Design, Synthesis and Anticancer Activities of Diaryl Urea Derivatives Bearing <i>N</i>-Acylhydrazone Moiety

A new series of diaryl urea derivatives bearing N-acylhydrazone moiety were designed and synthesized. All the target compounds were evaluated for their cytotoxic activities in vitro against human lung adenocarcinoma epithelial cell line (A549), human breast cancer cell line (MDA-MB-231) and human leukemia cell line (HL-60) by standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Several compounds (1a, 1f and 1h) were further evaluated against human embryonic fibroblast, lung-derived cell line (WI38). The pharmacological results indicated that some compounds exhibited promising anticancer activities. In particular, compound 1f showed the most potent cytotoxicity against the tested three cell lines with IC50 values of 0.41?μM, 0.24?μM and 0.23?μM, respectively.     

Synthesis and antiproliferative evaluation of 2,3-diarylquinoline derivatives

A number of 2,3-diarylquinoline derivatives were synthesized and evaluated for antiproliferative activities against the growth of six cancer cell lines including human hepatocellular carcinoma (Hep G2 and Hep 3B), non-small cell lung cancer (A549 and H1299), and breast cancer (MCF-7 and MDA-MB-231) cell lines. The preliminary results indicated that 6-fluoro-2,3-bis{4-[2-(piperidin-1-yl)ethoxy]phenyl}quinoline (16b) was one of the most active compounds against the growth of Hep 3B, H1299, and MDA-MB-231 with a GI(50) value of 0.71, 1.46, and 0.72 μM respectively which was more active than tamoxifen. Further investigations have shown that 16b induced cell cycle arrest at G2/M phase followed by DNA fragmentation via an increase in the protein expression of Bad, Bax and decrease in Bcl-2, and PARP which consequently cause cell death.     

Xanthatin induces cell cycle arrest at G2/M checkpoint and apoptosis via disrupting NF-κB pathway in A549 non-small-cell lung cancer cells

Xanthatin, a natural sesquiterpene lactone, has significant antitumor activity against a variety of cancer cells, yet little is known about its anticancer mechanism. In this study, we demonstrated that xanthatin had obvious dose-/time-dependent cytotoxicity against the human non-small-cell lung cancer (NSCLC) cell line A549. Flow cytometry analysis showed xanthatin induced cell cycle arrest at G2/M phase. Xanthatin also had pro-apoptotic effects on A549 cells as evidenced by Hoechst 33258 staining and annexin V-FITC staining. Mechanistic data revealed that xanthatin downregulated Chk1, Chk2, and phosphorylation of CDC2, which contributed to the cell cycle arrest. Xathatin also increased total p53 protein levels, decreased Bcl-2/Bax ratio and expression of the downstream factors procaspase-9 and procaspase-3, which triggered the intrinsic apoptosis pathway. Furthermore, xanthatin blocked phosphorylation of NF-κB (p65) and IκBa, which might also contribute to its pro-apoptotic effects on A549 cells. Xanthatin also inhibited TNFa induced NF-κB (p65) translocation. We conclude that xanthatin displays significant antitumor effects through cell cycle arrest and apoptosis induction in A549 cells. These effects were associated with intrinsic apoptosis pathway and disrupted NF-κB signaling. These results suggested that xanthatin may have therapeutic potential against NSCLC.     

A New Sphingolipid and Furanocoumarins with Antimicrobial Activity from <i>Ficus exasperata</i>

From the methanol extract of the stem bark of Ficus exasperata, a new sphingolipid named Ficusamide, (2S,3S,4R,11E)-2-[(2',3'-dihydroxyhexacosanoylamino)]-11-octadecene-1,3,4-triol (1), along with three known furanocoumarins, (S)-(－) oxypeucedanin hydrate (2), (R)-(+) oxypeucedanin hydrate (3), bergapten (5-methoxypsoralen) and six other known compounds, were isolated. Their structures were characterized basing on spectroscopic methods and chemical evidence. Compounds (1-3) were analyzed for their antimicrobial activity. Ficusamide (1) showed wick activity (minimal inhibitory concentration (MIC)=312.5?μg/mL) against Escherichia coli, while the furanocoumarins (2) and (3) showed significant activity (MIC=9.76?μg/mL) against Bacillus cereus, Candida albicans and Microsporum audouinii.     

