Indirubin derivatives as potent FLT3 inhibitors with anti-proliferative activity of acute myeloid leukemic cells

Indirubin derivatives were identified as potent FLT3 tyrosine kinase inhibitors with anti-proliferative activity at acute myeloid leukemic cell lines, RS4;11 and MV4;11 which express FLT3-WT and FLT3-ITD mutation, respectively. Among several 5 and 5′-substituted indirubin derivatives, 5-fluoro analog, 13 exhibited potent inhibitory activity at FLT3 (IC₅₀ = 15 nM) with more than 100-fold selectivity versus 6 other kinases and potent anti-proliferative effect for MV4;11 cells (IC₅₀ = 72 nM) with 30-fold selectivity versus RS4;11 cells. Cell cycle analysis indicated that compound 13 induced cell cycle arrest at G₀/G₁ phase in MV4;11 cells.     

Design,synthesis and anticancer activity of novel nopinone-based thiosemicarbazone derivatives

A series of new nopinone-based thiosemicarbazone derivatives were designed and synthesized as potent anticancer agents. All these compounds were identified by ¹H NMR, ¹³C NMR, HR-MS spectra analyses. In the in vitro anticancer activity, most derivatives showed considerable cytotoxic activity against three human cancer cell lines (MDA-MB-231, SMMC-7721 and Hela). Among them, compound 4i exhibited most potent antitumor activity against three cancer cell lines with the IC₅₀ values of 2.79 ± 0.38, 2.64 ± 0.17 and 3.64 ± 0.13 μM, respectively. Furthermore, the cell cycle analysis indicated that compound 4i caused cell cycle arrest of MDA-MB-231 cells at G2/M phase. The Annexin V-FITC/7-AAD dual staining assay also revealed that compound 4i induced the early apoptosis of MDA-MB-231 cells.     

Design and synthesis of piperazine acetate podophyllotoxin ester derivatives targeting tubulin depolymerization as new anticancer agents

In this paper, a series of podophyllotoxin piperazine acetate ester derivatives were synthesized and investigated due to their antiproliferation activity on different human cancer cell lines. Among the congeners, C5 manifested prominent cytotoxicity towards the cancer cells, without causing damage on the non-cancer cells through inhibiting tubulin assembly and having high selectively causing damage on the human breast (MCF-7) cell line (IC₅₀ = 2.78 ± 0.15 μM). Treatments of MCF-7 cells with C5 resulted in cell cycle arrest in G2/M phase and microtubule network disruption. Moreover, regarding the expression of cell cycle relative proteins CDK1, a protein required for mitotic initiation was up-regulated. Besides, Cyclin A, Cyclin B1 and Cyclin D1 proteins were down-regulated. Meanwhile, it seems that the effect of C5 on MCF-7 cells apoptosis inducing was observed to be not obvious enough. In addition, docking analysis demonstrated that the congeners occupy the colchicine binding pocket of tubulin.     

Synthesis and in vitro cytotoxic evaluation of new 1H-benzo[d]imidazole derivatives of dehydroabietic acid

A series of new 1H-benzo[d]imidazole derivatives of dehydroabietic acid were designed and synthesized as potent antitumor agents. Structures of the target molecules were characterized using MS, IR, ¹H NMR, ¹³C NMR and elemental analyses. In the in vitro cytotoxic assay, most compounds showed significant cytotoxic activities against two hepatocarcinoma cells (SMMC-7721 and HepG2) and reduced cytotoxicity against noncancerous human hepatocyte (LO2). Among them, compound 7b exhibited the best cytotoxicity against SMMC-7721 cells (IC₅₀: 0.36 ± 0.13 μM), while 7e was most potent to HepG2 cells (IC₅₀: 0.12 ± 0.03 μM). The cell cycle analysis indicated that compound 7b caused cell cycle arrest of SMMC-7721 cells at G2/M phase. Further, compound 7b also induced the apoptosis of SMMC-7721 cells in Annexin V-APC/7-AAD binding assay.     

Anti-tumor activity of a new series of benzoxazepine derivatives in breast cancer

A series of new benzoxazepine derivatives substituted with different alkoxy and aryloxy group were synthesized comprising synthetic steps of Mitsunobu reaction, lithium aluminum hydride (LAH) reduction, followed by debenzylation and finally intramolecular Mitsunobu cyclization. The new benzoxazepines specifically inhibited growth of breast cancer cell lines, MCF-7 and MDA-MB-231, but lack cytotoxicity to normal HEK-293 cells. The cell growth inhibition induced by the active compounds was due to cell cycle arrest at G₀/G₁ phase. The active compound could cause significant reduction in tumor volume of MCF-7 xenograft tumor in nude mice model and their activity was comparable to that of tamoxifen citrate at 16 mg kg^?1 dose at 30 days of treatment. The identified most active compounds of the series have specific advantages as anti-cancer agent in breast cancer than tamoxifen.     

