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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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

The interaction of cytochrome c (Cyt c) with cardiolipin (CL) is believed to play an important role in the initial events of apoptosis. Herein, we investigate the structural changes of CL-bound Fe 2+ Cyt c and the correlation with Cyt c release through surface-enhanced Raman spectroscopy (SERS) on nickel substrates. The SERS results together with molecular dynamics simulation reveal that Fe 2+ Cyt c undergoes autoxidation and a relatively larger conformational alteration after binding with CL, inducing higher peroxidase activity of Cyt c and higher permeability of the CL membrane compared with those induced by the Fe 3+ Cyt c. The proapoptotic activity and SERS effect of the Ni nanostructures allow the in situ study of the redox-state-dependent Cyt c release from isolated mitochondria, which reveals for the first time that the ferrous state of Cyt c most likely plays a more important role in triggering apoptosis., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Intrinsic properties of nickel have enabled its wide applications as an effective catalyst. In this study, nickel nanowires (Ni NWs) as electron donors for oxidized cytochrome c (Cyt c) are investigated, which are NW diameter, temperature, and pH value-dependent. The reductive and magnetic properties facilitate the Ni NWs to rapidly and conveniently reduce Cyt c in complicated biological samples. Moreover, we find that the Ni NWs combined with resonance Raman spectroscopy have specificity toward Cyt c detection in real biological samples, which is successfully used to distinguish the redox state of the released Cyt c from isolated mitochondria in apoptotic Hela cells. Moreover, rapid label-free Cyt c quantification can be achieved by surface-enhanced Raman spectroscopy with a limit of detection of 1 nM and long concentration linear range (1 nM-1 μM). The proposed Ni NWs-based reduction approach will significantly simplify the traditional biological methods and has great potential in the application of Cyt c-related apoptotic studies.

Pteridines are an important class of fused heterocycles found in natural products and drug molecules, and have shown diverse biological activities. A focused library of 5,8-dihydropteridine-6,7-dione derivatives were designed and evaluated for their antiproliferative activity against MGC-803, SGC-7901, A549 and PC-3 cancer cell lines. The SARs studies highlighted the importance of the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks for the activity and revealed essential structural elements. Among these compounds, compound 5n displayed the most potent and broad-spectrum antiproliferative inhibition against the tested cell lines and was sensitive to MGC-803 cell line, slightly more potent than 5-FU. Preliminary mechanistic studies showed that compound 5n could inhibit the colony formation and migration of MGC-803 cells. Besides, flow cytometry analysis showed that compound 5n concentration-dependently induced apoptosis of MGC-803 cells. Our studies suggest that the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks may be regarded as new chemotypes for designing effective antitumor agents targeting gastric cancer cells., (Copyright © 2017. Published by Elsevier Masson SAS.)

Despite advances in the development of radiation against nasopharyngeal carcinoma (NPC), the management of advanced NPC remains a challenge. Smac mimetics are designed to neutralize inhibitor of apoptosis (IAP) proteins, thus reactivating the apoptotic program in cancer cells. In this study, we investigated the effect of a novel bivalent Smac mimetic APG-1387 in NPC. In vitro, APG-1387 in combination with TNF-α potently decreased NPC cell viability by inducing apoptosis in majority of NPC cell lines. The in vitro antitumor effect was RIPK1-dependent, whereas it was independent on IAPs, USP11, or EBV. Of note, the inhibition of NF-κB or AKT pathway rendered resistant NPC cells responsive to the treatment of APG-1387/TNF-α. In vivo, APG-1387 displayed antitumor activity as a single agent at well-tolerated doses, even in an in vitro resistant cell line. In summary, our results demonstrate that APG-1387 exerts a potent antitumor effect on NPC. These findings support clinical evaluation of APG-1387 as a potential treatment for advanced NPC., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Objective: To investigate the effects of paeonol on neuron cell model of Parkinson disease (PD)., Methods: The cell model of Parkinson disease was induced by treatment of 1-Methyl-4-phenylpyridinium (MPP+) in PC12 cells, the PD model cells were treated with 1 μmol/L, 3 μmol/L or 9 μmol/L paeonol for 24h, respectively. Cell viability and LDH leakage were detected by MTT and lactate dehydrogenase (LDH) assay; the apoptosis of PC12 cells was assessed by Hoechst 33258 staining and flow cytometry; reactive oxygen species (ROS) production was detected by DCFH-DA method; and the ratio of Bax/Bcl-2 and activation of caspase-3 were determined by Western blotting., Results: MPP+ treatment significantly reduced cell viability, increased LDH leakage, enhanced the proportion of apoptotic cells and ROS production. In addition, MPP+ treatment dramatically increased the Bax/Bcl-2 ratio, and the activation of caspase-3. Compared to PD model group, paeonol treatment significantly enhanced cell viability, decreased LDH leakage, inhibited the proportion of apoptotic cells and ROS production, reduced the Bax/Bcl-2 ratio and the activated caspase-3 protein., Conclusion: Paeonol can prevent PC12 cells from apoptosis induced by MPP+, and the mechanism may be associated with the down-regulation of ROS production, Bax/Bcl-2 ratio and Caspase-3 activation.

