Chemical constituents from Abrus cantoniensis and their cytotoxic effects on cancer cells

Two new compounds named 4-(4-hydroxybenzyl)-isofraxidin (1) and 1''-methoxyl-bavacoumestan B (2), along with five known compounds (3–7) were isolated from the EtOAc-soluble extract of Abrus cantoniensis. Their structures were elucidated with spectroscopic and physico-chemical analyses. All isolates were evaluated for their cytotoxic activities against four cancer cell lines including HepG2, SMMC-7721, A549 and MCF-7. Among them, compounds 1 and 5 exhibited significant cytotoxic activity on the above four cell lines. In particular, 1 showed the potent cytotoxic activity on HepG2 and SMMC-7721 cells with IC₅₀ values of 4.31 ± 0.5 and 3.24 ± 0.9 μM, respectively.     

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.     

C21 steroidal glycosides with cytotoxic activities from Cynanchum otophyllum

Eight new C21 steroidal glycosides, namely cynanotins A–H (1–8), together with fifteen known analogues, were isolated from the roots of Cynanchum otophyllum. Their structures were elucidated by spectroscopic analysis and chemical methods. In this study, all of isolates were tested for their vitro inhibitory activities against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480). Compounds 3–15 showed moderate cytotoxic activities against HL-60 cell lines with IC₅₀ values ranging from 11.4 to 37.9?µM. Compounds 5, 9, and 10 showed marked or moderate cytotoxic activities against five human tumor cell lines with IC₅₀ values ranging from 11.4 to 36.7?µM. Compound 11 displayed moderate cytotoxic activities against HL-60, SMMC-7721, MCF-7 and SW480 cell lines with IC₅₀ values of 12.2–30.8?µM. Compared to the positive control (IC₅₀: 35.0?µM), compounds 5, 9–11 exhibited more potential inhibitory activity against MCF-7 cells (IC₅₀: 16.1–25.6?µM).     

Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors

A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure–activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC₅₀ value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.     

Chemical constituents from Lonicera japonica flower buds and their anti-hepatoma and anti-HBV activities

Three new naturally occurring monoterpenoids, japopenoid A (1), japopenoid B (23) japopenoid C (24), and one new caffeoylquinic acid derivative (28), together with thirty-one known compounds (2–22, 25–27, 29–35), were isolated and identified from the flower buds of Lonicera japonica Thunb. Their structures were determined by extensive 1D and 2D NMR spectroscopic methods, high-resolution mass spectrometry, and the absolute configurations of 1, 23, 24 were determined by comparison of their electronic circular dichroism (ECD) spectrum with literature and theoretical calculation. Structurally, compound 1 is a monoterpenoid featured with an unusual tricyclic skeleton. All compounds (1–35) were evaluated for their cytotoxicities against human liver cancer cell lines (HepG 2 and SMMC-7721). Compound 12 exhibited the most potent activity with IC₅₀ values of 26.54 ± 1.95 and 8.72 ± 1.57 μg/ml against HepG 2 and SMMC-7721, and the IC₅₀ values of compound 13 were 26.54 ± 1.95 and 12.35 ± 1.43 μg/ml, respectively. Western blot results further proved that compound 13 induces hepatoma cell apoptosis via the intrinsic apoptosis pathway. In addition, most terpenoids showed inhibitory activity against HBsAg and HBeAg secretion, and HBV DNA replication. In particular, 25 μg/mlof compound 11 inhibits HBsAg and HBeAg secretion, and HBV DNA replication by 39.39 ± 5.25, 15.64 ± 1.25, and 16.13 ± 4.10% compared to the control (p < 0.05). These results indicated that L. japonica flower buds could be served as functional food for anti-hepatoma and anti-HBV activities.     

Cytotoxic Terpenes from the Flowers of Inula japonica against Human Hepatocarcinoma Cells

Two new 1,10-seco-eudesmanolides ( 1 and 2 ) were isolated from the flowers of Inula japonica together with two eudesmanolide analogs ( 3 and 4 ) and two monoterpene derivatives ( 5 and 6 ). Their structures were established on the basis of detailed spectroscopic analyses and electronic circular dichroism data. All isolates were evaluated for their antiproliferative activities against human hepatocarcinoma HepG2 and SMMC-7721 cells. Japonipene B ( 3 ) exhibited the most potent effect with the IC₅₀ values of 14.60±1.62 and 22.06±1.34 μM against HepG2 and SMMC-7721 cells, respectively. Furthermore, japonipene B ( 3 ) showed significant efficacies of arresting the cell cycle at the S/G2-M stages, inducing mitochondria-mediated apoptosis, and inhibiting cell migration in HepG2 cells.     

