT FROM AUTHOR]

Histone deacetylases, as a new class of anticancer targets, could maintain homeostasis by catalyzing histone deacetylation and play important roles in regulating the expression of target genes. Due to the fact that simultaneous intervention with dual tumor related targets could improve treatment effects, researches on innovative design of dual-target drugs are underway. HDAC is known as a "sensitizer" for the synergistic effects with other anticancer-target drugs because of its flexible structure design. The synergistic effects of HDAC inhibitor and other target inhibitors usually show enhanced inhibitory effects on tumor cells, and also provide new strategies to overcome multidrug resistance. Many research groups have reported that simultaneously inhibiting HDAC and other targets, such as tubulin, EGFR, could enhance the therapeutic effects. The o-aminobenzamide group is often used as a ZBG group in the design of HDAC inhibitors with potent antitumor effects. Given the prolonged inhibitory effects and reduced toxic side effects of HDAC inhibitors using o-aminobenzamide as the ZBG group, the o-aminobenzamide group is expected to become a more promising alternative to hydroxamic acid. In fact, o-aminobenzamide-based dual inhibitors of HDAC with different chemical structures have been extensively prepared and reported with synergistic and enhanced anti-tumor effects. In this work, we first time reviewed the rational design, molecular docking, inhibitory activities and potential application of o-aminobenzamide-based HDAC inhibitors with dual targeting capabilities in cancer therapy, which might provide a reference for developing new and more effective anticancer drugs. [Display omitted] • HDAC is an attractive target for the anticancer drug development. • The o-aminobenzamide-based HDAC inhibitors with dual-targeting capabilities were summarized for the first time. • The advantages and design strategies of o-aminobenzamide-based HDAC dual inhibitors were discussed. [ABSTRACT FROM AUTHOR]

• Compound 20 inhibited ESCC cell growth in vitro and in vivo. • Compound 20 induced G2/M phase arrest. • Compound 20 induced cell apoptosis via up-regulating Noxa. A series of novel indoline derivatives were synthesized and evaluated for antiproliferative activity against four selected cancer cell lines (Hela, A549, HepG2 and KYSE30). Among them, compound 20 displayed the potent inhibition activity against esophageal cancer cells (Kyse30, Kyse450, Kyse510 and EC109). Cellular mechanism studies in esophageal squamous cell carcinoma (ESCC) cells elucidated compound 20 inhibited cell growths in vitro and in vivo , reduced colony formation, arrested cell cycle at M phase, and induced Noxa-dependent apoptosis in ESCC. Importantly, compound 20 was identified as a novel Noxa mediated apoptosis inducer. These results suggested that compound 20 might be a promising anticancer agent with potential for development of further clinical applications. [ABSTRACT FROM AUTHOR]

We have evaluated the antiproliferative activity of (E)-3-(3,5-difluorophenyl)-1-(2,4,6-trimethoxyphenyl)- prop-2-en-1-one (chalcone 5) against MGC-803 cells. This chalcone analog displayed a potent antiproliferative activity with an IC50 value of 0.23 μM against MGC-803 cells. It could induce apoptosis and regulate the apoptosis-related markers (Bax, Bcl-2, Bcl-xl, and Bid) in a concentration dependent manner. Treatment with NAC almost completely attenuated chalcone-induced cell inhibition and cell apoptosis in MGC-803 cells, indicating that the apoptotic mechanisms were related to ROS generation. Therefore, this chalcone derivative is a new apoptosis inducer for prevention and treatment of gastric cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] The microtubule system plays an important role in the mitosis and growth of eukaryotic cells, and it is considered as an appealing and highly successful molecular target for cancer treatment. In fact, microtubule targeting agents, such as paclitaxel and vinblastine, have been approved by FDA for tumor therapy, which have achieved significant therapeutic effects and sales performance. At present, microtubule targeting agents mainly include microtubule-destabilizing agents, microtubule-stabilizing agents, and a few tubulin degradation agents. Although there are few reports about tubulin degradation agents at present, tubulin degradation agents show great potential in overcoming multidrug resistance and reducing neurotoxicity. In addition, some natural drugs could specifically degrade tubulin in tumor cells, but have no effect in normal cells, thus showing a good biosafety profile. Therefore, tubulin degradation agents might exhibit a better application. Currently, some small molecules have been designed to promote tubulin degradation with potent antiproliferative activities, showing the potential for cancer treatment. In this work, we reviewed the reports on tubulin degradation, and focused on the degradation mechanism and important functional groups of chemically synthesized compounds, hoping to provide help for the degradation design of tubulin. [ABSTRACT FROM AUTHOR]