Occurrence of molecular abnormalities of cell cycle in L132 cells after in vitro short-term exposure to air pollution PM2.5

To improve the knowledge of the underlying mechanisms implying in air pollution Particulate Matter (PM)-induced lung toxicity in humans, we were interested in the sequential occurrence of molecular abnormalities from TP53-RB gene signaling pathway activation in the L132 target human lung epithelial cell model. The most toxicologically relevant physical and chemical characteristics of air pollution PM_2.5 collected in Dunkerque, a French highly-industrialized sea-side city, were determined. L132 cells were exposed during 24, 48 and 72 h to Dunkerque City's PM_2.5 (i.e. Lethal Concentration (LC)₁₀ = 18.84 μg PM/mL or 5.02 μg PM/cm²; LC₅₀ = 75.36 μg PM/mL or 20.10 μg PM/cm²), TiO₂ and desorbed PM (i.e. dPM; EqLC₁₀ = 15.42 μg/mL or 4.11 μg PM/cm²; EqLC₅₀ = 61.71 μg/mL or 16.46 μg PM/cm²), benzene (7 μM) or Benzo[a]Pyrene (B[a]P; 1 μM). Dunkerque City's PM_2.5 altered the gene expression and/or the protein concentration of several key cell cycle controllers from TP53-RB gene signaling pathway (i.e. P53; BCL2; P21; cyclin D1, cyclin-dependent kinase 1; retinoblastoma protein) in L132 cells, thereby leading to the occurrence of cell proliferation and apoptosis together. The activation of the critical cell cycle controllers under study might be related to PM-induced oxidative stress, through the possible involvement of covalent metals in redox systems, the metabolic activation of organic chemicals by enzyme-catalyzed reactions, and phagocytosis. Taken together, these results might ask the critical question whether there is a balance or, in contrast, rather an imbalance between the cell proliferation and the apoptosis occurring in PM-exposed L132 cells, with possible consequences in term of PM-induced lung tumorgenesis.     

Hybrid liposomes inhibit the growth of Cholangiocarcinoma by induction of cell cycle arrest in G1 phase

Specific accumulation and cell cycle arrest were observed in human cholangiocarcinoma cells by hybrid liposomes composed of 90 mol % l-α-dimyristoylphosphatidylcholine (DMPC) and 10 mol % polyoxyethylene(21)dodecyl ether (C₁₂(EO)₂₁) without affecting normal cholangiocytes.     

Design,synthesis and in vitro anticancer activity of novel quinoline and oxadiazole derivatives of ursolic acid

A series of new quinoline derivatives of ursolic acid were designed and synthesized in an attempt to develop potential anticancer agents. The structures of these compounds were identified by ¹H NMR, ¹³C NMR, IR and ESI-MS spectra analysis. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (MDA-MB-231, Hela and SMMC-7721). From the results, compounds 3a–d displayed significant antitumor activity against three cancer cell lines. Especially, compound 3b was found to be the most potent derivative with IC₅₀ values of 0.61 ± 0.07, 0.36 ± 0.05, 12.49 ± 0.08 μM against MDA-MB-231, HeLa and SMMC-7721 cells, respectively, stronger than positive control etoposide. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound 3b could significantly induce the apoptosis of MDA-MB-231 cells in a dose-dependent manner. The cell cycle analysis also indicated that compound 3b could cause cell cycle arrest of MDA-MB-231 cells at G0/G1 phase.     

Synthesis and anti-cancer activity of chalcone linked imidazolones

A series of novel chalcone linked imidazolones were prepared and evaluated for their anti-cancer activity against a panel of 53 human tumour cell lines derived from nine different cancer types: leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast. Some of these hybrids (6, 7 and 8) showed good anti-cancer activity with GI₅₀ values ranging from 1.26 to 13.9 μM. When breast carcinoma cells (MCF-7) were treated with 10 μM concentration of compounds TMAC, CA-4, 6 and 8 cell cycle arrest was observed in G2/M phase. Surprisingly, the increased concentration of the same compound to 30 μM caused accumulation of cells in G0/G1 phase of the cell cycle.     