Background: Colorectal cancer has become one of the leading cause of cancer morbidity and mortality throughout world. Hederagenin, a derivative of oleanolic acid isolated from the leaves of ivy (Hedera helix L.), has been shown to have potential anti-tumor activity. The study was conducted to evaluate whether hederagenin could induce apoptosis of human colon cancer LoVo cells and explore the possible mechanism., Methods: MTT assay was used for evaluating cell viability while Annexin V-FITC/PI assay and Hoechst 33342 nuclear stainining were used for the determination of apoptosis and mitochondrial membrane potential. DCFH-DA fluorescence staining and flow cytometry were used to measure ROS generation. Real-time PCR and western blot analysis were performed for apoptosis-related protein expressions., Results: MTT assay showed that hederagenin could significantly inhibit the viability of LoVo cells in a concentration-dependent and time-dependent manner by IC50 of 1.39 μM at 24 h and 1.17 μM at 48 h. The apoptosis ratio was significantly increased to 32.46% and 81.78% by the induction of hederagenin (1 and 2 μM) in Annexin V-FITC/PI assay. Hederagenin could also induce the nuclear changes characteristic of apoptosis by Hoechst 33342 nuclear stainining under fluorescence microscopy. DCFH-DA fluorescence staining and flow cytometry showed that hederagenin could increase significantly ROS generation in LoVo cells. Real-time PCR showed that hederagenin induced the up-regulation of Bax and down-regulation of Bcl-2, Bcl-xL and Survivin. Western blotting analysis showed that hederagenin decreased the expressions of apoptosis-associated proteins Bcl-2, procaspase-9, procaspase-3, and polyADP- ribosepolymerase (PARP) were increased, while the expressions of Bax, caspase-3, caspase-9 were increased. However, there was no significant change on caspase-8., Conclusions: These results indicated that the disruption of mitochondrial membrane potential might contribute to the apoptosis of hederagenin in LoVo cells. Our findings suggested that hederagenin might be a promising therapeutic candidate for human colon cancer.

Objective: Obesity can affect periodontal tissues and exacerbate periodontitis. Pyroptosis, a newly identified type of inflammatory cell death, is involved in the development of periodontal inflammation. The saturated fatty acid palmitic acid (PA) is elevated in obese patients. The effect of PA on pyroptosis in periodontal ligament cells (PDLCs) and its underlying mechanisms remain unknown. Materials and Methods: Human PDLCs were isolated from healthy individuals and cultured for experiments. The effects of PA on PDLC pyroptosis and the underlying mechanisms were examined by transmission electron microscopy, quantitative real‐time PCR and western blotting. Results: The morphology of PDLCs in the PA group indicated pyroptotic characteristics, including swollen cells, plasma membrane rupture and changes in subcellular organelles. PA induced inflammatory responses in PDLCs, as indicated by an increase in IL‐1β in the cell culture supernatant. Furthermore, we found that the pyroptosis‐related proteins caspase‐1, caspase‐4 and GSDMD were involved in PA‐induced cell death. GSDMD and caspase‐4 inhibitors alleviated pyroptotic death of PDLCs. Moreover, PA promoted NF‐κB P65 phosphorylation. A NF‐κB inhibitor decreased IL‐1β expression and partly rescued cell death induced by PA. Conclusion: PA activated the NF‐κB pathway and induced the inflammatory response in PDLCs. Caspase‐4/GSDMD mediated PDLC pyroptosis induced by PA. [ABSTRACT FROM AUTHOR]