Triterpene Saponins from <i>Pleurospermum kamtschaticum</i> and Their Biological Activity

Eleven new triterpene saponins (1-11), together with fourteen known triterpene and triterpene saponins (12-25) were isolated from a MeOH extract of Pleurospermum kamtschaticum HOFFMANN (Umbelliferae). The chemical structures of the new compounds (1-11) were determined by means of MS, ¹H-NMR, ¹³C-NMR, correlated spectroscopy (COSY), heteronuclear multiple bond correlation (HMBC), total correlated spectroscopy (TOCSY) and nuclear Overhauser effect spectroscopy (NOESY) to be pleurosaponin A (1)-K (11). The isolated compounds were tested for their cytotoxicity against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, HCT15) in vitro using the sulforhodamine B bioassay (SRB) assay. All compounds showed little cytotoxicity against tested cell lines (IC50 >30?μM).     

Prisconnatanones A,a cytotoxic naphthoquinone from Prismatomeris connata,suppresses the proliferation of human laryngocarcinoma HEp-2 cells in vitro

Prisconnatanones A (Priscon-A) is a rare tetrahydroanthraquinone isolated from herbal Prismatomeris connate. In this study, we examine its anti-tumour activity on human laryngocarcinoma HEp-2 cells in vitro. The CCK-8 assay was performed to evaluate its cytotoxicity. Cell cycle and apoptosis were analysed using flow cytometric analysis. Here, we showed Priscon-A inhibited the proliferation of HEp-2 cells in a dose-dependent manner, and at 5 μM it almost completely inhibited cell growth. Its cytotoxicity was associated with the cell cycle arrest at G2/M phase. The Annexin V-FITC/PI binding assay showed that the cell death induced by Priscon-A was associated with apoptosis. And, western blot analysis revealed that the levels of the apoptosis protein, cleaved caspase-3, PARP, p21 and Bax protein increased, while the level of anti-apoptosis protein Bcl-2 decreased.. These data demonstrated that Priscon-A significantly inhibited HEp-2 cell growth, induced the cell cycle arrest at the G2/M phase and efficiently induced cell apoptosis.     

Chamaejasmine induces apoptosis in human lung adenocarcinoma A549 cells through a Ros-mediated mitochondrial pathway

In the present study, the anticancer activity of chamaejasmine towards A549 human lung adenocarcinoma cells was investigated. In order to explore the underlying mechanism of cell growth inhibition of chamaejasmine, cell cycle distribution, ROS generation, mitochondrial membrane potential (Δψ(m)) disruption, and expression of cytochrome c, Bax, Bcl-2, caspase-3, caspase-9 and PARP were measured in A549 cells. Chamaejasmine inhibited the growth of A549 cells in a time and dose-dependent manner. The IC?? value was 7.72 μM after 72 h treatment. Chamaejasmine arrested the cell cycle in the G2/M phase and induced apoptosis via a ROS-mediated mitochondria-dependent pathway. Western blot analysis showed that chamaejasmine inhibited Bcl-2 expression and induced Bax expression to desintegrate the outer mitochondrial membrane and causing cytochrome c release. Mitochondrial cytochrome c release was associated with the activation of caspase-9 and caspase-3 cascade, and active-caspase-3 was involved in PARP cleavage. All of these signal transduction pathways are involved in initiating apoptosis. To the best of our knowledge, this is the first report demonstrating the cytotoxic activity of chamaejasmine towards A549 in vitro.     