Design and synthesis of new triazoles linked to xanthotoxin for potent and highly selective anti-gastric cancer agents

Two series of xanthotoxin-triazole derivatives were designed, synthesized, and studied for their antiproliferative properties. The in vitro cytotoxicity of the compounds in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay. Among the synthesized compounds, 9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one (6p) was found to have the greatest antiproliferative activity against AGS cells (IC₅₀ = 7.5 μM) and showed better activity than the lead compound (xanthotoxin, IC₅₀ > 100 μM) and the reference drug (5-fluorouracil, IC₅₀ = 29.6 μM) did. The IC₅₀ value of 6p in L02 cells was 13.3 times higher than that in the AGS cells. Therefore, the compound exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil. Cell cycle analysis revealed that compound 6p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells. Compound 6p was identified as a promising lead compound for the further development and identification of 1,2,3-triazole-based anticancer agents.     

Effect of 5-fluoro-2′-deoxyuridine on toxin production and cell cycle regulation in marine dinoflagellate,Alexandrium tamarense

The effect of metabolic inhibitor, 5-fluoro-2′-deoxyuridine (FUdR) on toxin production and the cell cycle of marine dinoflagellate, Alexandrium tamarense, was investigated. Compared to untreated cells, FUdR at 3 μM (p < 0.05) to 300 μM (p < 0.01) inhibited the cell proliferation and toxin production in a dose-dependent manner for A. tamarense cultured in modified T₁ medium. FUdR at 203 μM resulted in cell cycle arrest at the S phase at day 4 and toxigenesis was inhibited after day 2. The toxin profiles of the FUdR-treated cultures were similar to those of the control culture. These results suggest that FUdR inhibits saxitoxin (STX) biosynthesis in the early stage of the pathway. This report is the first to demonstrate the inhibition of toxin production in A. tamarense by a nucleoside analog.     

A novel disintegrin protein from Naja naja venom induces cytotoxicity and apoptosis in human cancer cell lines in vitro

Animal venoms and toxins are potential bioresources that have been known to mankind as a therapeutic tool for more than a century through folk and traditional medicine. The purified “disintegrin protein” (64 kDa) from the venom of the Indian cobra snake (Naja naja) exhibited cytotoxic effects of various types of human cancer cell lines such as breast cancer (MCF-7), lung cancer (A549) and liver cancer (HepG2). In vitro cytotoxicity, DNA fragmentation, an apoptotic assay and a cell cycle analysis were performed to evaluate the anticancer activity of disintegrin against the above cell lines. The IC₅₀ value of disintegrin was determined to be 2.5 ± 0.5 μg/mL, 3.5 ± 0.5 μg/mL, and 3 ± 0.5 μg/mL for the MCF-7, A549 and HepG2 cell lines respectively. Moreover, the increased distribution of G0/G1 and S phase led to decreased populations of cells in the G2/M phase of MCF-7, HepG2 and A549 cells.     

Design,synthesis and biological evaluation of β-boswellic acid based HDAC inhibitors as inducers of cancer cell death

The synthesis and bio-evaluation of naturally occurring boswellic acids (BAs) as an alternate CAP for the design of new HDAC inhibitors is described. All the compounds were screened against a panel of human cancer cell lines to identify leads, which were subsequently examined for their potential to inhibit HDACs. The identified lead compound showed IC₅₀ value of 6 μm for HDACs, found to induce G₁ cell cycle arrest at significantly low concentration (1 μM) and caused significant loss in mitochondrial membrane potential at 5 and 10 μM. Furthermore, specific interactions of the lead molecule inside the catalytic domain were also studied through in silico molecular modeling.     

Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX

In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC₅₀ = 0.23 ± 0.16 μM for COX-2, IC₅₀ = 0.87 ± 0.07 μM for 5-LOX, IC₅₀ = 4.48 ± 0.57 μM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC₅₀ = 0.41 ± 0.28 μM for COX-2, IC₅₀ = 7.68 ± 0.55 μM against A549) and Zileuton (IC₅₀ = 1.35 ± 0.24 μM for 5-LOX). Further investigation confirmed that 11g could induce human non-small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents.     

