Synthesis and biological evaluation of novel derivatives of gambogic acid as anti-hepatocellular carcinoma agents

A series of novel derivatives of gambogic acid (GA) were synthesized and evaluated for their in vitro cytotoxicity against human hepatocellular carcinoma (HCC) cells. All derivatives showed better aqueous solubility than GA, and compounds 3a, 3e, and 3f displayed potent inhibition of HCC cell proliferation (IC(50): 0.045-0.59 μM on Bel-7402 cells and 0.067-0.94 μM on HepG2 cells) superior to GA and taxol. Additionally, the most potent compound 3e did not affect significantly the proliferation of non-tumor liver cells, suggesting that it might selectively inhibit HCC proliferation. Furthermore, 3e induced high frequency of Bel-7402 cell apoptosis. Our findings suggest that these novel GA derivatives may hold a great promise as therapeutic agents for the intervention of human HCC.     

New cytotoxic tricycloalternarenes from fungus Alternaria brassicicola

Seven previously undescribed metabolites, designated as tricycloalternarenes Q–W (1–7), were isolated and identified from the fermented rice substrate of fungus Alternaria brassicicola. The planar and absolute structures of all new compounds were determined on the basis of extensive NMR spectroscopic data, a modified Mosher’s method, X-ray crystallographic analysis, and electronic circular dichroism (ECD) spectral analyses. All the isolates were evaluated for in vitro cytotoxicity against five human tumor MM231, MM468, HeLa, SW1990, and SW480 cell lines, and compounds 1, 2, 5, and 7 showed selective cytotoxicity against certain human tumor cell lines with IC₅₀ values ranging from 12.83 to 32.87 μM, with no obvious cytotoxicity to the normal LO2 cell.     

Indole alkaloids from Muntafara sessilifolia with antiplasmodial and cytotoxic activities

Four vobasinyl-iboga bisindole and one 2-acyl monomeric indole alkaloids were isolated from the stem bark of Muntafara sessilifolia along with eleven known compounds. Their structures and relative stereochemistry were elucidated on the basis of spectroscopic data including 1D and 2D NMR and mass spectrometry (MS). All isolated compounds were evaluated in vitro for antiplasmodial activity against the chloroquine-resistant strain FcB1 of Plasmodium falciparum, and for cytotoxicity against the human lung cell line MRC-5 and the rat skeletal muscle cell line L-6. 3'-Oxo-tabernaelegantine A exhibited antiplasmodial activity (4.4 μM IC(50)) associated with non-significant cytotoxicity (selectivity index of 48). Tabernaelegantine B and D displayed the highest cytotoxicity with IC(50) values of 0.47 and 1.89 μM on MRC-5 cells, and 0.42 and 2.7 μM on L-6 cells, respectively.     

Design and synthesis of the novel oleanolic acid-cinnamic acid ester derivatives and glycyrrhetinic acid-cinnamic acid ester derivatives with cytotoxic properties

Oleanolic acid (OA) and glycyrrhetinic acid (GA) are natural products with anticancer effects. Cinnamic acid (CA) and its derivatives also exhibited certain anticancer activity. In order to improve the anticancer activity of OA and GA, we designed and synthesized a series of novel OA-CA ester derivatives and GA-CA ester derivatives by using molecular hybridization approach. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to assess their in vitro cytotoxicity on three cell lines (HeLa (cervical cancer), MCF-7 (breast cancer) and L-O2 (a normal hepatic cell)). Among the evaluated compounds, 3o presented the strongest selective cytotoxicity on HeLa cells (IC₅₀ = 1.35 μM) and showed no inhibitory activity against MCF-7 cells (IC₅₀ > 100 μM) and L-O2 cells (IC₅₀ > 100 μM), and 3e presented the strongest selective inhibition of the MCF-7 cells (IC₅₀ = 1.79 μM). What’s more, compound 2d also showed very strong selective inhibitory activity against HeLa cells (IC₅₀ = 1.55 μM). The further research using Hoechst 33342, AO/EB dual-staining, flow cytometric analysis and DCFH-DA fluorescent dye staining assay presented that 2d and 3o could induce HeLa cells apoptosis and autophagy.     