Three new chlorinated phenolic glycosides from Przewalskia tangutica

Three new chlorinated phenolic glycosides, namely przewatangosides A-C (1-3), along with one known compound, globosumoside A (4), were isolated from the whole plants of Przewalskia tangutica. Their structures were unequivocally determined by extensive spectroscopic analysis and chemical method. The cytotoxic activities of the isolated phenolic glycosides (1-4) were evaluated against the five human cancer cell lines A549, MCF-7, SMMC-7721, HepG2 and HL-60. Przewatangoside A (1) exhibited weak cytotoxicity against SMMC-7721 with the IC₅₀ value of 38.1 μM. All the tested compounds were inactive (IC₅₀ > 50 μM) to the normal human hepatocyte cell line (L02).     

Design,synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC₅₀ values in range of 3.42–8.05?μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.     

Osteopontin enhances the expression and activity of MMP-2 via the SDF-1/CXCR4 axis in hepatocellular carcinoma cell lines

Background and Aims

Osteopontin, SDF-1α, and MMP-2 are important secreted molecules involved in the pathophysiology of human hepatocellular carcinoma (HCC). This study investigates the effect of the SDF-1α/CXCR4 axis on expression and activity of MMP-2 induced by osteopontin.

Methods

The expression of CXCR4, SDF-1α, MMP-2 and their associated cellular signaling cascades, involving Akt and MAP Kinases, were determined by Western blotting. The activities of MMP-2 and MMP-9 were assayed by gel zymography. The role of the osteopontin receptors integrin α_vβ₃ and CD44v6 was evaluated using neutralizing antibodies. We also established CXCR4-deficient SMMC7721 cell lines by transfection with miRNA-CXCR4 plasmids and determined cell invasion activity in a transwell assay.

Results

In comparison with untreated cells, recombinant human osteopontin (rhOPN) up-regulated CXCR4, SDF-1α, and MMP-2 expression about 5-, 4-, and 6-fold on the protein levels through binding to integrin α_vβ₃ and CD44v6 in hepatocellular carcinoma cells (SMMC7721 and HepG2). Inhibition of the SDF-1α/CXCR4 axis down-regulated the rhOPN-induced MMP-2 expression and activity. rhOPN also activated Akt, p38 and JNK. Down-regulation of CXCR4 decreased the rhOPN-induced invasion in SMMC7721 cells.

Conclusion

These results indicate that rhOPN up-regulates MMP-2 through the SDF-1α/CXCR4 axis, mediated by binding to integrin α_vβ₃ and CD44v6 and activating the PI-3K/Akt and JNK pathways in HepG2 and SMMC7721 cells. Therefore, the osteopontin-SDF-1α/CXCR4-MMP-2 system may be a new therapeutic target for treating HCC progression.     

USP9X低表达通过下调Mcl-1促进肝癌细胞凋亡

研究抑制泛素特异性蛋白酶9X（ubiquitin-specific protease 9X,USP9X）对人肝癌（primary hepatocellular carcinoma,HCC）细胞SMMC7721和HepG2中髓细胞白血病-1（myeloid cell leukemia-1,Mcl-1）蛋白的表达调控及对细胞凋亡和生长活力的影响。实验分为USP9X-siRNA组和阴性对照NC组两组进行分析。通过Western blot技术分别检测USP9X在肝癌细胞SMMC7721、HepG2和正常人肝细胞株L02中的蛋白表达情况;应用化学合成USP9X-siRNA转染肝癌细胞SMMC7721和HepG2,通过Western blot、流式细胞仪和MTT检测转染前后Mcl-1的蛋白表达差异以及细胞凋亡和生长活力变化。结果表明,USP9X在肝癌细胞SMMC7721和HepG2中的蛋白表达水平均高于正常肝细胞L02（t=15.155,P=0.000;t=9.171,P=0.001）;SMMC7721和HepG2细胞中抑制USP9X能明显下调Mcl-1的蛋白表达,并导致细胞凋亡增加和生长活力降低。提示,肝癌细胞SMMC7721和HepG2中USP9X表达上调;USP9X表达降低可能通过下调Mcl-1的蛋白表达进而诱导人肝癌细胞SMMC7721和HepG2的凋亡。     

Synthesis and biological evaluation of farnesylthiosalicylamides as potential anti-tumor agents