[Display omitted] • A new coumarin-dihydroquinoxalone derivative MY-673 was designed and synthesized. • MY-673 exhibited potent inhibitory activities against 13 cancer cells. • MY-673 could inhibit tubulin polymerization and ERK signaling pathway. • MY-673 was effective in the inhibition of MGC-803 cells Xenograft Model. 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 IC 50 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. [ABSTRACT FROM AUTHOR]

• Chalcone-dithiocarbamates were novel apoptosis inducers. • 12d arrested cell cycle at G2/M phase and induced DNA damage. • 12d induced ROS-mediated apoptosis by catalase inhibition. • 12d inhibited epithelial-mesenchymal transition process. Novel chalcone-dithiocarbamate hybrids were designed, synthesized and evaluated for antiproliferative activity against selected cancer cell lines (MGC803, MCF7, and PC3). Among these analogues, (E)-2-oxo-2-((4-(3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)amino)ethyl-4-(2-hydroxyethyl)piperazine-1-carbodithioate (12d) showed the best inhibitory activity against PC3 cells (IC 50 = 1.05 μM). Cellular mechanism studies elucidated 12d could inhibit colony formation, arrest cell cycle at G2/M phase and induce DNA damage against PC3 cells. Compound 12d also induced mitochondrial apoptosis by caspase activation, MMP decrease, ROS production and catalase (CAT) inhibition. Importantly, 12d inhibited epithelial-mesenchymal transition (EMT) process by regulating EMT-related proteins (E-cadherin, N-cadherin, Vimentin, MMP2, MMP9). These results indicated that 12d is a promising lead compound and deserves further investigation for prevention and treatment of human prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract Structurally diverse trimethoxyphenyl-1,2,3-triazole hybrids were designed, synthesized and evaluated for their antiproliferative activity against three cancer cell lines (PC3, MGC803 and HepG2). Among them, trimethoxyphenyl-1,2,3-triazole containing the coumarin fragement 19c displayed better antiproliferative activity results with IC50 values from 0.13 μM to 1.74 μM than anticancer drug colchicine. Compound 19c could inhibit MGC803 cell growth and colony formation, induce G2/M phase arrest by down expression of CDK1, and promote apoptosis by regulating DR5 and Bcl-2 family. Moreover, 19c strongly inhibited tubulin polymerization by interacting with the colchicine site. Graphical abstract Image 1 Highlights • Molecular diversity of trimethoxyphenyl-1,2,3-triazoles was explored. • 19c inhibited colony formation against MGC803 cells at 30 nM. • 19c arrested cell cycle at G2/M phase and induced apoptosis. • 19c was a novel colchicine site tubulin polymerization inhibitor. [ABSTRACT FROM AUTHOR]

Abstract Multi-component pesticide residues, especially pesticide residues with synergistic toxicity, are a serious threat to food safety. With risk assessment, we found that Chlorpyrifos (CPF) and Carbofuran (CBF) are 2 pesticide residues with highest risk for Actinidia chinensis planch. The results showed CPF and CBF have a synergistic neurotoxicity on neural cell SK-N-SH. The toxicity was partly depending on oxidative stress (OS) and had effects on cell apoptosis and cell cycle arrest. Furthermore, the toxicity remained on long-term low-dose condition. Graphical abstract Unlabelled Image Highlights • Chlorpyrifos and carbofuran combination show the synergistic effect. • Chlorpyrifos and carbofuran induce apoptosis via ROS generation. • Chlorpyrifos and carbofuran induce cell cycle G2 phase arrest by ROS generation. • CPF and CBF harm cells in long-term and low-dose circumstance. [ABSTRACT FROM AUTHOR]

(E)-3-(3-(Allyloxy)-2-methoxyphenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one displayed potent antiproliferative activity against the PC-3 cell line. For colony assay, it can inhibit the colony formation at a concentration of 10 μM. Morphological changes of PC-3 cells were determined using DAPI (4′,6-diamidino-2-phenylindole) staining and chromatin condensation. Treatment with this compound at 10 μM induced apoptosis from 2.0% to 30.4% compared with control according to flow cytometry analysis. It also induced the downregulation of apoptosis-related markers Bcl-2 and XIAP (X-linked inhibitor of apoptosis protein). However, treatment with NAC (N-acetyl-L-cysteine) almost completely attenuated chalcone-induced cell inhibition and cell apoptosis in PC-3 cells. [ABSTRACT FROM AUTHOR]