Synthesis and in vitro evaluation of novel coumarin-chalcone hybrids as potential anticancer agents

A series of coumarin-chalcone hybrids have been synthesized and evaluated for their in vitro cytotoxicity against a panel of four human cancer cell lines and normal fibroblasts (NIH3T3). Among 21 compounds screened, three compounds (23, 25 and 26) showed IC(50) range from 3.59 to 8.12 μM. The most promising compound 26 showed around 30-fold more selectivity towards C33A (cervical carcinoma) cells over normal fibroblast NIH3T3 cells with an IC(50) value of 3.59 μM.     

Lanceoleins A–G,hydroxychalcones, from the flowers of Coreopsis lanceolata and their chemopreventive effects against human colon cancer cells

Seven new chalcones, lanceolein A–G (compounds 5 and 7–12), as well as five known chalcones (1–4 and 6), were isolated from the methanolic extract of Coreopsis lanceolata flowers. The chemical structures of 5 and 7–12 were determined on the basis of spectroscopic data interpretation. All compounds inhibited the production of nitrite oxide (NO) induced by LPS in RAW264.7 macrophage cells. Also, compounds 1–6 showed moderated cytotoxicity against human colon cancer cell lines, while compounds 7–12 hardly showed the cytotoxicity. Especially, compounds 2, 5, and 6 exhibited a little higher cytotoxicity on HCT15 cells, with IC₅₀ values of 43.7 ± 2.17 μM, 35.6 ± 0.24 μM, and 47.9 ± 1.18 μM, respectively. In the Tali assay, compounds 2 and 5 increased the numeral of apoptotic cells. These compounds also significantly promoted the expression of apoptotic proteins including PARP and caspase-3.     

Antioxidant Activity of New Sulphur- and Selenium-Containing Analogues of Potassium Phenosan against H2O2-Induced Cytotoxicity in Tumour Cells

Among known phenolic antioxidants, the overwhelming majority of compounds have lipophilic properties and the number of known water-soluble compounds is very small. The list of hydrophilic phenolic antioxidants can be expanded via the synthesis of a structurally related series of polyfunctional compounds for further research on their biological activity in vitro. New sulphur- and selenium-containing analogues of antioxidant potassium phenosan were synthesised. In vitro cytotoxicity and cytostaticity as well as antioxidant activity against H₂O₂-induced cytotoxicity to human cell lines (HepG2, Hep-2 and MCF-7) were investigated by high-content analysis. A selenium-containing analogue showed higher biological activity than did a sulphur-containing one. As compared to the activity of potassium phenosan, the selenium-containing analogue had a cell line-dependent antioxidant effect against H₂O₂-induced cytotoxicity: comparable in HepG2 cells and greater in Hep-2 cells. The selenium-containing analogue significantly increased the death of MCF-7 cells at concentrations above 50 µM. The sulphur-containing analogue has lower biological activity as compared to potassium phenosan and the selenium-containing analogue.     

Semi-Synthesis of Flavonoid Glycosides and Their Anti-Inflammatory and Antitumor Activities towards Triple Negative Breast Cancer