Fourteen hybrids of farnesylthiosalicylic acid (FTS) with various diamines were synthesized and biologically evaluated. It was found that FTS-monoamide molecules (10a–g) displayed strong anti-proliferative activity against seven human cancer cell lines, superior to FTS and FTS-bisamide compounds (11a–g). The mono-amide 10f was the most active, with IC₅₀s of 3.78–7.63 μM against all tested cancer cells, even more potent than sorafenib (9.12–22.9 μM). In addition, 10f induced SMMC-7721 cell apoptosis, down-regulated the expression of Bcl-2 and up-regulated Bax and caspase-3. Furthermore, 10f had the improved aqueous solubility relative to FTS. Finally, treatment with 10f dose-dependently inhibited the Ras-related signaling pathways in SMMC-7721 cells. Collectively, 10f could be a promising candidate for the intervention of human cancers.     

Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety

A series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC₅₀ value of 2.84 μM. Compounds 8k and 8n displayed highly effective antitumor activities against MCF-7 cells, with IC₅₀ values of 4.56 and 4.25 μM, respectively. Compounds 8a and 8n exhibited significant antiproliferative activity against A549 cells, with IC₅₀ values of 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for modulating antiproliferative activities against various tumor cell lines.     

Synthesis and cytotoxic activity of metallic complexes of lawsone

In the present study, a series of metallic complexes of the 1,4-naphthoquinone lawsone (2–6) were synthesized and evaluated for potential cytotoxicity in a mouse leukemic macrophagic RAW 264.7 cell line. Cell viability was determined by the MTT assay. Significant growth inhibition was observed for the copper complex (4) with an IC₅₀ value of 2.5 μM. This compound was selected for further evaluation of cytotoxic activity on several human cancer cells including HT-29 (human colorectal adenocarcinoma), HepG2 (human hepatocellular carcinoma) and HeLa, (human cervical adenocarcinoma cells). Significant cell viability decrease was also observed in HepG2 cells. The apoptotic potential of this complex was evaluated in these cells. Compound 4 induced apoptosis by a mechanism that involves the activation of caspases 3, 8 and 9 and modulation of apoptotic-related proteins such as Bax, Bad, and p53. These results indicate that metal complexes of lawsone derivatives, in particular compound 4, might be used for the design of new antitumoral agents.     

Five new triterpenoid saponins from the Roots of Camellia oleifera C. Abel with cytotoxic activities

Five new triterpenoid saponins, oleiferosides P–T (1–5) were isolated from the EtOH extract of the roots of Camellia oleifera C. Abel. The structures of saponins 1–5 were elucidated on the basis of integrated spectroscopic techniques. All the compounds were characterized to be oleanane-type saponins with sugar moieties linked to the C-3 of the aglycone. By using the MTT assay, an in vitro analysis of the cytotoxic activities of these saponins on the human tumor cell lines (lung adenocarcinoma A549 cells, hepatic carcinoma SMMC-7721 cells and breast cancer MCF-7 cells). Among them, compound 4 showed a certain cytotoxic activity against all the tested cell lines.     

Cytotoxic polyketides from endophytic fungus Phoma bellidis harbored in Ttricyrtis maculate

Four new polyketides, namely bellidisins A-D (1-4), were isolated from rice fermentation extract of endophytic fungus Phoma bellidis, along with three known compounds pinolidoxin (5), 5,6-epoxypinolidoxin (6), and 2-epi-herbarumin II (7). Their structures and absolute configurations were determined by 1D and 2D NMR, HRESIMS and ECD calculation. Their cytotoxicity was evaluated against human cancer cell lines HL-60, A549, SMMC-7721, MCF-7, and SW480. Compound 4 showed significant cytotoxicity on these five cell lines with IC₅₀ value ranged from 3.40 to 15.25 μM, which is stronger than cisplatin (4.86–27.70 μM).     

Platachromone A–D: Cytotoxic 2-styrylchromones from the bark of Platanus × acerifolia (Aiton) Willd.

Four novel 2-styrylchromones, 4′,5,7-trihydroxy-6-isopentene-2-styrylchromone (1), 4′,5,7-trihydroxy-8-isopentene-2-styrylchromone (2), 4′,5,7-trihydroxy-6-(2-hydroxy-3-methylbut-3-enyl)-2-styrylchromone (3) and 4′,5,7-trihydroxy-8-(2-hydroxy-3-methylbut-3-enyl)-2-styrylchromone (4), were isolated from shed bark of Platanus × acerifolia (Aiton) Willd., as well as four known compounds, 4′,5,7-trihydroxy-2-styrylchromone (5), scutellarein (6), 4′,5,7-trihydroxy-6-prenylflavone (7), and 4′,5,7-trihydroxy-8-prenylflavone (8). The structures of compounds 1–4 were established by direct interpretation of their spectral data, mainly high resolution electrospray ionization mass spectrometry (HR-ESI-MS), 1D and 2D NMR (¹H–¹H COSY, HSQC and HMBC). The cytotoxicity of the compounds 1–8 was evaluated in four human carcinoma cell lines, including HepG2, SMMC-7721, MDA-MB-231, and KB. Compounds 1–4 exhibited significantly cytotoxic activity toward HepG2 and KB cells, with IC₅₀ values ranging from 3.0 to 9.7 μM.     