Abstract Novel bioactive heterocycles containing a 3,4,5-trimethoxyphenyl fragment as antiproliferative agents by targeting tubulin were synthesized and their preliminary structure activity relationships (SARs) were explored. Among all these chemical agents, 2-(Benzo[d]oxazol-2-ylthio)- N -(4-methoxybenzyl)- N -(3,4,5-trimethoxyphenyl)acetamide (4d) exhibited the potent antiproliferative activity against MGC-803 cells with an IC 50 value of 0.45 μM by induction of G2/M pahse arrest and cell apoptosis. In addition, 4d could change the membrane potential (ΔΨ) of the mitochondria against MGC-803 cells. Importantly, 4d acted as a novel tubulin polymerization inhibitor binding to colchicine site with an IC 50 value of 3.35 μM. Graphical abstract Image 1 Highlights • 4d exhibited the potent antiproliferative activity against MGC-803 cells. • 4d induced cell cycle G2/M phase arrest and apoptosis. • 4d changed the mitochondrial membrane potential against MGC-803 cells. • 4d acted as a novel colchicine site tubulin polymerization inhibitor. [ABSTRACT FROM AUTHOR]

In this work, N- benzylarylamide-dithiocarbamate based derivatives were designed, synthesized, and their biological activities as anticancer agents were explored. Some of the 33 target compounds displayed significant antiproliferative activities with IC 50 values at the double-digit nanomolar level. The representative compound I-25 (also named MY-943) not only showed the most effective inhibitory effects on three selected cancer cells MGC-803 (IC 50 = 0.017 μM), HCT-116 (IC 50 = 0.044 μM) and KYSE450 (IC 50 = 0.030 μM), but also exhibited low nanomolar IC 50 values from 0.019 to 0.253 μM against the other 11 cancer cells. Compound I-25 (MY-943) effectively inhibited tubulin polymerization and suppressed LSD1 at the enzymatic levels. Compound I-25 (MY-943) could act on the colchicine binding site of β-tubulin, thus disrupting the construction of cell microtubule network and affecting the mitosis. In addition, compound I-25 (MY-943) could dose-dependently induce the accumulation of H3K4me1/2 (MGC-803 and SGC-7091 cells) and H3K9me2 (SGC-7091 cells). Compound I-25 (MY-943) could induce G2/M phase arrest and cell apoptosis, and suppress migration in MGC-803 and SGC-7901 cells. In addition, compound I-25 (MY-943) significantly modulated the expression of apoptosis- and cycle-related proteins. Furthermore, the binding modes of compound I-25 (MY-943) with tubulin and LSD1 were explored by molecular docking. The results of in vivo anti-gastric cancer assays using in situ tumor models showed that compound I-25 (MY-943) effectively reduced the weight and volume of gastric cancer in vivo without obvious toxicity. All these findings suggested that the N -benzylarylamide-dithiocarbamate based derivative I-25 (MY-943) was an effective dual inhibitor of tubulin polymerization and LSD1 that inhibited gastric cancers. [Display omitted] • Compound MY-943 showed low nanomolar IC 50 values of 0.017–0.253 μM against 14 cancer cells. • Compound MY-943 inhibited tubulin polymerization by binding to the colchicine site. • Compound MY-943 suppressed LSD1, and induced the accumulation of H3K4me1/2 and H3K9me2. • Compound MY-943 induced G2/M phase arrest and apoptosis, and suppress migration. • Compound MY-943 effectively reduced the weight and volume of gastric cancer in vivo without obvious toxicity. [ABSTRACT FROM AUTHOR]

As an important epigenetic regulator, histone lysine specific demethylase 1 (LSD1) has become an attractive target for the discovery of anticancer agents. In this work, a series of tranylcypromine-based derivatives were designed and synthesized. Among them, compound 12u exhibited the most potent inhibitory potency on LSD1 (IC 50 = 25.3 nM), and also displayed good antiproliferative effects on MGC-803, KYSE450 and HCT-116 cells with IC 50 values of 14.3, 22.8 and 16.3 μM, respectively. Further studies revealed that compound 12u could directly act on LSD1 and inhibit LSD1 in MGC-803 cells, thereby significantly increasing the expression levels of mono-/bi-methylation of H3K4 and H3K9. In addition, compound 12u could induce apoptosis and differentiation, inhibit migration and cell stemness in MGC-803 cells. All these findings suggested that compound 12u was an active tranylcypromine-based derivative as a LSD1 inhibitor that inhibited gastric cancer. [Display omitted] • Novel tranylcypromine-based derivatives were designed and synthesized. • Compound 12u showed low nanomolar IC 50 value against LSD1 and high selectivity for MAO-A and MAO-B. • Compound 12u suppressed LSD1 and induced the accumulation of H3K4 Me1/2 and H3K9 Me2/3. • Compound 12u induced apoptosis and differentiation, and inhibited migration and cell stemness. [ABSTRACT FROM AUTHOR]