TAR DNA-Binding Protein 43 (TDP-43) has been well studied in neurodegenerative diseases, but its potential role in malignance is still unclear. Here, we demonstrate that TDP-43 contributes to the suppression of apoptosis by facilitating lipid metabolism in hepatocellular carcinoma (HCC). In HCC cells, TDP-43 is able to suppress apoptosis while deletion of it markedly induces apoptosis. RNA-sequencing identifies the lipid metabolism gene abhydrolase domain containing 2 (ABHD2) as the target gene of TDP-43. Tissue microarray analysis shows the positive correlation of TDP-43 and ABHD2 in HCC. Mechanistically, TDP-43 binds with the UG-rich sequence1 of ABHD2 3'UTR to enhance the mRNA stability of ABHD2, thereby upregulating ABHD2. Afterwards, TDP-43 promotes the production of free fatty acid and fatty acid oxidation-originated reactive oxygen species (ROS) in an ABHD2-dependent manner, so as to suppress apoptosis of HCC. Our findings provide insights into the mechanism of HCC progression and reveal TDP-43/ABHD2 as potential targets for the precise treatment of HCC. TDP-43 acts as an RNA-binding protein that regulates the RNA stability of ABHD2 and affects the release of fatty acids and ROS, which in turn regulates apoptosis and affects the growth of liver tumors. [ABSTRACT FROM AUTHOR]

Pyroptosis, a form of programmed cell death, that plays a significant role in the occurrence and progression of tumors, has been frequently investigated recently. However, the prognostic significance and therapeutic value of pyroptosis in glioma remain undetermined. In this research, we revealed the relationship of pyroptosis-related genes to glioma by analyzing whole transcriptome data from The Cancer Genome Atlas (TCGA) dataset serving as the training set and the Chinese Glioma Genome Atlas (CGGA) dataset serving as the validation set. We identified two subgroups of glioma patients with disparate prognostic and clinical features by performing consensus clustering analysis on nineteen pyroptosis-related genes that were differentially expressed between glioma and normal brain tissues. We further derived a risk signature, using eleven pyroptosis-related genes, that was demonstrated to be an independent prognostic factor for glioma. Furthermore, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to implement functional analysis of our gene set, and the results were closely related to immune and inflammatory responses in accordance with the characteristics of pyroptosis. Moreover, Gene Set Enrichment Analysis (GSEA) results showed that that the high-risk group exhibited enriched characteristics of malignant tumors in accordance with its poor prognosis. Next, we analyzed different immune cell infiltration between the two risk groups using ssGSEA. Finally, CASP1 was identified as a core gene, so we subsequently selected an inhibitor targeting CASP1 and simulated molecular docking. In addition, the inhibitory effect of belnacasan on glioma was verified at the cellular level. In conclusion, pyroptosis-related genes are of great significance for performing prognostic stratification and developing treatment strategies for glioma. [ABSTRACT FROM AUTHOR]

The interaction of cytochrome c (Cyt c) with cardiolipin (CL) is believed to play an important role in the initial events of apoptosis. Herein, we investigate the structural changes of CL‐bound Fe2+Cyt c and the correlation with Cyt c release through surface‐enhanced Raman spectroscopy (SERS) on nickel substrates. The SERS results together with molecular dynamics simulation reveal that Fe2+Cyt c undergoes autoxidation and a relatively larger conformational alteration after binding with CL, inducing higher peroxidase activity of Cyt c and higher permeability of the CL membrane compared with those induced by the Fe3+Cyt c. The proapoptotic activity and SERS effect of the Ni nanostructures allow the in situ study of the redox‐state‐dependent Cyt c release from isolated mitochondria, which reveals for the first time that the ferrous state of Cyt c most likely plays a more important role in triggering apoptosis. [ABSTRACT FROM AUTHOR]

Summary: Aims: Nerve growth factor (NGF) has been reported to prevent neuronal damage and contributes to the functional recovery in animal brain injury models and human ischemic disease as well. We aimed to investigate a potential therapeutic effect of NGF gene treatment in ischemic stroke and to estimate the functional recovery both at the cellular and cognitive levels in an ischemia rat model. Methods: After microinjection of pseudolentivirus‐delivered β‐NGF into an established ischemic stroke model in rats (tMCAO), we estimated neuronal cell apoptosis with TUNEL labeling and neurogenesis by cell proliferation marker Ki67 staining in both ischemic core and penumbra of striatum. Furthermore, we used behavioral functional tests, Morris water maze performance, to evaluate cognitive functional recovery in vivo and propose a potential underlying mechanism. Results: We found that pseudolentivirus‐mediated delivery of β‐NGF gene into the brain induced high expression in striatum of the infarct core area after ischemia in rats. The β‐NGF overexpression in the striatal infarction core after ischemia not only improved neuronal survival by reducing cell apoptosis and increasing cell proliferation, but also rescued cognitive functional impairment through upregulation of GAP‐43 protein expression in tMCAO rat model of ischemia. Conclusion: This study demonstrates a potential β‐NGF gene therapy by utilization of pseudolentivirus in ischemia and indicates future applications of NGF gene treatment in ischemic patients. [ABSTRACT FROM AUTHOR]