Two new glycosides isolated from Sapindus mukorossi fruits: effects on cell apoptosis and caspase-3 activation in human lung carcinoma cells

Two new glycosides (1, 2) and two saponins (3, 4) were isolated from the fruits of Sapindus mukorossi Gaertn. The two glycosides were designated as sapindoside G (1) and 4′′,4′′′′′-O-diacetylmukurozioside IIa (2). All four compounds exhibited inhibitory effects against A549 human lung adenocarcinoma cells with inhibition rates up to 69.2–83.3% at a concentration of 100 μg/mL. Flow cytometric analysis revealed that compounds 1–4 could suppress A549 cell growth by promoting cell apoptosis, which was related to the activation of caspase-3.     

Engineered Bacteriorhodopsin May Induce Lung Cancer Cell Cycle Arrest and Suppress Their Proliferation and Migration

Highly expressible bacteriorhodopsin (HEBR) is a light-triggered protein (optogenetic protein) that has seven transmembrane regions with retinal bound as their chromophore to sense light. HEBR has controllable photochemical properties and regulates activity on proton pumping. In this study, we generated HEBR protein and incubated with lung cancer cell lines (A549 and H1299) to evaluate if there was a growth-inhibitory effect with or without light illumination. The data revealed that the HEBR protein suppressed cell proliferation and induced the G₀/G₁ cell cycle arrest without light illumination. Moreover, the migration abilities of A549 and H1299 cells were reduced by ~17% and ~31% after incubation with HEBR (40 μg/mL) for 4 h. The Snail-1 gene expression level of the A549 cells was significantly downregulated by ~50% after the treatment of HEBR. In addition, HEBR significantly inhibited the gene expression of Sox-2 and Oct-4 in H1299 cells. These results suggested that the HEBR protein may inhibit cell proliferation and cell cycle progression of lung cancer cells, reduce their migration activity, and suppress some stemness-related genes. These findings also suggested the potential of HEBR protein to regulate the growth and migration of tumor cells, which may offer the possibility for an anticancer drug.     

Daphnoretin induces cell cycle arrest and apoptosis in human osteosarcoma (HOS) cells

In this study antiproliferation, cell cycle arrest and apoptosis induced by daphnoretin in human osteosarcoma (HOS) cells were investigated. Antiproliferative activity was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC(50) value of daphnoretin was 3.89 μM after 72 h treatment. Induction of apoptosis was evidenced by apoptotic body appearance and Annexin V-FITC/PI apoptosis detection kit. Flow cytometric analysis indicated daphnoretin arrested the cell cycle in the G2/M phase. Western-blot assay showed that the G2/M phase arrest was accompanied by down-regulation of cdc2, cyclin A and cyclin B1. Moreover, daphnoretin inhibited Bcl-2 expression and induced Bax expression to desintegrate the outer mitochondrial membrane and causing cytochrome c release. Mitochondrial cytochrome c release was associated with the activation of caspase-9 and caspase-3 cascade. Our results demonstrated that daphnoretin caused death of HOS cells by blocking cells successively in G2/M phases and activating the caspase-3 pathway.     

Luteolin induces mitochondria-dependent apoptosis in human lung adenocarcinoma cell

The effects of luteolin on the proliferation of A549 cells were evaluated by MTT and clone formation assays. DNA ploidy and apoptotic cell percentage were calculated by flow cytometry. The expression of Bax, Bcl-xl, Bcl-2, Mcl-1, caspase-9, caspase-3, and PARP was analyzed by Western blotting. The membrane potential of mitochondria was detected by JC-1 fluorescence microscopy assay. Our results demonstrated that luteolin could inhibit the proliferation of A549 cells via induction of apoptosis, with the evidence of characteristic morphological changes of apoptosis in the nucleus. Furthermore, DNA flow cytometric analysis indicated that luteolin induced a S phase arrest of the cell cycle. The membrane potential of mitochondria was decreased. The protein levels of Bax, Bcl-xl, Bcl-2, Mcl-1, caspase-9, caspase-3, and PARP were activated after treatment with luteolin. Luteolin can inhibit the proliferation of A549 cells and trigger mitochondria- dependent apoptosis in them.     

