Antiproliferative effect of 2-Hydroxy-6-tridecylbenzoic acid from ginkgo biloba sarcotestas through the aryl hydrocarbon receptor pathway in triple-negative breast cancer cells

Abstract

This study aims to isolate the potential antiproliferative and cytotoxic compounds from ginkgo biloba sarcotestas (GBS) and investigates the underlying mechanism in human MDA-MB-231 and mouse 4T-1 triple-negative breast cancer cells. Our results showed that 2-Hydroxy-6-tridecylbenzoic acid was isolated by cytotoxicity-guided fractionation where different fractions were assessed using MTT assay against MDA-MB-231 and 4T-1 cells. Colony formation assay showed that 2-Hydroxy-6-tridecylbenzoic acid significantly inhibited cell proliferation. The inhibition was associated with the enhancement of cytochrome P450 (CYP) 1B1 expression in a dose- and time-dependent manner and no significant change of CYP1A1 expression by qPCR and Western blot assays in MDA-MB-231 and 4T-1 cells. The mechanism was further demonstrated by the activation of aryl hydrocarbon receptor (AhR) pathway with the upregulation of AhR, AhR nuclear translocator (ARNT) and AhR-dependent xenobiotic response elements (XRE) activity. These findings may have implications for development of anticancer agents containing 2-Hydroxy-6-tridecylbenzoic acid as functional additives.     

Synthesis of heteroannulated cyclopent[b]indoles: Exploration of in vitro cytotoxicity and molecular docking studies

A series of novel cyclopent[b]indole analogues that hold isoxazolo-, pyrido-templates were designed and synthesized in good yields. The in vitro cytotoxicity was concerned for all the newly synthesized compounds by MTT assay against HeLa (cervix adeno carcinoma) and MCF-7 (breast cancer). These synthesized compounds were further compared with the standard drug ellipticine, 5-fluorouracil, cisplatin, and methotrexate. The synthesized heteroannulated cyclopent[b]indole compounds were found to show better cytotoxic activity against HeLa and MCF-7 with primary structure activity relationship studies. To identify with the nature of interactions of these molecules, we performed molecular docking studies using the protein kinase CK2 inhibitors. The docking results afforded some valuable information for the future design of more potent inhibitors.     

The cytotoxic activities of imidazole derivatives prepared from various guanylhydrazone and phenylglyoxal monohydrate

Abstract

A series of imidazole derivatives were synthesized from two-component condensation reaction of phenylgloxal monohydrate with guanylhydrazone. They were characterized by spectroscopic and analytical techniques. The in vitro anticancer evaluation of these compounds was done on human breast cancer (MCF-7) and human liver cancer (HepG2) cell lines using the MTT assay method. Most of the newly synthesized compounds displayed cytotoxic activity against these cancerous cells. In fact, compounds 3a, 3e, and 3?h exhibited more cytotoxic activities than the positive control drugs, fluro-5, and irinocam, against the MCF-7 cell line. Almost all the compounds, except for three, 3b, 3d, and 3f, gave more cytotoxic results than cisplatin. Therefore, these compounds could be considered for further development as anticancer drug candidates.     

Synthesis and Evaluation of Pyrido[2,3‐d]pyrimidine and 1,8‐Naphthyridine Derivatives as Potential Antitumor Agents

New series of pyrido[2,3‐d]pyrimidine and 1,8‐naphthyridine derivatives were synthesized from 2‐amino‐6‐(phenoxathiin‐2‐yl)‐4‐(thiophene‐2‐yl) nicotinonitrile as starting material, and their structures were characterized on the basis of the spectral data. Most of the synthesized compounds were evaluated for their cytotoxic activity against two cancer cell lines, namely, breast cancer Michigan Cancer Foundation‐7 (MCF‐7) and prostate cancer human prostatic carcinoma cell line (PC‐3) using MTT assay. Some of these compounds showed potent cytotoxic effect concluded from their IC₅₀ values.     

Synthesis, Characterization and Antiproliferative Activity of 1,2-Naphthoquinone and Its Derivatives

In the present study substituted 1,2-naphthoquinones were synthesized, purified and characterized by spectroscopic studies (UV, FT-IR, ¹H NMR, ¹³?C NMR and elemental analysis). These compounds were evaluated for cytotoxicity against a panel of human cancer cell lines (Hep-G₂ for liver sarcoma_, MG-63 for osteosarcoma and MCF-7 for human breast cancer). The cells were dosed with these ortho-naphthoquinone derivatives at varying concentrations, and cell viability was measured by a 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay with doxorubicin as positive control. Significant anticancer activities were observed in vitro for some members of the series, and compounds 1,2-naphthoquinone 2-thiosemicarbazone (3), 1,2-naphthoquinone-2-semicarbazone (4), 4-amino-1,2-naphthoquinone 2-thiosemicarbazone (7) and 4-amino-1,2-naphthoquinone-2-semicarbazone (8) are active cytotoxic agents against different cancer cell lines with IC₅₀ values in the range of 5.73?C17.67???M. The obtained data suggested that better anticancer activity was linked with introduction of thiosemicarbazone and semicarbazone moiety in 1,2-naphthoquinone ring system. Outcomes of experimentation also reveal that incorporation of amino group in 1,2-naphthoquinone moiety contributes positively for cytotoxic action of compounds. Docking experiments showed a good correlation between their calculated interaction energies with the topoisomerase-II and the observed IC₅₀ values of all these compounds.     