Due to the imbalance between hyper-inflammation and hypo-inflammation, which are characterized by excessive cytokine productions and programmed death 1 (PD-1) upregulation, respectively, sepsis remains a highly lethal inflammatory syndrome with limited effective therapies. Mycophenolate mofetil (MMF), an immunosuppressant, has been reported to attenuate various inflammatory diseases. However, the role of MMF in sepsis therapy remains to be elucidated. C57BL-6J mice underwent cecal ligation and puncture (CLP) and were treated either with or without MMF. Survival rate and organ injuries were compared. Cytokine levels, bacteria clearance, apoptosis of spleen and peritoneal macrophages, and PD-1 expression were assessed. At the beginning of CLP, 60 mg/kg MMF administered by gavage significantly protected septic mice, which was evidenced by improved survival and attenuated organ injuries, decreased cytokines, lower bacterial loads, and alleviated immune cell apoptosis. In addition, immune cells in the MMF mice showed lower PD-1 expression and improved immune response to pathogeny stimuli. MMF protects septic mice via the dual inhibition of cytokine releasing and PD-1 expression. [ABSTRACT FROM AUTHOR]

Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC 50 = 0.336 ± 0.003 μM) significantly suppressed proliferation, induced apoptosis, arrested cell cycle of EC109 cells at G2/M phase, and caused changes of the associated protein markers correspondingly. We also found that compound LPE-1 potently inhibited the migration and invasion of EC-109 cells. Docking studies showed that the cyano group formed hydrogen bonds with Val811 and Thr810. Additionally, the thiophene moiety formed arene-H interaction with Trp761 residue. In vivo studies showed that compound LPE-1 inhibited tumor growth of xenograft models bearing EC-109 without obvious toxicity. Collectively, our findings indicate that LSD1 may be a potential therapeutic target in ESCC, and compound LPE-1 could serve as a lead compound for further development for anti-ESCC drug discovery. [ABSTRACT FROM AUTHOR]

Gliomas are the most common primary malignancy in the brain, accounting for 50-60%. Despite all the efforts of cytoreductive surgery in combination with intense chemoradiotherapy, glioma remains an incurable disease. Recent studies have shown that long noncoding RNAs (lncRNAs) are involved in the pathology of gliomas. LncRNAs are involved in many cellular processes, such as angiogenesis, invasion, cell proliferation, and apoptosis. In this review we focus on the dysregulation of lncRNAs in gliomas. We also address that epigenetic modification such as DNA methylation and microRNAs interact with lncRNAs in gliomas. In addition, the interaction of lncRNAs with signaling pathways in gliomas is discussed systematically, with particular emphasis on the interaction of lncRNAs with EZH2. Such approaches provide valuable insights into the potential future applications of lncRNAs in the treatment of gliomas. J. Cell. Physiol. 230: 496-503, 2015. © 2014 Wiley Periodicals, Inc., A Wiley Company [ABSTRACT FROM AUTHOR]

Five undescribed eremophilane-type sesquiterpenes, remophilanetriols E -I (1 – 5), along with seven known compounds (6 – 12) were isolated from the fresh roots of Rehmannia glutinosa. Their structures were characterized by extensive spectroscopic data analysis and their absolute configurations were determined by comparing their calculated electronic circular dichroism (ECD) spectra and experimental ECD spectra. The anti-pulmonary fibrosis activities of all compounds were evaluated in vitro by MTT methods, and compounds 2 , 8 , 10 , and 12 exhibited excellent anti-pulmonary fibrosis activities. In addition, compound 2 can reduce the levels of ROS and apoptosis in TGF-β1-induced BEAS-2B cells. [Display omitted] [ABSTRACT FROM AUTHOR]

