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Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC50 of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC50 = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC50 = 0.093 µM) compared to Sorafenib (IC50 = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds. [ABSTRACT FROM AUTHOR]

Two new alliacane sesquiterpenes, named purpuracolide B (1) and purpuracolide C (2), have been isolated from the fruiting bodies of edible mushroom Gomphus purpuraceus. Their structures were elucidated based on spectroscopic studies including electronic circular dichroism calculation. Furthermore, their antiproliferative effects were evaluated in breast cancer cells MCF7, MDA-MB-231 and 4T1. [Display omitted] • Two new alliacane sesquiterpenes were isolated from edible mushroom Gomphus purpuraceus. • The structures were determined by MS data, NMR spectroscopy and ECD. • New compounds showed no inhibitory activity against three breast cancer cell lines. [ABSTRACT FROM AUTHOR]

A series of novel 4,6,7-substituted quinazoline derivatives were designed, synthesized and evaluated for their antiproliferative activities against human cancer cell lines (PC-3, MGC-803, HGC-27, A549 and H1975). Among all the target compounds, compound 22s displayed the most potent anti-proliferative activity against MGC-803 cells in vitro. Further mechanism studies revealed that compound 22s could obviously inhibit the colony formation and migration of MGC-803 cells. At the same time, compound 22s could induced apoptosis of MGC-803 cells and induced cell cycle arrest at G1-phase. Collectively, those work suggested that compound 22s might be a valuable solution to optimize anilinoquinazoline-based antineoplastic agents. [ABSTRACT FROM AUTHOR]

Moringa oleifera leaf polyphenols (Mopp) were encapsulated with phytosomes to enhance their efficacy on 4T1 cancer cell lines. The Mopp were extracted via microwave-assisted extraction. Moringa oleifera polyphenol-loaded phytosomes (MoP) were prepared with the nanoprecipitation method and characterized using the dynamic light scattering and dialysis membrane techniques. The in vitro cytotoxic and antiproliferative activity were investigated with the (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazole) MTT assay. Acute toxicity was assessed using Swiss albino mice. An MoP particle size of 296 ± 0.29 nm, −40.1 ± 1.19 mV zeta potential, and polydispersity index of 0.106 ± 0.002 were obtained. The total phenolic content was 50.81 ± 0.02 mg GAE/g, while encapsulation efficiency was 90.32 ± 0.11%. The drug release profiles demonstrated biphasic and prolonged subsequent sustained release. In vitro assays indicated MoP had a low cytotoxicity effect of 98.84 ± 0.53 μg/mL, doxorubicin was 68.35 ± 3.508, and Mopp was 212.9 ± 1.30 μg/mL. Moreover, MoP exhibited the highest antiproliferative effect on 4T1 cancer cells with an inhibitory concentration of 7.73 ± 2.87 μg/mL and selectivity index > 3. The results indicated a significant difference (p ≤ 0.001) in MoP when compared to Mopp and doxorubicin. The in vivo investigation showed the safety of MoP at a dose below 2000 mg/kg. The present findings suggest that MoP may serve as an effective and promising formulation for breast cancer drug delivery and therapy. [ABSTRACT FROM AUTHOR]

Four new drimane sesquiterpenoids (1–4) and three known ones (5–7) were isolated from the fermentation broth of the mangrove-derived Aspergillus ustus 094102. Compound 5 was further resolved as four purified compounds 5a–5d. By means of extensive spectroscopic and ECD analysis as well as the chemical transformation, their structures were identified as (2R,3R,5S,9R,10S)-2,3,9,11-tetrahydroxydrim-7-en-6-one (ustusol F, 1), (2R,3R,5R,9S,10R)-2,3,11-trihydroxydrim-7-en-6-one (9-deoxyustusol F, 2), (3S,5R,9R,10R)-3,11,12-trihydroxydrim-7-en-6-one (ustusol G, 3), (5S,6R,9S,10S, 11R,2′E,4′E)-(11-dideoxy-11-hydroxystrobilactone A-6-yl)-5-carboxypenta-2,4-dienoate (ustusolate H, 4), ((5S,6R,9S,10S)-strobilactone A-6-yl) (2E,4E)-6,7-dihydroxyocta-2,4-dienoate (ustusolate I, 5), (2′E,4′E;6′,7′-erythro)-ustusolate I (5a) and (2′E,4′E;ent-6′,7′-erythro)-ustusolate I (5b), (2′E,4′E,6′R,7′R)-ustusolate I (5c) and (2′E,4′E,6′S,7′S)-ustusolate I (5d), (5S,6R,9S,10S,2′E,4′E)-(strobilactone A-6-yl)-5-carboxypenta-2,4-dienoate (ustusolate J, 6), and (2S,5S,9R,10S)-2,9,11-trihydroxydrim-7-en-6-one (ustusol B, 7), respectively. Compound 5 showed antiproliferation against the human tumor cells CAL-62 and MG-63 with the IC50 values of 16.3 and 10.1 µM, respectively. [ABSTRACT FROM AUTHOR]