Background : Flavonoid glycosides are known to possess diverse bioactivities including antitumor and anti-inflammatory properties. Hesperetin is abundant in nature and can be used to synthesize bioactive flavonoids. This has the advantages of low cost, short synthetic steps, simple operation, and good yields. Objective : In this study, we aimed to synthesize bioactive flavonoids and flavonoid glycosides from hesperetin and evaluate the antitumor and anti-inflammatory activities of these compounds. Methods : A series of flavonoids and their derivatives were synthesized by methoxylation, oxidative dehydrogenation, benzylation, debenzylation, and deacetylation as well as using a modified peroxyacetone method and a glycoside condensation reaction. Their anti-inflammatory activities were evaluated for their inhibitory effects on nitric oxide (NO), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) production in LPS-induced RAW264.7 mouse macrophages. Their structures were characterized by HRMS, ¹H-NMR, and ¹³C-NMR, and their cytotoxicity on the human triple-negative breast cancer cell (TNBC) line, SUM 149, was tested by using the MST assay. Results : Most of the compounds markedly reduced NO production in LPS-stimulated murine macrophages at the tested concentrations in a dose-dependent manner. Among these, compounds 1 , 7 , 9 , and 17 showed significant anti-inflammatory activities against NO production in LPS-induced RAW264.7 mouse macrophages. In addition, they could also reduce the release of TNF-α and IL-6 in a concentration-dependent manner. Most of the tested compounds showed remarkable anti-human TNBC activities. Compounds 1b – 1m , 1 , and 3 showed a certain degree of growth inhibition effect on the human TNBC cell lines and their IC₅₀ values were all below 16.61 μM. In addition, compound 1l was the most cytotoxic with IC₅₀ values of 1.38±0.31 μM, while the other compounds were inactive with inhibition rates <50 % at the highest concentration tested (20 μM). Conclusions : A novel series of flavonoids were synthesized from the natural flavonoid, hesperetin, including 17 new compounds. Screening tests indicated that most of these compounds reduced NO production in LPS-stimulated murine macrophages at concentrations of 15 to 60 μM, and the inhibition generally increased in a dose-dependent manner. Some compounds showed different degrees of cytotoxicity on the human TBNC cell lines, SUM 149.     

Synthesis and biological evaluation of tetracyclic thienopyridones as antibacterial and antitumor agents

A facile synthesis of model 4-oxopyrido[3',2':4,5]thieno[3,2-b]indole-3-carboxylic acids 9a-e was achieved via Stille arylation of 2-chloro-3-nitro-4-oxothieno[2,3-b]pyridine-5-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. Compounds 9a-c and 9e exhibited very high potency against Gram positive Bacillus subtilis and Bacillus megaterium at concentrations 0.000015-0.007 μg/mL. They also displayed excellent activity towards other Gram positive bacilli and staphylococci and Gram negative Haemophilus influenzae, being in most cases superior or equal to commercial fluoroquinolones. Both 9a and 9c were inhibitors of the DNA gyrase activity. As concerns antitumor properties, compounds 9b-e showed growth inhibition of MCF-7 breast tumor and A549 non-small cell lung cancer cells with IC(50) 1.6-2.8 μM and 2.6-6.9 μM, respectively, coupled with absence of cytotoxicity towards normal cells. These compounds are promising as dual acting chemotherapeutics.     

Antitumor dinuclear platinum(II) complexes derived from a novel chiral ligand

A new chiral ligand, 2-(((1R,2R)-2-aminocyclohexyl)amino)acetic acid (HL), was designed and synthesized to prepare a series of novel dinuclear platinum(II) complexes with dicarboxylates or sulfate as bridges. The evaluation of these metal complexes in vitro cytotoxicity against human HCT-116, MCF-7 and HepG-2 cell lines were made. All compounds showed antitumor activity to HCT-116 and MCF-7. Particularly, compounds M3 and M5 not only exhibited better activity than carboplatin against MCF-7 and HepG-2, but also showed very close activity to oxaliplatin against HCT-116.     

牛膝多糖对小鼠腹腔巨噬细胞的细胞毒作用影响及机制

研究牛膝多糖(ABPS)对巨噬细胞细胞毒作用的影响及机制。以200 mg/L浓度的ABPS体外刺激小鼠腹腔来源巨噬细胞,采用MTT法检测细胞毒作用,Griess试剂盒检测NO的生成,Real-Time PCR和Western blot分别检测i NOS mRNA和蛋白的表达。结果显示,浓度为200 mg/L的ABPS对巨噬细胞细胞毒作用和NO表达有显著的促进作用,对i NOS mRNA和蛋白表达均有明显的促进作用。研究结果提示ABPS可能通过增强细胞内i NOS表达,促进NO生成和释放,从而促进巨噬细胞细胞毒作用。     

One-step synthesis of biodegradable curcumin-derived hydrogels as potential soft tissue fillers after breast cancer surgery