Synthesis and evaluation of novel 7-azaindazolyl-indolyl-maleimide derivatives as antitumor agents and protein kinase C inhibitors

A series of novel 7-azaindazolyl-indolyl-maleimides were synthesized and evaluated for their antiproliferative activity in vitro against various human cancer cell lines and protein kinase C inhibitory activity. Compounds 8a–c, 8e and 14a were the most promising compounds against K562, A549, ECA-109, KB and SMMC-7721 cell lines in vitro. Compounds 9a–j showed moderate PKC inhibition. Further mechanism of action studies revealed that the antiproliferative activity of compound 8b in KB cells might involve the mitochondria-mediated apoptosis pathway.     

Two new polycyclic polyprenylated acylphloroglucinols from Hypericum curvisepalum N. Robson

Phytochemical investigation of the whole plant of Hypericum curvisepalum led to the isolation of nine polycyclic polyprenylated acylphloroglucinols (1–9). Among them, curvisepalumiones A (1) and B (2) are two new compounds and their structures were elucidated based on extensive spectroscopic data analysis combined with Rh₂(OCOCF₃)₄-induced electronic circular dichroism experiment. Cytotoxic assay showed that all the tested compounds except for 1 was moderately cytotoxic against human hepatocarcinoma cell line SMMC-7721 cell line, while compounds 3 and 4 also exhibited cytotoxicity toward MGC-803 cells. In addition, compound 2 exhibited weak inhibitory activity against Bacillus subtilis.     

Oleanolic acid-NO donor-platinum(II) trihybrid molecules: Targeting cytotoxicity on hepatoma cells with combined action mode and good safety

By taking advantage of good affinity of oleanolic acid (OA) to the bile acid transporter, a series of hybrid compounds from oleanolic acid (OA) or OA-nitric oxide (NO) donor derivative coordinating to platinum(II) complexes were designed and synthesized. As expected, complexes 1c and 1d showed selective cytotoxicity to hepatoma carcinoma cells (e.g. HepG2, SMMC-7721, BEL-7402 cells) rather than other tumor cells. Interestingly, they had only a weak toxicity to normal hepatic cells (e.g. LO2 cells). Mechanism studies revealed that 1c could effectively bind to the ligand domain of the farnesoid X receptor and maintain the normal function of liver cells. Furthermore, the NO donor moiety could moderately release cytotoxic NO and finally enhance the cytotoxic effect, while the cytotoxicity of the corresponding complexes was decreased when the cells were pretreated with NO scavenger. Additionally, the agarose gel electrophoresis revealed that the Pt(II) part could also offer DNA binding activity, suggesting the complexes possess a combined action mode which may help to overcome the resistance of cisplatin. The flow cytometry studies found that 1c caused tumor apoptosis and blocked cell-cycle progression in the G2 phase.     

Design and synthesis of novel nitrogen mustard-evodiamine hybrids with selective antiproliferative activity

A series of novel nitrogen mustard-evodiamine hybrids were synthesized and evaluated for their antitproliferative properties. The antiproliferative activities of 10a–d, 11a–d, and 12a–d against four different kinds of human cancer cell lines (PC-3, HepG2, THP-1 and HL-60) and human normal peripheral blood mononuclear cells (PBMC) were determined. The results showed that all the target hybrid compounds exhibited antiproliferative activities against tested human tumor cell lines to some extent and no antiproliferative activities (>200?μM) against human normal PBMC cells. The antiproliferative selectivity between tumorous and normal cells was very useful for further antitumor drug development. Among the target compounds, 12c showed the strongest cytotoxicity against two tumor cell lines (THP-1 and HL-60) with IC₅₀ values of 4.05?μM and 0.50?μM, respectively, and selected for further mechanism study in HL-60 cells. The results showed that 12c could induce HL-60 cells apoptosis and arrest at G₂ phase at low sub-micromolar concentrations via mitochondria-related pathways.