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.     

Design,Synthesis, and In Vitro Evaluation of Novel Indolyl DiHydropyrazole Derivatives as Potential Anticancer Agents

Indoles derived from both natural sources or artificial synthetic methods have been known to interact with aryl hydrocarbon receptors (AhR), and exhibit anticancer activity. In light of these attractive properties, a series of hybrid molecules with structural features of indoles, i.e., those bearing a pyrazoline nucleus, were evaluated for their enhanced anticancer activity. The designed molecules were subjected to molecular docking in order to screen for potential AhR interacting compounds, and the identified indolyl dihydropyrazole derivatives were synthesized. The synthesized compounds were characterized, and their cytotoxicity was evaluated against four human cancer cell lines using the MTT assay. Based on the Glide g-score, H-bonding interactions and bonding energy of 20 candidate molecules were selected for further analysis from the 64 initially designed molecules. These candidate molecules have shown promising anti-proliferative activity against the cell lines tested. Among these candidate molecules, the compounds with hydroxy phenyl substitution on the pyrazoline ring have shown potent activity across all the tested cell lines. The designed scaffold was proven effective for screening potential candidate molecules with anticancer properties, and may be further optimized structurally for yielding the ideal anti-tumorigenic compound for the treatment of various cancers.     

Tridentate bipyrazole compounds with a side-arm as a new class of antitumor agents

Eight tridentate bipyrazole derivatives with different side arms have been prepared in one step and with good yields. The products were screened for their cytotoxic activity against three tumor cell lines—human breast cancer cell line MDA-MB231, human prostate cancer cell line PC3, and human colorectal cell line LoVo, by use of colorimetric MTT assay. Structure–activity relationships reflected the effect of substituted drugs. Among this series, two compounds had remarkable in-vitro antiproliferative activity against the LoVo cell line with IC50 values ranging from 2.6 to 2.7 μg ml^?1. All the compounds had suitable drug-like characteristics according to Lipinski’s rule.     

Açai (Euterpe oleracea Mart.) Seed Extract Induces ROS Production and Cell Death in MCF-7 Breast Cancer Cell Line

Euterpe oleracea Mart. (açai) is a native palm from the Amazon region. There are various chemical constituents of açai with bioactive properties. This study aimed to evaluate the chemical composition and cytotoxic effects of açai seed extract on breast cancer cell line (MCF-7). Global Natural Products Social Molecular Networking (GNPS) was applied to identify chemical compounds present in açai seed extract. LC-MS/MS and molecular networking were employed to detect the phenolic compounds of açai. The antioxidant activity of açai seed extract was measured by DPPH assay. MCF-7 breast cancer cell line viability was evaluated by MTT assay. Cell death was evaluated by flow cytometry and time-lapse microscopy. Autophagy was evaluated by orange acridin immunofluorescence assay. Reactive oxygen species (ROS) production was evaluated by DAF assay. From the molecular networking, fifteen compounds were identified, mainly phenolic compounds. The açai seed extract showed cytotoxic effects against MCF-7, induced morphologic changes in the cell line by autophagy and increased the ROS production pathway. The present study suggests that açai seed extract has a high cytotoxic capacity and may induce autophagy by increasing ROS production in breast cancer. Apart from its antioxidant activity, flavonoids with high radical scavenging activity present in açai also generated NO (nitric oxide), contributing to its cytotoxic effect and autophagy induction.     

Evaluation of novel coumarin-proline sulfonamide hybrids as anticancer and antidiabetic agents

Abstract

Cancer and diabetes are considered as two major diseases affecting human health worldwide. Various therapies are available for treatment of cancer and diabetes individually, peptide linkage containing proline sulfonamide can be a promising therapy for treatment of both cancer as well as diabetes. Here, we report design and synthesis of novel coumarin-proline sulfonamide derivatives as anticancer and antidiabetic agents. All the synthesized compounds were screened for their anticancer activity against lungs cancer cell line (A549) and breast cancer cell line (MCF7) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye (MTT)assay and antidiabetic activity using DPP-IV inhibition assay. Compound 16b showed excellent activity against breast cancer cell line (MCF7) with IC₅₀ value of 1.07?µM. All compounds showed moderate DPP-IV inhibition.     