Garcinielliptone G from Garcinia subelliptica Induces Apoptosis in Acute Leukemia Cells

Cytotoxicity and apoptosis-inducing properties of compounds isolated from Garcinia subelliptica leaves were investigated. The hexane-soluble portion of MeOH extracts of G. subelliptica leaves that showed cytotoxic activity was separated to yield seven compounds 1–7. Chemical structure analysis using NMR spectroscopy and mass spectrometry confirmed that compound 1 was canophyllol, and compounds 2–7 were garcinielliptones N, O, J, G, F, and garcinielliptin oxide, respectively. Among them, garcinielliptone G (5) showed growth inhibition by causing apoptosis in THP-1 and Jurkat cells derived from human acute monocytic leukemia and T lymphocyte cells, respectively. Apoptosis induced by garcinielliptone G (5) was demonstrated by the detection of early apoptotic cells with fluorescein-labeled Annexin V and increases in cleaved caspase-3 and cleaved PARP protein levels. However, the addition of caspase inhibitor Z-VAD-FMK did not affect growth arrest or apoptosis induction. These results suggest that garcinielliptone G (5) can induce both caspase-3 activation and caspase-independent apoptosis. Therefore, garcinielliptone G (5) may be a potential candidate for acute leukemia treatment.     

Hybrid of the 1,2,3-triazole nucleus and sesquiterpene skeleton as a potential antitumor agent: Hemisynthesis,molecular structure,Hirshfeld surface analysis,density functional theory,and in vitro cytotoxic and apoptotic effects

A new 1,2,3-triazole sesquiterpenic named (4aR,5aS,7aR,10aR,10bR)-10-benzyl-5,5-dichloro-1,1,4a,7a-tetramethyl-1,2,3,4,4a,5,7a,10,10a,10b decahydrocyclopropa[2′,3′]cyclohepta [1′,2′:3,4]benzo[1,2-d][1,2,3]triazol-7(6H)-one was synthesized by a dipolar cycloaddition 1,3 between benzyl azide and α,β-unsaturated sesquiterpene ketone catalyzed by titanium tetrachloride TiCl₄. It was obtained with a good yield and characterized using single-crystal X-ray diffraction technique, infra red (IR) spectroscopy, High Resolution Mass Spectrometry (HRMS), UV-Visible, and ¹H and ¹³C NMR spectroscopies. The optimization by the density functional theory (DFT) method was carried out to study the formation mechanism of the derivative. The selected compounds 1 – 4 exhibited anticancer activities in vitro against namely fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast (MCF-7 and MDA-MB-231 cell lines with IC₅₀ in the range of 10.02–44.71 μM). In addition to using flow cytometry and the apoptosis assay, cell cycle arrest at the S phase (10 μM) and G2/M arrest in (5 and 10 μM) was performed for compound 4 in fibrosarcoma (HT-1080) cancer cells. Results suggested that compound 4 test with good activity against HT-1080 cells with IC₅₀ value from 10.02 μM and induced the apoptotic effect. Theoretical studies were realized to estimate the molecular proprieties that lead to a high potential of cytotoxic effect, which is in agreement with the experimental results.     

Design, Synthesis and Anticancer Activity of 4-Morpholinothieno[3,2-<i>d</i>]pyrimidine Derivatives Bearing Arylmethylene Hydrazine Moiety

Three series of 4-morpholinothieno[3,2-d]pyrimidine derivatives containing arylmethylene hydrazine moiety (11a-f, 13a-k and 15a-h) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. The synthesized compounds were evaluated for their cytotoxicity against three cancer cell lines (H460, HT-29, MDA-MB-231). Most of them exhibited moderate to significant cytotoxicity and high-selectivity against one or more cell lines, especially compounds 11c, 13b, 15f and 15g possessing dramatically increased cytotoxicity as compared with the positive controls, which were further evaluated for six other cancer cell lines and one normal cell line. The most promising compound 11c, bearing 3,4-methylenedioxy phenyl group, showed remarkable cytotoxicity against H460, HT-29 and MDA-MB-231 cell lines with IC50 values of 0.003?μM, 0.42?μM and 0.74?μM, which was 1.6- to 290-fold more potent than GDC-0941.     