A series of 5,6-diaryl-1,2,4-triazines hybrids bearing a 1,2,3-triazole linker were synthesized by molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, EC-109 and PC-3). The first structure-activity relationship (SAR) for these 5,6-diaryl-1,2,4-triazines is explored in this report with evaluation of 15 variants of the structural class. Among these chemical derivatives, 3-(((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5,6-diphenyl-1,2,4-triazine ( 11E ) showed the more potent inhibitory effect against three cell lines than 5-Fu. Cellular mechanism studies in MGC-803 cells elucidated 11E inhibited colony formation and arrested cell cycle at G2/M phase. Furthermore, compound 11E caused morphological changes, decreased mitochondrial membrane potential, and induced apoptosis through the apoptosis-related proteins in MGC-803 cells. It was the first time, to our knowledge, that 5,6-diaryl-1,2,4-triazines bearing a 1,2,3-triazole linker were used as potential apoptosis inducers. [ABSTRACT FROM AUTHOR]

[Display omitted] • VEGFR-2 is aberrantly expressed in many malignant tumors. • Developments or discoveries of VEGFR-2-based inhibitors with multi-targeting capabilities were summarized. • The rational design and SARs of multi-targeting agents were discussed. • The therapeutic effects might be improved by simultaneously inhibiting VEGFR-2 and other targets. Vascular epidermal growth factor receptor-2 (VEGFR-2), as an important tyrosine transmembrane protein, plays an important role in regulating endothelial cell proliferation and migration, regulating angiogenesis and other biological functions. VEGFR-2 is aberrantly expressed in many malignant tumors, and it is also related to the occurrence, development, and growth of tumors and drug resistance. Currently, there are nine VEGFR-2 targeted inhibitors approved by US.FDA for clinical use as anticancer drugs. Due to the limited clinical efficacy and potential toxicity of VEGFR inhibitors, it is necessary to develop new strategies to improve the clinical efficacy of VEGFR inhibitors. The development of multitarget therapy, especially dual-target therapy, has become a hot research field of cancer therapy, which may provide an effective strategy with higher therapeutic efficacy, pharmacokinetic advantages and low toxicity. Many groups have reported that the therapeutic effects could be improved by simultaneously inhibiting VEGFR-2 and other targets, such as EGFR, c-Met, BRAF, HDAC, etc. Therefore, VEGFR-2 inhibitors with multi-targeting capabilities have been considered to be promising and effective anticancer agents for cancer therapy. In this work, we reviewed the structure and biological functions of VEGFR-2, and summarized the drug discovery strategies, and inhibitory activities of VEGFR-2 inhibitors with multi-targeting capabilities reported in recent years. This work might provide the reference for the development of VEGFR-2 inhibitors with multi-targeting capabilities as novel anticancer agents. [ABSTRACT FROM AUTHOR]

[Display omitted] • Dual inhibitor of focal adhesion kinase (FAK) and histone deacetylases 6 (HDAC6) was first reported. • MY-1259 exhibited potent inhibitory activities in gastric cancer cells. • MY-1259 displayed highly potent activities against FAK and HDAC6. • MY-1259 was superior in the inhibition of in gastric cancer cells MGC-803 Xenograft Model than that of SAHA and TAE-226, either alone or and in combination. Epigenetic regulation and Focal adhesion kinase (FAK) are considered to be two important targets for the development of antitumor drugs. Studies have shown that the combination of FAK and HDAC inhibitors could exhibit synergistic effects in a subset of cancer cells in vitro and in vivo. At present, there are few reports on dual target inhibitors of FAK and HDAC. Here, we first reported a new compound MY-1259 as a dual FAK and HDAC6 inhibitor, which exhibited efficient treatment effects on gastric cancers in vitro and in vivo. MY-1259 exhibited potent inhibitory activities against FAK (IC 50 = 132 nM) and HDAC6 (IC 50 = 16 nM). Notably, MY-1259 showed selective inhibitory potency on HDAC6 over HDAC1, HDAC2 and HDAC3. In addition, MY-1259 could potently inhibit the proliferative activities of MGC-803 and BGC-823 cells (IC 50 = 3.91 and 15.46 nM, respectively, using flow cytometry counting), induce cell apoptosis, and cellular senescence. MY-1259 could effectively down-regulate the levels of Ac-Histone H3 and Ac-α-tubulin, and also inhibit the phosphorylation of FAK at three phosphorylation sites Y397, Y576/577 and Y925, thereby inhibiting the activation of ERK and AKT/mTOR. MY-1259 exhibited more effective antitumor effect in vivo than the HDAC inhibitor SAHA and FAK inhibitor TAE-226 alone or in combination, showing the advantages of FAK/HDAC dual inhibitors in the treatment of gastric cancers. Therefore, the results in this work suggested that inhibition of FAK and HDAC by MY-1259 might represent a promising strategy for the treatment of gastric cancers. [ABSTRACT FROM AUTHOR]