Synthesis and evaluation of nitrate derivatives of colchicine as anticancer agents

To search for more potent antitumor agent,a series of novel nitric oxide-donating colchicine(Col) derivatives(6a-f,8a and b) were synthesized by coupling nitrates with N-methyl colchiceinamide.Their cytotoxicity against four human cancer cell lines in vitro were evaluated by MTT assay.It was found that many of the derivatives displayed significant activity,particularly,compounds 6c,8a and 8b showed more potent cytotoxic activities than Col.     

Zeolite-catalyzed synthesis of pyrazolo[1,2-<Emphasis Type="Italic">a</Emphasis>][1,2,4]triazole-1,3-dione derivatives as anti-breast cancer agents

A series of pyrazolo[1,2-a][1,2,4]triazole-1,3-dione derivatives were synthesized under the catalytic effect of Natrolite zeolite, and their cytotoxic effects on three human breast cancer cell lines viz. breast cancer (BT-474), triple negative breast cancer (MDA-MB 231), and breast carcinoma (MCF-7) were explored using MTT assay. Apoptotic effects of the compounds were investigated by western blot analysis on the caspase-3 protein. Moreover, we examined the level of reactive oxygen species in all three cell lines. The most promising compound, 7-Amino-1,3-dioxo-5-(4-nitrophenyl)-2-phenyl-1,2,3-trihydropyrazolo[1,2-a][1,2,4]triazole-6-carbonitrile (4c), showed high levels of cytotoxicity against all cell lines with IC₅₀ values of 2.3, 2.5 and 3 μg/ml, respectively.     

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.     

Synthesis and Biological Evaluation of a Novel Series of Chalcones Incorporated Pyrazole Moiety as Anticancer and Antimicrobial Agents

A newly synthesized series of chalcone derivatives containing pyrazole rings were synthesized and evaluated for their cytotoxic activities in vitro against several human cancer cell lines. Most of the prepared compounds showed potential cytotoxicity against human breast cancer cell lines MCF-7, HEPG-2, and HCT-116. Also the compounds were evaluated as antimicrobial agents. The three compounds 3, 4, and 5 were proved to be better anticancer agents than the positive standard doxorubicin with IC50 values (4.7, 4.4, and 3.9???g/ml) against the same human cancer cell lines, whereas compounds 5 and 6 showed the most active antimicrobial compounds in comparison to the other chalcones.     

Synthesis,Cytotoxic Activity Evaluation of Novel 1,2,3‐Triazole Linked Quinazoline Derivatives

A series of novel 1,2,3‐triazole‐quinazoline derivatives were synthesized in five steps starting from anthranilamide by conventional methods. All the title compounds 10a — 10r were evaluated for cytotoxic activity against four human cancer cell lines (MGC ‐803, EC ‐109, MCF ‐7 and HGC ‐27) using MTT assay in vitro . Some of the synthesized compounds exhibited moderate to potent activity against tested cancer cell lines. Among them, compounds 10 h and 10q exhibited excellent growth inhibition against HGC ‐27 and compound 10 m also possessed excellent activity against MCF ‐7, with IC₅₀ values less than 1 µmol/L. Especially, compound 10 h was more cytotoxic than 5‐fluorouracil against all tested four human cancer cell lines.     

Exploring the molecular basis for selective cytotoxicity of lamellarins against human hormone-dependent T47D and hormone-independent MDA-MB-231 breast cancer cells

Abstract  

The common structural requirements for cytotoxicity of lamellarins against two human breast cancer cell lines were determined using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Twenty lamellarins were selected to serve as the training set, whereas another group of six compounds were used as the test set. The best CoMFA and CoMSIA models for both cell lines yielded satisfactory predictive ability with r _cv² values in the range of 0.659–0.728. Additionally, the contour maps obtained from both the CoMFA and CoMSIA models agreed well with the experimental results and may be used in the design of more potent cytotoxic compounds for human breast cancers. Both analyses not only suggested structural requirements of various substituents around the lamellarin skeleton for their cytotoxic activity against both human breast cancer cell lines but also revealed the molecular basis for the differences between the saturated and unsaturated D-rings of the lamellarins.     