3, 3′, 4, 4′, 5-pentachlorobiphenyl (PCB126) is extensively utilized in electronic products, lubricant, and insecticide due to its excellent chemical stability and insulation prosperity, resulting in its frequent detection in environment. In addition, atmospheric deposition, as well as industrial and urban wastewater discharge can also lead to PCB126 contamination in marine environment, triggering damages to the tissues of aquatic organisms through oxidative stress. Astilbin is a type of flavonoid compound found in plants that plays a crucial role in providing powerful antioxidant and anti-inflammatory properties. In this study, we aimed to investigate the specific mechanism of PCB126-induced damage and the potential protective effect of Astilbin. To achieve this, we treated grass carp hepatocytes (L8824) with 75 μM PCB126 and/or 0.5 mM Astilbin for 24 h and used experimental methods such as Flow cytometry, molecular docking, PPI analysis, detection of commercial kits (ATP concentration and ATPnase activity) and measurement of mitochondrial membrane potential (ΔΨm). Our findings revealed that PCB126 exposure resulted in a decrease in expression levels of Sirt1, factors related to mitochondrial fusion (Opa1, Mfn1, and Mfn2), antioxidant (CAT, SOD1, and SOD2), energy metabolism (PKM2, IDH, and SDH) and anti-apoptosis (Bcl-2), and an increase in expression levels of Nrf2 acetylation, mitochondrial fission (Drp1), factors that promote apoptosis (Cytc, Bax, Cas9, and Cas3) in L8824 cells. Furthermore, our findings revealed a decrease in ΔΨm, ATP concentration and ATPnase activity and apoptosis levels in L8824 cells. Noteworthy, treatment with Astilbin reversed these results. Molecular docking provides solid evidence for the interaction between Astilbin and Sirt1. In summary, our findings suggested that Astilbin promoted the deacetylation of Nrf2 by interacting with Sirt1, thereby alleviating PCB126-induced mitochondrial apoptosis mediated by mitochondrial dynamics imbalance and energy metabolism disorder through the inhibition of oxidative stress in L8824 cells. Our research has initially revealed the correlation between acetylation and apoptosis induced by PCB126, which provided a foundation for a better comprehension of PCB126 toxicity. Additionally, it expanded the potential application value of Astilbin. • Research initially uncovers the role of deacetylation in PCB126-induced hepatotoxicity in grass carp hepatocyte. • Molecular docking reveals the target relationship between Astilbin and Sirt1. • Astilbin suppresses acetylation of Nrf2 to attenuate apoptosis in grass carp hepatocytes through interaction with Sirt1. [ABSTRACT FROM AUTHOR]

Pteridines are an important class of heterocyclic compounds with diverse biological activities. Here, we report a series of pteridin-7(8 H )-one derivatives and their antiproliferative activities toward MKN-45, MGC-803, EC-109, and H1650. Structure-activity relationship studies showed that compound 12 exerted the most potent antiproliferative activity against MKN-45 and MGC-803 with the IC 50 values of 4.32 and 7.01 μM, respectively. Besides, compound 12 induced morphological changes and apoptosis of MKN-45 cells, increased expression of Bax, down-regulated expression of Bcl-2 and caused cleavage of caspase-3/9. Additionally, we first reported the construction of the novel bicyclic 8,9-dihydro-7 H -purine-8-carboxylate scaffold through the competitive 5-endo cyclization reaction with two C-N bonds and a chiral carbon center established. [ABSTRACT FROM AUTHOR]

Human gliomas are related to high rates of morbidity and mortality. TGF‐β promotes the growth of glioma cells, and correlate with the degree of malignancy of human gliomas. However, the molecular mechanisms involved in the malignant function of TGF‐β are not fully elucidated. Here, we showed that TGF‐β induced the downregulation of MST1 expression in U87 and U251 glioma cells. Treatment of glioma cells with the DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-AzadC) prevented the loss of MST1 expression. Addition of 5-AzadC also reduced the TGF-β-stimulated proliferation, migration and invasiveness of glioma cells. Furthermore, Knockdown of DNMT1 upregulated MST1 expression in gliomas cells. In addition, the inhibition of DNMT1 blocked TGF-β-induced proliferation, migration and invasiveness in glioma cells. These results suggest that TGF-β promotes glioma malignancy through DNMT1-mediated loss of MST1 expression. [ABSTRACT FROM AUTHOR]