Triptolide sensitizes lung cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inhibition of NF-kappaB activation

TNF-related apoptosis-inducing ligand (TRAIL/Apo- 2L), a newly identified member of the TNF family promotes apoptosis by binding to the transmembrane receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). TRAIL known to activate NF-kappaB in number of tumor cells including A549 (wt p53) and NCI-H1299 (null p53) lung cancer cells exerts relatively selective cytotoxic affects to the human tumor cell lines without much effect on the normal cells. We set out to identify an agent that would sensitize lung cancer cells to TRAIL-induced apoptosis through inhibition of NF-kappaB activation. We found that triptolide, an oxygenated diterpene extracted and purified from the Chinese herb Tripterygium wilfordii sensitized A549 and NCI-H1299 cells to TRAIL-induced apoptosis through inhibition of NF-kappaB activation. Pretreatment with MG132 which is a well-known NF-kappaB inhibitor by blocking degradation of IkappaBalpha also greatly sensitized lung cancer cells to TRAIL-induced apoptosis. Triptolide did not block DNA binding of NF-kappaB activated by TRAIL as in the case of TNF-alpha. It has been already proven that triptolide blocks transactivation of p65 which plays a key role in NF-kappaB activation. These observations suggest that triptolide may be a potentially useful drug to enhance TRAIL-induced tumor killing in lung cancer.     

Synthesis and in vitro antitumor activity of 1,3,4-oxadiazole derivatives based on benzisoselenazolone

A series of novel 1,3,4-oxadiazole derivatives based on benzisoselenazolone has been prepared and tested for antiproliferative activity in vitro against the cells of human cancer cell lines: SSMC-7721 (human liver cancer cell), MCF-7 (human breast cancer cell) and A549 (human lung cancer cell). All the compounds obtained exhibited antiproliferative activity and showed selective cytotoxicity against different cancer cells. Compounds 7d and 7i showed significant antiproliferative activities against MCF-7 cells, with IC50 values of 1.07 and 1.76?μM respectively. Compound 7d were found to be the most potent compound against SSMC-7721 cells, with IC50 values 4.46?μM.     

Design,Synthesis, and Anticancer Activity of 3H–benzo[f]chromen‐3‐one Derivatives

A series of substituted aminomethylbenzocoumarin derivatives 8a–i have been synthesized, characterized, and structure of compound 8g was confirmed by X‐ray single crystal analysis. All the synthesized compounds were tested for their anticancer activity against cancer cell lines A549 (lung carcinoma cell line), MCF7 (breast cancer cell line), and A375 (melanoma cell line). Compounds 8a , 8f , and 8h showed excellent growth inhibitory activity against all three cell lines, respectively. Compounds 8a and 8f were also found to be quite promising at very low concentration as an anticancer agent against MCF7 and A549 cell lines. Compounds 8g and 8i showed excellent antimitotic activity with IC₅₀ 0.32 and19.98 nM for A549 cell line.     

Marcanine G,a new cytotoxic 1-azaanthraquinone from the stem bark of Goniothalamus marcanii Craib

The ethanolic extract from the stem bark of Goniothalamus marcanii Craib was shown in preliminary brine shrimp lethality data having good cytotoxic activity. Further bioassay guided isolation was done by means of solvent partition, chromatography and precipitation to provide four isolated compounds: a novel compound 1 with the core structure of 1-azaanthraquinone moiety referred as marcanine G; as well as compounds 2–4 with known aristolactam structures namely, piperolactam C, cepharanone B and taliscanine. These compounds were characterised by spectroscopic techniques. The assessment of cytotoxicity was established on an SRB assay using doxorubicin as a positive control. Marcanine G (1) was considered the most active compound indicating the IC₅₀ values of 14.87 and 15.18 μM against human lung cancer cells (A549) and human breast cancer cells (MCF7), respectively. However, 2 showed mild activity with the IC₅₀ values of 83.72 and 82.32 μM against A549 and MCF7 cells, respectively.