A series of novel formononetin-dithiocarbamate derivatives were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell line (MGC-803, EC-109, PC-3). The first structure-activity relationship (SAR) for this formononetin-dithiocarbamate scaffold is explored in this report with evaluation of 14 variants of the structural class. Among these analogues, tert -butyl 4-(((3-((3-(4-methoxyphenyl)-4-oxo-4 H -chromen-7-yl)oxy)propyl)thio)carbonothioyl)piperazine-1-carboxylate ( 8i ) showed the best inhibitory activity against PC-3 cells (IC 50 = 1.97 μM). Cellular mechanism studies elucidated 8i arrests cell cycle at G1 phase and regulates the expression of G1 checkpoint-related proteins in concentration-dependent manners. Furthermore, 8i could inhibit cell growth via MAPK signaling pathway and inhibit migration via Wnt pathway in PC-3 cells. [ABSTRACT FROM AUTHOR]

50 New drugs including 36 chemical entities and 14 biologics were approved by the U.S. Food and Drug Administration during 2021. Among the marketed drugs, 31 new small molecule agents (29 small molecule drugs and 2 diagnostic agents) with privileged structures and novel clinical applications represent as promising leads for the development of new drugs with the similar indications and improved therapeutic efficacy. This review is mainly focused on the clinical applications and synthetic methods of 29 small molecule drugs newly approved by the FDA in 2021. We believed that insight into the synthetic approaches of drug molecules would provide creative and practical inspirations for the development of more efficient and practical synthetic technologies to meet with new drug discovery. [Display omitted] • 50 New drugs including 36 chemical entities and 14 biologics were approved by the FDA during 2021. • Clinical applications and synthetic methods of 29 small-molecule drugs are summarized. • These new drugs provide privileged structures for the development of new drugs. [ABSTRACT FROM AUTHOR]

A series of pyrido[3,4- d ]pyrimidine derivatives were designed and synthesized. Compound 30 showed the most effective inhibitory effect on MGC-803 cells and induced apoptosis. [Display omitted] In order to find high-efficiency and low-toxic anti-tumor drugs, 29 pyrido[3,4- d ]pyrimidine compounds were designed, synthesized and evaluated by MTT assay in vitro. The results presented that most of the compounds had good antitumor activities, among which compound 30 had the best anti-tumor activity on MGC803 cells (IC 50 = 0.59 μM). Mechanistic studies exhibited that compound 30 inhibited migration of MGC803 and induced apoptosis. It was proved that compound 30 up-regulated expression of Bid and PARP, down-regulated expression of CycD1 by western blot experiments. This study indicated that compound 30 might be served as a lead agent for the treatment of human gastric cancers. [ABSTRACT FROM AUTHOR]

Novel N -benzylarylamide saderivatives were designed and synthesized, and their antiproliferative activities were explored. Some of 51 target compounds exhibited potent inhibitory activities against MGC-803, HCT-116 and KYSE450 cells with IC 50 values in two-digit nanomolar. Compound I-33 (MY-875) displayed the most potent antiproliferative activities against MGC-803, HCT-116 and KYSE450 cells (IC 50 = 0.027, 0.055 and 0.067 μM, respectively) and possessed IC 50 values ranging from 0.025 to 0.094 μM against other 11 cancer cell lines. Further mechanism studies indicated that compound I-33 (MY-875) inhibited tubulin polymerization (IC 50 = 0.92 μM) by targeting the colchicine bingding site of tubulin. Compound I-33 (MY-875) disrupted the construction of the microtubule networks and affected the mitosis in MGC-803 and SGC-7901 cells. In addition, although it acted as a colchicine binding site inhibitor, compound I-33 (MY-875) also activated the Hippo pathway to promote the phosphorylation status of MST and LATS, resulting in the YAP degradation in MGC-803 and SGC-7901 cells. Due to the degradation of YAP, the expression levels of TAZ and Axl decreased. Because of the dual actions on colchicine binding site and Hippo pathway, compound I-33 (MY-875) dose-dependently inhibited cell colony formatting ability, arrested cells at the G2/M phase and induced cells apoptosis in MGC-803 and SGC-7901 cells. Moreover, compound I-33 (MY-875) could regulate the levels of cell cycle and apoptosis regulatory proteins in MGC-803 and SGC-7901 cells. Furthermore, molecular docking analysis suggested that the hydrogen bond and hydrophobic interactions made compound I-33 (MY-875) well bind into the colchicine binding site of tubulin. Collectively, compound I-33 (MY-875) is a novel anti-gastric cancer agent and deserves to be further investigated for cancer therapy by targeting the colchicine binding site of tubulin and activating the Hippo pathway. [Display omitted] • Novel N -benzylarylamide derivatives were prepared. • Compound 875 displayed excellent antiproliferative activity. • Compound 875 inhibited tubulin polymerization by binding to the colchicine site. • Compound 875 activated the Hippo pathway. • Compound 875 induced cell cycle arrest and cells apoptosis in gastric cells. [ABSTRACT FROM AUTHOR]