A series of thiazolo[5,4- d ]pyrimidine derivatives were designed through the atom replacement strategy based on biologically validated scaffolds and then evaluated for their antiproliferative activities on cancer cell lines. The structure-activity relationship studies were conducted, leading to the identification of compound 22 , which exhibited good antiproliferative activity against HGC-27 with an IC 50 value of 1.22 μM and low toxicity against GES-1 cells. Mechanistic studies showed that compound 22 inhibited the colony formation and migration of HGC-27 as well as induced apoptosis. The western blot experiments proved that compound 22 up-regulated expression of Bax, down-regulated expression levels of Bcl-2 and cleaved caspased-3/9. These findings indicate that compound 22 may serve as a template for designing new agents for the treatment of human gastric cancers. The atom replacement strategy could be viable strategy for designing new anticancer drugs and may find its applications in drug design. [ABSTRACT FROM AUTHOR]

A series of structurally new diheteroaryl thioether analogs was designed, prepared and screened toward MGC-803, MKN-45, EC-109 and H1650. Most of the target compounds displayed moderate to potent antiproliferative activities. Among them, compound 5 showed the best antiproliferative activity against the tested cell lines with the half maximal inhibitory concentration (IC 50 ) values below 10 μM. In addition, flow cytometry analysis showed that compound 5 increased Bax expression, down-regulated expression of Bcl-2, cleaved caspases-3/9, finally inducing apoptosis of MKN-45 cells as well as arrested the cell cycle at G2/M phase. This study suggests that the diheteroaryl thioethers are a class of emerging chemotypes for developing antitumor agents or biological probes, and compound 5 could serve as a good starting point to design new apoptosis inducers. [ABSTRACT FROM AUTHOR]

A series of thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activities on three cancer cell lines. The structure-activity relationship studies were conducted through the variation in the three regions of the thiazolo-pyrimidine core. Substitution with morpholine led to compound 24 , which exerted the most potent antiproliferative activity as well as good selectivity between cancer and normal cells (IC 50 values of 1.03 μM against MGC803 and 38.95 μM against GES-1). In addition, compound 24 inhibited the colony formation and migration of MGC803 as well as induced apoptosis. Western blot experiments indicated the expression changes of apoptosis-related proteins, including up-regulation of Bax and caspase-3/9, as well as down-regulation of Bcl-2. [ABSTRACT FROM AUTHOR]

A series of [1,2,3]triazolo[4,5- d ]pyrimidine derivatives bearing a hydrazone moiety were designed, synthesized and evaluated for their antiproliferative activity against several cancer cell lines of different origins by MTT assay. Most of the synthesized compounds demonstrated moderate to good activity against the cancer cell lines selected. Especially, compound 43 showed the most potent antiproliferative activity as well as good selectivity between cancer and normal cells (IC 50 values of 0.85 μM against MGC-803 and 56.17 μM against GES-1). In addition, compound 43 evidently inhibited the colony formation of MGC-803 cells at 0.8 μM. Further mechanism studies revealed that compound 43 could induce apoptosis of MGC-803 cells probably through the mitochondrial pathway accompanied with decrease of the mitochondrial membrane potential (MMP), activations of caspase-9/3, up-regulation of the expression of Bax, Bak and PUMA, as well as down-regulation of that of Bcl-2 and Mcl-1. [ABSTRACT FROM AUTHOR]

Potent and safe anticancer drugs research and development are still on the way to human health. In this report, a series of novel thiosemicarbazone derivatives containing indole fragment were designed and synthesized. Most compounds exhibited excellent antiproliferative activity against PC3, MGC803 and EC109 cell lines with low micromolar IC 50 (0.14–12μM). Especially, compound 5j can selectively inhibit PC3 cells in three tested tumor cells with IC 50 value of 0.14 μM, which may be attributed to a synergistic effect after introducing indole fragment into the TSC structure. Meanwhile, compound 5j displayed more selectivity in PC3 cells toward two normal WPMY-1 and GES-1 cell lines, compared to those of 3-AP and DPC. We also found that 5j can effectively inhibit PC3 cell proliferation, colonization and induce apoptosis. What's more, 5j may significantly suppress migration and invasion by blocking the EMT process but had no effect on cell cycle. Collectively, our findings indicate that 5j with structure of thiosemicarbazone containing indole may serve as a useful anticancer lead for further optimization and development. Image 1 • Thiosemicarbazone derivatives containing indole were designed and synthesized. • 5j displayed more selectivity in PC3 toward WPMY-1, compared to those of 3-AP. • 5j can effectively inhibit PC3 proliferation, colonization and induce apoptosis. • 5j could suppress migration and had no effect on cell cycle arrest. [ABSTRACT FROM AUTHOR]