A one-step synthesis of a curcumin-derived hydrogel (curcumin content of 25-75 mol %) is reported. Curcumin is incorporated into the hydrogel backbone and cross-linked through biodegradable carbonate linkages. Curcumin as a part of the polymer backbone is protected from oxidation and degradation, while hydrogel hydrolysis results in the release of active curcumin. Nontoxic poly(ethylene glycol) and desaminotyrosyl-tyrosine ethyl ester are used to tune the hydrophilic/hydrophobic hydrogel properties. In this way, hydrogels with a wide range of physical properties including water-uptake (100-550%) and compression moduli (7-100 kPa) were obtained. Curcumin release is swelling-controlled and could be extended to 80 days. In vitro, curcumin-derived hydrogels showed selective cytotoxicity against MDA-MB-231 (IC(50) 9 μM) breast cancer cells but no cytotoxicity to noncancerous quiescent human dermal fibroblasts even at high curcumin concentrations (160 μM). One possible application of these curcumin-derived hydrogels is as soft tissue filler after surgical removal of cancerous tissue.     

Vitamin C inhibits glycidamide‐induced genotoxicity and apoptosis in Sertoli cells

Exposure to the food contaminant acrylamide and its reactive epoxide metabolite glycidamide (GA) induces reactive oxygen species (ROS)‐mediated oxidative stress and subsequent cellular death. Recent studies have revealed that the toxic effects of acrylamide may be due to GA, especially on male reproductive system cells. In this regard, it is important to determine the effects of GA on Sertoli cells, which are essential cells for the male reproductive system. Antioxidants should be consumed in sufficient quantities to minimise the effects of environmental pollutants. This study aimed to determine the direct toxic effects of GA and protective effects of vitamin C (VitC) against GA‐induced damage in Sertoli cells by measuring cell viability, cytotoxicity, lipid peroxidation, ROS, antioxidant enzyme levels, apoptosis and DNA damage. Sertoli cells were exposed to GA for 24 hours at four different concentrations (ranging between 1 and 1000 μM) and in addition to these GA concentrations to VitC (50 μM). The results of cytotoxicity markers, such as cell viability and lactate dehydrogenase (LDH) showed that GA significantly reduced cell viability and increased LDH levels. We also found that GA induced overproduction of intracellular ROS, increased lipid peroxidation in cellular membrane and triggered cell apoptosis and genotoxicity. In addition, VitC supplementation ameliorated the adverse effects of GA on Sertoli cells. Consequently, these findings suggest that GA may damage the cell function in Sertoli cells, depending on the concentration. Additionally, it was evidenced that VitC has an ameliorative effect on toxicity caused by GA.     

New Derivatives from Microbial Transformation of ent‐Kaur‐16‐en‐19‐oic Acid by Cunninghamella echinulata

Biotransformation of ent‐kaur‐16‐en‐19‐oic acid using fungus Cunninghamella echinulata resulted in two novel hydroxylated metabolites together with five known compounds. Their structures were elucidated by means of extensive NMR and HR‐ESI‐MS data analysis. The eight compounds were measured for their cytotoxicity against the human breast carcinoma (MCF‐7) and human hepatoblastoma (HepG‐2) cell lines. Seven compounds showed no cytotoxicity to the two cell lines. One compound displayed moderate cytotoxicity against HepG‐2 and MCF‐7 with the IC₅₀ values of 12.6 and 27.1 μM, respectively.     

Synthesis,Antiproliferative, and Antiviral Evaluation of Certain Acyclic 6-Substituted Pyrrolo[2,3-D]-pyrimidine Nucleoside Analogs Related to Sangivamycin and Toyocamycin