Novel coumarin-indole derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors targeting the colchicine binding site. Among these compounds, compound MY-413 displayed the most potent inhibitory activities against gastric cancer cell line MGC-803 with an IC 50 value of 0.011 μM. Furthermore, the IC 50 values of compound MY-413 was less than 0.1 μM for other 17 cancer cell lines and less than 0.05 μM for other 8 cancer cell lines. Compound MY-413 effectively inhibited the tubulin polymerization (IC 50 = 2.46 μM) by binding to the colchicine site. Screening for the inhibitory effects of compound MY-413 on 61 kinases, it was found that compound MY-413 could inhibit MAPK pathways-related kinases. Because of the inhibitory effects of compound MY-413 on tubulin polymerization and MAPK signaling pathway, compound MY-413 induced cell apoptosis, arrested the cell cycle in the G2/M phase, induced the inhibition of cell proliferation and migration in gastric cancer cells MGC-803 and HGC-27. In addition, compound MY-413 could significantly inhibit tumor growth in MGC-803 xenograft tumor models with tumor growth inhibition (TGI) rates of 70% (15 mg/kg) and 80% (30 mg/kg) without obvious toxicity. Consistent with the in vitro results, compound MY-413 also inhibited MAPK signaling pathway, and induced apoptosis and proliferation inhibition in vivo. In conclusion, this work indicated that compound MY-413 was a promising lead compound for the further investigation as a potential anti-gastric cancer agent. [Display omitted] • Novel coumarin-indole derivatives were prepared. • Compound MY-413 displayed excellent antiproliferative activity in vitro. • Compound MY-413 inhibited tubulin polymerization by binding to the colchicine site. • Compound MY-413 inhibited MAPK pathways. • Compound MY-413 significantly inhibit tumor growth in MGC-803 xenograft tumor models. [ABSTRACT FROM AUTHOR]

[Display omitted] Given the essential role of Epigenetic regulation in many biological processes, targeted epigenetic drugs have been gradually applied to the treatment of tumors. Histone deacetylases (HDACs) are a class of epigenetic enzymes, which play key roles in chromosome structural modification and gene expression regulation. Targeted microtubules drugs have achieved great success in clinical application for decades. Development of novel agents with multitargeting capabilities specially dual-target has become a popular research field for the treatment of human cancers, which may provide synergistic anticancer effects. Here, we reported a novel aromatic amide derivative SY-65 co-targeted tubulin and histone deacetylase 1 with potent anticancer activity in vitro and in vivo. Compound SY-65 was identified as a dual inhibitor of tubulin/HDAC1 (IC 50 = 3.64 and 0.529 μM, respectively) with excellent antiproliferative activity against MGC-803, HCT-116, KYSE-450, HGC-27, SGC-7901 and MKN-45 cells. Especially, compound SY-65 exhibited potent antiproliferative activity against MGC-803, HGC-27 and SGC-7901 cells with IC 50 values <55 nM, which was better than that of Colchicine , MS-275 and SAHA. Compound SY-65 effectively inhibited tubulin polymerization and bound to the colchicine binding site of tubulin, as well as inhibited HDAC1 activity both intra/extracellularly. Molecular docking results suggested there were the well-defined binding modes of compound SY-65 in HDAC1 and tubulin. In addition, compound SY-65 inhibited colony formation, interfered with the cell cycle distribution, induced cell cycle arrest at the G2/M phase and apoptosis in MGC-803 and HGC-27 cells. Compound SY-65 also exhibited a good tumor inhibitory effect in vivo without obvious toxicity. Therefore, compound SY-65 could be developed as a novel tubulin/HDAC1 candidate inhibitor for future cancer therapeutics. [ABSTRACT FROM AUTHOR]