Diel activities of antioxidant enzymes,photosynthetic pigments and malondialdehyde content in stationary-phase cells of Tetraselmis gracilis (Prasinophyceae)

The activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX), as well as photosynthetic pigment contents and free malondialdehyde (MDA), were determined in senescent batch cultures of Tetraselmis gracilis (Kylin) Butcher, under a cyclic light regime. A 2.6-fold increase in SOD activity (from 53 to 137 U mg⁻¹ protein) was observed in the light phase, contrasting with a 9-fold increase in CAT (from 1 to 9 μmol H₂O₂ min⁻¹ mg⁻¹ protein) and a 1.7-fold increase in APX (from 3 to 5 μmol ascorbate min⁻¹ mg⁻¹ protein) activities, both enzymes peaking in the dark phase. The β-carotene and lycopene content did not vary significantly with the light–dark cycle. The Chl a, Chl b, lutein, zeaxanthin, violaxanthin and neoxanthin pigments exhibited the highest values in the first half (3–6 h) of the light phase, followed by a declining trend and a plateau or a slight increase 3 h from the beginning of the dark phase onwards. The highest values for prasinoxanthin were observed in the second half of the dark phase and the first half of the light phase. None of the pigments displayed any discernible cyclic trend. The possibility of the xanthophyll cycle occurring during senescence is discussed in light of the high value (∼0.9) obtained for the zeaxanthin/(zeaxanthin + violaxanthin) ratio. The free MDA content was enhanced during the experimental period, which may be an indicator of oxidative stress in aging cell cultures. Our results indicated the occurrence of an imbalance between the production of reactive oxygen species and the antioxidant defense in stationary T. gracilis cells.     

Caspase-dependent apoptosis is induced by Artemisia afra Jacq. ex Willd in a mitochondria-dependent manner after G2/M arrest

Artemisia afra is one of the oldest, most well known and widely used traditional medicinal plants in South Africa. It is used to treat many different medical conditions, particularly respiratory and inflammatory ailments (Liu et al., 2009). There is no reported evidence of its use for the treatment of cancer but due to its reported cytotoxicity (Fouche et al., 2008, Mativandlela et al., 2008), we investigated the mode of cell death induced by an ethanolic A. afra extract by using two cancer cell lines. IC₅₀ values of 18.21 and 31.88 μg/mL of ethanol extracts were determined against U937 and HeLa cancer cells, respectively. An IC₅₀ value of the aqueous extract was greater than 250 μg/mL. The effect of the cytotoxic ethanolic A. afra extract on U937 and HeLa cells and their progression through the cell cycle, apoptosis and mitochondrial membrane potential were investigated. Melphalan was used as a positive control. After 12 h of treatment with A. afra a delay in G2/M phase of the cell cycle was evident. Apoptosis was confirmed by using the TUNEL assay for DNA fragmentation, as well as fluorescent staining with annexin V-FITC. Apoptosis was evident with the positive control and A. afra treatment at 24 and 48 h. JC-1 staining showed a decrease in mitochondrial membrane potential at 24 h. The results obtained suggest that A. afra potentially has medicinal anticancer properties.     

Syntheses and biological evaluation of 1-heteroaryl-2-aryl-1H-benzimidazole derivatives as c-Jun N-terminal kinase inhibitors with neuroprotective effects

1-Heteroaryl-2-aryl-1H-benzimidazole derivatives were synthesized as inhibitors of c-Jun N-terminal kinases, JNK3. Their activities were evaluated through measurement of K_d using SPR, JNK3 kinase assay, and cell-viability of human neuroblastoma cells. Most tested compounds showed high affinity (10 μM–46 nM) to JNK3. Among them, compound 16f exhibited potent activities (K_d = 46 nM). Especially, 16f was also found to present a potent cell protective effect (IC₅₀ = 1.09 μM) against toxicity induced by anisomycin, showing a possibility as protective therapeutics in neuronal cell apoptosis.     

Terpenoids with cytotoxic activity from the branches and leaves of Pyrus pashia

Twenty terpenoids, including a new triterpenoid (1) and a new monoterpenoid (20), were isolated from the branches and leaves of Pyrus pashia. The structures of two new compounds were determined to be 2α, 3β, 27-trihydroxyolean-12-en-28-oic acid (1) and (4α)-3-(5,5-dimethyltetrahydrofuranyl)-1-buten-3-ol 3-O-β-d-glucopyranoside (20) on the basis of spectroscopic analysis (IR, HRESIMS, 1D and 2D NMR) and chemical method. Some of the isolated compounds were evaluated for their cytotoxic activity against a panel of human cancer cell lines by MTT assay, using cisplatin as a positive control. Compound 14 exhibited cytotoxic activities against A549 (IC₅₀ = 19.18 ± 4.26 μM), Hela (IC₅₀ = 12.56 ± 3.89 μM), SGC7901 (IC₅₀ = 10.48 ± 1.95 μM) and NHI-1975 (IC₅₀ = 7.38 ± 2.31 μM) cell lines as well as compound 12 displayed cytotoxic activities against A549 (IC₅₀ = 14.71 ± 1.47 μM) and Hela (IC₅₀ = 12.22 ± 1.88 μM) cell lines.