Abstract

A number of 6-substituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine and 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidine derivatives related to the nucleoside antibiotics toyocamycin and sangivamycin were prepared and tested for their biological activity. Treatment of 2-amino-5-bromo-3,4-dicyanopyrrole (2) with triethylorthoformate, followed by alkylation via the sodium salt method with either 2-(acetoxyethoxy)methyl bromide or (1,3-diacetoxy-2-propoxy)methyl bromide, furnished the corresponding N-substituted pyrroles 3a and 3b. These compounds were then smoothly converted to the requisite deprotected 4-amino-6-bromopyrrolo[2,3-d]-pyrimidine-5-carbonitriles 5a and 5b (toyocamycin analogs) by methanolic ammonia. The 6-amino-derivatives were obtained by a displacement of the bromo group with liquid ammonia. Conventional functional group transformations involving the 5-cyano group furnished the 5-carboxamide (sangivamycin) and 5-thioamide analogs. Compounds substituted at the 7-position with a ribosyl moiety were active against human cytomegalovirus (HCMV) at micromolar concentrations, but the apparent activity was not selective. The 7-ribosyl compounds also had no activity against human immunodeficiency virus (HIV), though they were all cytotoxic. The new compounds were also evaluated against HCMV, herpes simplex virus type I (HSV-1), HIV, and also for their ability to inhibit the growth of L1210 murine leukemic cells in vitro. None of these compounds with (2-hydroxyethoxy)methyl substituents or 7-(1,3-dihydroxy-2-propoxy)methyl substituent at N-7 showed significant cytotoxicity toward L1210, or toward uninfected human foreskin fibroblasts (HFF cells), and KB cells. Nor were they cytotoxic in human lines CEM or MT2. Only compound 4a was found to be active against HCMV, having an IC₅₀ of 32 μM.     

Arthrinins A-D: novel diterpenoids and further constituents from the sponge derived fungus Arthrinium sp

Bioassay-guided fractionation of a methanolic extract of the fungus Arthrinium sp., isolated from the Mediterranean sponge Geodia cydonium, afforded 10 natural products including five new diterpenoids, arthrinins A-D (1-4) and myrocin D (5). In addition, five known compounds were obtained, which included myrocin A (6), norlichexanthone (7), anomalin A (8), decarboxycitrinone (9) and 2,5-dimethyl-7-hydroxychromone (10). The structures of all isolated compounds were unambiguously elucidated based on extensive 1D and 2D NMR and HR-MS analyzes. The absolute configuration of arthrinins A-D (1-4) was established by the convenient Mosher method performed in NMR tubes and by interpretation of the ROESY spectra. Antiproliferative activity of the isolated compounds was assessed in vitro against four different tumor cell lines, including mouse lymphoma (L5178Y), human chronic myelogenous leukemia (K562), human ovarian cancer (A2780) and cisplatin-resistant ovarian cancer cells (A2780CisR), using the MTT assay. Norlichexanthone (7) and anomalin A (8) exhibited the strongest activities with IC?? values ranging from 0.40 to 74.0 μM depending on the cell line investigated. This was paralleled by the inhibitory activity of both compounds against 16 cancer related protein kinases including aurora-B, PIM1, and VEGF-R2. In vitro IC?? values of 7 and 8 against these three protein kinases ranged from 0.3 to 11.7 μM. Further investigation of the potential antitumoral activity of compounds 5-8 was performed in an in vitro angiogenesis assay against human umbilical vascular endothelial cells (HUVEC) sprouting induced by vascular endothelial growth factor A (VEGF-A). Anomalin A (8), myrocin D (5) and myrocin A (6) inhibited VEGF-A dependent endothelial cell sprouting with IC?? values of 1.8, 2.6 and 3.7 μM, respectively, whereas norlichexanthone (7) was inactive.     

In vitro impact of amino acid-derived bacterial metabolites on colonocyte mitochondrial activity,oxidative stress response and DNA integrity