As the continuation of our work on the development of tubulin inhibitors with potential anticancer activities, novel bis-substituted aromatic amide dithiocarbamate derivatives were designed by contacting bis-substituted aryl scaffolds (potential anti-tubulin fragments) with N -containing heterocycles (potential anti-tubulin fragments) in one hybrid using the anticancer dithioformate unit as the linker. The antiproliferative activity against three digestive tract tumor cells was evaluated and preliminary structure activity relationships were summarized. Among these compounds, compound 20q exhibited most potent antiproliferative activity against MGC-803, HCT-116, Kyse30 and Kyse450 cells with IC 50 values of 0.084, 0.227, 0.069 and 0.078 μM, respectively. In further studies, compound 20q was identified as a novel tubulin inhibitor targeting the colchicine binding site. Compound 20q could inhibit the microtubule assembly and disrupt cytoskeleton in Kyse30 and Kyse450 cells. The results of molecular docking suggested that compound 20q could tightly bind into the colchicine binding site of tubulin by hydrogen bonds and hydrophobic interactions. Compound 20q dose-dependently inhibited the cell growth and colony formation, effectively arrested cells at the G2/M phase and induce mitochondrial apoptosis in Kyse30 and Kyse450 cells. In addition, Compound 20q could regulate the expression of G2/M phase and mitochondrial apoptosis related proteins. Collectively, compound 20q was here reported as a novel tubulin inhibitor with potential anticancer activities. [Display omitted] • Bis-substituted aromatic amide dithiocarbamate derivatives were prepared. • Compound 20q exhibited low nanomolar antiproliferative efficacies. • Compound 20q acted as a novel colchicine site tubulin polymerization inhibitor. • Compound 20q arrested ESCC cells at G2/M phase and caused cells apoptosis. [ABSTRACT FROM AUTHOR]

NEDDylation process regulates multiple physiological functions and signaling pathways, which are still in an equilibrium that favors the survival and proliferation of tumor cells. Unlike inhibitors, NEDDylation agonists are rarely studied. In this work, novel 1,2,4-triazine-dithiocarbamate derivatives were synthesized and evaluated for antiproliferative activity against MGC-803, PC-3 and EC-109 cells. Among them, compound K3 displayed the most potent activity MGC-803, PC-3 and EC-109 cells with IC 50 values of 2.35, 5.71 and 10.1 μM, respectively, which were more potent than 5-FU. Further cellular mechanisms suggested that compound K3 inhibited the cell viability, induced proliferation inhibition, arrested cell cycle at G2/M phase and induced cell apoptosis in MGC-803 and HGC-27 cells. Importantly, compound K3 could interact with NAE1 to promote the NEDDylation of MGC-803 and HGC-27 cells. The promotion of NEDDylation resulted in the degradation of c-IAP and YAP/TAZ, which leads to the induction of cell apoptosis and inhibition of proliferation in MGC-803 and HGC-27 cells. Therefore, as a NEDDylation agonist, compound K3 could effectively inhibit gastric cancer cells. Here, we reported NEDDylation promotion induced by compound K3 , which could inhibit the cancer cell lines MGC-803 and HGC-27 and induce the cancer cell apoptosis via prompting the degradation of c-IAP and YAP/TAZ. [Display omitted] ● Novel 1,2,4-triazine dithiocarbamate derivatives were designed and prepared. ● K3 as a NEDDylation agonist exhibited potent antiproliferative activity. ● K3 promoted the NEDDylation, resulting in degradation of c-IAP and YAP/TAZ. ● K3 inhibited gastric cancer cells via promoting degradation of c-IAP and YAP/TAZ. [ABSTRACT FROM AUTHOR]

Abstract: Henry reactions of a novel higher sugar derivative, (1R)-(1,4:3,6-dianhydro-d-mannitol-2-yl)-1,4:3,6-dianhydro-d-fructose 5,5′-dinitrate (Alternate nomenclature: (1R)-(isomannid-2-yl)-1,4:3,6-dianhydro-d-fructose 5,5′-dinitrate), with nitromethane and nitroethane were studied. The kinetic and thermodynamic reactions with nitromethane under different conditions were carried out to afford (2S)- and (2R)-β-nitroalcohols, respectively. But when using nitroethane the reaction gave a (2S)-β-nitroalcohol with an inverted configuration at vicinal carbon C-1. Two stereogenic centers were generated, and one was altered in the reaction. [Copyright &y& Elsevier]