Biological Activity of an Epilobium angustifolium L. (Fireweed) Infusion after In Vitro Digestion

The biological activity of an in vitro digested infusion of Epilobium angustifolium (fireweed) was examined in a model system of intestinal epithelial and colon cancer tissues. The content of selected phenolic compounds in the digested aqueous extract of fireweed was determined using HPLC-ESI-QTOF-MS/MS. Biological activity was examined using the human colon adenocarcinoma cell lines HT-29 and CaCo-2 and the human colon epithelial cell line CCD 841 CoTr. Cytotoxicity was assessed by an MTT assay, a Neutral Red uptake assay, May-Grünwald-Giemsa staining, and a label-free Electric Cell-Substrate Impedance Sensing cytotoxicity assay. The effect of the infusion on the growth of selected intestinal bacteria was also examined. The extract inhibited the growth of intestinal cancer cells HT-29. This effect can be attributed to the activity of quercetin and kaempferol, which were the most abundant phenolic compounds found in the extract after in vitro digestion. The cytotoxicity of the fireweed infusion was dose-dependent. The highest decrease in proliferation (by almost 80%) compared to the control was observed in HT-29 line treated with the extract at a concentration of 250 μg/mL. The fireweed infusion did not affect the growth of beneficial intestinal bacteria, but it did significantly inhibit E. coli. The cytotoxic effect of the fireweed extract indicates that it does not lose its biological activity after in vitro digestion. It can be concluded that the fireweed infusion has the potential to be used as a supporting agent in colon cancer therapy.     

Design,Synthesis and Cytotoxicity of Thiazole-Based Stilbene Analogs as Novel DNA Topoisomerase IB Inhibitors

A series of new thiazole-based stilbene analogs were designed, synthesized and evaluated for DNA topoisomerase IB (Top1) inhibitory activity. Top1-mediated relaxation assays showed that the synthesized compounds possessed variable Top1 inhibitory activity. Among them, (E)-2-(3-methylstyryl)-4-(4-fluorophenyl)thiazole (8) acted as a potent Top1 inhibitor with high Top1 inhibition of ++++ which is comparable to that of CPT. A possible binding mode of compound 8 with Top1–DNA complex was further provided by molecular docking. An MTT assay against human breast cancer (MCF-7) and human colon cancer (HCT116) cell lines revealed that the majority of these compounds showed high cytotoxicity, with IC₅₀ values at micromolar concentrations. Compounds 8 and (E)-2-(4-tert-butylstyryl)-4-(4-fluorophenyl)thiazole (11) exhibited the most potent cytotoxicity with IC₅₀ values of 0.78 and 0.62 μM against MCF-7 and HCT116, respectively. Moreover, the preliminary structure–activity relationships of thiazole-based stilbene analogs was also discussed.     

Synthesis of chalcones with anticancer activities

Several chalcones were synthesized and their in vitro cytotoxicity against various human cell lines, including human breast adenocarcinoma cell line MCF-7, human lung adenocarcinoma cell line A549, human prostate cancer cell line PC3, human adenocarcinoma cell line HT-29 (colorectal cancer) and human normal liver cell line WRL-68 was evaluated. Most of the compounds being active cytotoxic agents, four of them with minimal IC?? values were chosen and studied in detail with MCF-7 cells. The compounds 1, 5, 23, and 25 were capable in eliciting apoptosis in MCF-7 cells as shown by multiparameter cytotoxicity assay and caspase-3/7, -8, and -9 activities (p < 0.05). The ROS level showed 1.3-fold increase (p < 0.05) at the low concentrations used and thus it was concluded that the compounds increased the ROS level eventually leading to apoptosis in MCF-7 cells through intrinsic as well as extrinsic pathways.     

Chemical composition and biological evaluation of the volatile constituents from the aerial parts of Nephrolepis exaltata (L.) and Nephrolepis cordifolia (L.) C. Presl grown in Egypt

The essential oil from the aerial parts of Nephrolepis exaltata and Nephrolepis cordifolia obtained by hydro-distillation were analyzed by gas chromatography/ mass spectrometry. The essential oils exhibited potential antibacterial and antifungal activities against a majority of the selected microorganisms. NEA oil showed promising cytotoxicity in breast, colon and lung carcinoma cells. The results presented indicate that NEA oil could be useful alternative for the treatment of dermatophytosis.

Comparative investigation of hydro-distilled volatile constituents from aerial parts (A) of Nephrolepis exaltata (NE) and Nephrolepis cordifolia (NC) (Family Nephrolepidaceae) was carried out. Gas chromatography/mass spectrometry revealed that oils differ in composition and percentages of components. Oxygenated compounds were dominant in NEA and NCA. 2,4-Hexadien-1-ol (16.1%), nonanal (14.4%), β-Ionone (6.7%) and thymol (2.7%) were predominant in NEA. β-Ionone (8.0%), eugenol (7.2%) and anethol (4.6%) were the main constituents in NCA. Volatile samples were screened for their antibacterial and antifungal activities using agar diffusion method and minimum inhibitory concentrations. The cytotoxic activity was evaluated using viability assay in breast (MCF-7), colon (HCT-116) and lung carcinoma (A-549) cells by the MTT assay. The results revealed that NEA oil exhibited potential antimicrobial activity against most of the tested organisms and showed promising cytotoxicity.