Background4-hydroxyphenylacetic acid (HO-PAA) is produced by intestinal microbiota from L-tyrosine. High concentrations in human fecal water have been associated with cytotoxicity, urging us to test HO-PAA's effects on human colonocytes. We compared these effects with those of phenylacetic acid (PAA), phenol and acetaldehyde, also issued from amino acids fermentation.MethodsHT-29 Glc^−/+ human colonocytes were exposed for 24 h to metabolites at concentrations between 350 and 1000 μM for HO-PAA and PAA, 250-1500 μM for phenol and 25-500 μM for acetaldehyde. We evaluated metabolites'cytotoxicity with 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and DNA quantification assays, reactive oxygen species (ROS) production with H2DCF-DA, and DNA damage with the comet assay. We measured cell oxygen consumption and mitochondrial complexes activity by polarography.ResultsAlthough HO-PAA displayed no cytotoxic effect on colonocytes, it decreased mitochondrial complex I activity and oxygen consumption. This was paralleled by an increase in ROS production and DNA alteration. Cells pretreatment with N-acetylcysteine, a ROS scavenger, decreased genotoxic effects of HO-PAA, indicating implication of oxidative stress in HO-PAA's genotoxicity. PAA and phenol did not reproduce these effects, but were cytotoxic towards colonocytes. Last, acetaldehyde displayed no effect in terms of cytotoxicity and mitochondrial metabolic activity, but increased DNA damage.ConclusionsSeveral bacterial metabolites produced from amino acids displayed deleterious effects on human colonocytes, in terms of genotoxicity (HO-PAA and acetaldehyde) or cytotoxicity (PAA and phenol).General significanceThis study helps understanding the consequences of intestinal microbiota's metabolic activity on the host since amino acids fermentation can lead to the formation of compounds toxic towards colonic epithelial cells.     

Cytotoxic cytochalasins from the endozoic fungus Phoma sp. of the giant jellyfish Nemopilema nomurai

Four new cytochalasin derivatives (1-4), together with cytochalasin B (5), were isolated from the fungus Phoma sp. obtained from the giant jellyfish Nemopilema nomurai. The planar structure and relative stereochemistry were established by analysis of 1D and 2D NMR data. The absolute configuration was defined by the modified Mosher's method. The compounds showed significant cytotoxicity against a small panel of human solid tumor cell lines (A549, SK-OV-3, SK-MEL-2, XF 498, and HCT15) with IC(50) values in the range of 0.5-30 μM. The cytochalasin B (5) showed obvious cytotoxicity with IC(50) of 7.9 μM against HeLa human cervical carcinoma cells.     

New Spirostane from a Fungus Neohelicomyces hyalosporus and Its Bioactivity

A new spirostane, namely neohelicomyine B ( 1 ), together with six known steroids ( 2 – 7 ) were isolated from the fermentation of fungus Neohelicomyces hyalosporus. The structures of these compounds were elucidated by extensive analyses of spectroscopic methods including 1D and 2D NMR and HR-ESI-MS. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction. The bioactivities of compounds 1 – 7 were evaluated using cellular assays. Compound 1 displayed moderate cytotoxicity against HepG2 cells (hepatoma cells) with IC₅₀ value of 8.4±2.1 μM. Compound 7 also exhibited cytotoxic activity against HepG2 cells with the IC₅₀ value of 3.0±0.2 μM.     

Forms of Selenium Affect its Transport, Uptake and Glutathione Peroxidase Activity in the Caco-2 Cell Model

The aim of this study was to investigate the possible time- and dose-dependent cytotoxic effects of cobalt chloride on Vero cells. The cultured cells were incubated with different concentrations of cobalt chloride ranging from 0.5 to 1,000 μM, and cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) and resazurin assays. Possible protective effects of vitamin E, coenzyme Q(10), and zinc chloride were also tested in this system. A gradual decrease in cell proliferation was observed at concentrations ~≥ 200 μM in incubation periods of 24, 48, 72, and 96 h with MTT assay. Exposure of cells to 500 and 1,000 μM cobalt chloride caused significant decrease in cell survival. A biphasic survival profile of cells was observed at 1-25 μM concentration range following 96 h of incubation. With resazurin assay, cytotoxicity profile of CoCl(2) was found comparable to the results of MTT assay, particularly at high concentrations and long incubation periods. Dose-dependent cytotoxicity was noted following exposure of cells to ≥ 250 μM of CoCl(2) for 24 h and ≥ 100 μM concentrations of CoCl(2) for 48-96 h. Pretreatment of cells with ZnCl(2) for 4 or 24 h provided significant protection against cobalt chloride-induced cytotoxicity when measured with MTT assay. However, vitamin E or coenzyme Q(10) was not protective. CoCl(2) had dose- and time-dependent cytotoxic effects in Vero cells. Preventive effect of ZnCl(2) against CoCl(2)-induced cytotoxicity should be considered in detail to define exact mechanism of toxicity in Vero cells.