[Display omitted] Bruton tyrosine kinase (BTK) is a key kinase in the B cell antigen receptor signal transduction pathway, which is involved in the regulation of the proliferation, differentiation and apoptosis of B cells. BTK has become a significant target for the treatment of hematological malignancies and autoimmune diseases. Ibrutinib , the first-generation BTK inhibitor, has made a great contribution to the treatment of B cell malignant tumors, but there are still some problems such as resistance or miss target of site mutation. Therefore, there is an imperative need to develop novel BTK inhibitors to overcome these problems. Besides, proteolysis targeting chimera (PROTAC) technology has been successfully applied to the development of BTK degradation agents, which has opened a fresh way for the BTK targeted treatment. This paper reviews the biological function of BTK, the discovery and development of BTK targeted drugs as a promising cancer therapy. It mainly reviews the binding sites and structural characteristics of BTK, structure–activity relationships, activity and drug resistance of BTK inhibitors, as well as potential treatment strategies to overcome the resistance of BTK, which provides a reference for the rational design and development of new powerful BTK inhibitors. [ABSTRACT FROM AUTHOR]

The chalcone and quinoline scaffolds are frequently utilized to design novel anticancer agents. As the continuation of our work on effective anticancer agents, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC50 values of 1.38, 5.34, and 5.21 µM, respectively. The structure–activity relationship of quinoline-chalcone derivatives was preliminarily explored in this report. Further mechanism studies suggested that compound 12e inhibited MGC-803 cells in a dose-dependent manner and the cell colony formation activity of MGC-803 cells, arrested MGC-803 cells at the G2/M phase and significantly upregulated the levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that directly linking chalcone fragment to the quinoline scaffold could produce novel anticancer molecules, and compound 12e might be a valuable lead compound for the development of anticancer agents. [ABSTRACT FROM AUTHOR]

[Display omitted] Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d , which exhibited potent antiproliferative activity with IC 50 values of 1.84 μM (MGC-803 cells), 6.82 μM (A549 cells), 1.61 μM (Kyse30 cells), 1.49 μM (Kyse450 cells), 2.08 μM (Kyse510 cells) and 2.24 μM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC 50 value of 3.4 µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of β-tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in time and dose-dependent manners. All the results suggest that the indoline derivatives might be a class of novel tubulin inhibitors with potential anticancer activity and is worthy of further study. [ABSTRACT FROM AUTHOR]

FAK is a nonreceptor intracellular tyrosine kinase which plays an important biological function. Many studies have found that FAK is overexpressed in many human cancer cell lines, which promotes tumor cell growth by controlling cell adhesion, migration, proliferation, and survival. Therefore, targeting FAK is considered to be a promising cancer therapy with small molecules. Many FAK inhibitors have been reported as anticancer agents with various mechanisms. Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase I), and BI-853520 (Phase I) are undergoing clinical trials in different phases. Up to now, there have been many novel FAK inhibitors with anticancer activity reported by different research groups. In addition, FAK degraders have been successfully developed through "proteolysis targeting chimera" (PROTAC) technology, opening up a new way for FAK-targeted therapy. In this paper, the structure and biological function of FAK are reviewed, and we summarize the design, chemical types, and activity of FAK inhibitors according to the development of FAK drugs, which provided the reference for the discovery of new anticancer agents. [ABSTRACT FROM AUTHOR]

Tubulin has been regarded as an attractive and successful molecular target in cancer therapy and drug discovery. Vicinal diaryl is a simple scaffold found in many colchicine site tubulin inhibitors, which is also an important pharmacophoric point of tubulin binding and anti-cancer activity. As the continuation of our research work on colchicine binding site tubulin inhibitors, we designed and synthesized a series of diarylamide N-containing heterocyclic derivatives by the combination of vicinal diaryl core and N-containing heterocyclic skeletons into one hybrid though proper linkers. Among of these compounds, compound 15b containing a 5-methoxyindole group exhibited the most potent inhibitory activity against the tested three human cancer cell lines (MGC-803, PC-3 and EC-109) with IC50 values of 1.56 μM, 3.56 μM and 14.5 μM, respectively. Besides, the SARs of these compounds were preliminarily studied and summarized. The most active compound 15b produced the inhibition of tubulin polymerization in a dose-dependent manner and caused microtubule network disruption in MGC-803 cells. Therefore, compound 15b was identified as a novel tubulin polymerization inhibitor targeting the colchicine binding site. In addition, the results of molecular docking also suggested compound 15b could tightly bind into the colchicine binding site of β-tubulin. [ABSTRACT FROM AUTHOR]

[Display omitted] Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d , which exhibited potent antiproliferative activity with IC 50 values of 1.84 μM (MGC-803 cells), 6.82 μM (A549 cells), 1.61 μM (Kyse30 cells), 1.49 μM (Kyse450 cells), 2.08 μM (Kyse510 cells) and 2.24 μM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC 50 value of 3.4 µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in a time and dose-dependent manner. All the results suggest that the indoline derivatives may be a class of novel tubulin inhibitors with potential anticancer activity, and which is worthy of further study. [ABSTRACT FROM AUTHOR]