Hypoxia‐mimicking agents (HMAs) are molecules or compounds used to mimic hypoxia via the activation of the hypoxia‐inducible factor (HIF) pathway. HMAs have been reported to exert both pro‐ and anti‐proliferative in human breast cancer cell lines, although the reason for such dichotomy remains unclear. To investigate this, we first studied the proliferative effects of HMAs using metabolic‐based MTT assay in comparison to manual cell counting. The MTT assay did not reproduce the results from manual cell counting, suggesting that such metabolic‐based assays are unreliable in studies involving the hypoxia pathway. Next, using the manual cell counting method, we investigated the effects of HMAs with distinct mechanisms of action, including IOX2, a well‐characterised and selective inhibitor of the HIF prolyl‐hydroxylases (PHDs). All tested HMAs inhibit proliferation of MCF7 cells but induced proliferation of MDA‐MB‐231 cells to a certain extent. The results show that the HMAs affect proliferation of human breast cancer cells, likely via upregulation of HIF. The effects of HIF activation on cancer cell proliferation are important given the ongoing clinical trials of inhibitors targeting the PHDs for the treatment of anaemia. [ABSTRACT FROM AUTHOR]

Lung cancer continues to be the world's leading cause of cancer death and the treatment of non-small cell lung cancer (NSCLC) has attracted much attention. The tubers of Bletilla striata are regarded as "an excellent medicine for lung diseases" and as the first choice to treat several lung diseases. In this study, seventeen phenanthrene derivatives, including two new compounds (1 and 2), were isolated from the tubers of B. striata. Most compounds showed cytotoxicity against A549 cells. An EdU proliferation assay, a cell cycle assay, a wound healing assay, a transwell migration assay, a flow cytometry assay, and a western blot assay were performed to further investigate the effect of compound 1 on A549 cells. The results showed that compound 1 inhibited cell proliferation and migration and promoted cell apoptosis in A549 cells. The mechanisms might correlate with the regulation of the Akt, MEK/ERK, and Bcl-2/Bax signaling pathways. These results suggested that the phenanthrenes of B. striata might be important and effective substances in the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

A series of diphenyl-N-heteroaromatic compounds were designed, synthesized, and evaluated for anticancer efficacies (antimigration and antiproliferation) against human cancer cell lines. The favorable 2H-1,2,3-triazole compound 4a was optimized, leading to the discovery of compounds 4b and 4c with more potent antimigratory and antiproliferative activities. The transwell assay showed that compounds 4b and 4c dose-independently inhibited the migration of the two cancer cell lines (human breast cancer cell line MDA-MB-231 and pancreatic cancer cell line PANC1) with the low IC50 values of 0.24 and 0.47 µM, respectively. The sulforhodamine-B (SRB) assay showed that compounds 4b and 4c inhibited the proliferation of PANC1 cells with the IC50 values 0.86 µM and 1.41 µM, respectively. These results indicate that compounds 4b and 4c with 1,2,3-triazole scaffold may be further developed as potent anticancer agents in the future. [ABSTRACT FROM AUTHOR]

Research on multitargeting drugs is emerging, focusing on the discovery of agents that simultaneously act on more than one biological target. Here, a novel synthetic route to access the fused-heterocycles 1,4-dihydropyrazolo[4,3- b ]indoles (4) from pyrazolo[4,3- c ][2,1]benzothiazine 4,4-dioxide (3) via [H2O–SO2] elimination and an intramolecular ring-closing reaction is reported. Two lead compounds 3b and 4b were found to show significant inhibition of cell growth by suppressing cell cycle progression at the G0/G1 phases and inducing apoptosis of the acute myeloid leukemia OCI-AML3 cell line. Both compounds also significantly decreased tumor necrosis factor-α and transforming growth factor-β (at all tested concentrations), whereas no effect was seen on other cytokines (interleukin-4, interferon-γ, interleukin-9, interleukin-12). Thus, these compounds are promising leads in the discovery of novel anticancer agents. [ABSTRACT FROM AUTHOR]

BackgroundFrom the earliest times, manna has been widely used as a tasty local sweet or folk medicine. The type of manna being investigated in the present study is called Gaz-alafi, a mixture of insect and Quercus brantii leaves secretions from oak forests in the north of Iraq and west of Iran.MethodsAqueous and ethanol extracts were prepared as decoction. Various phytochemical tests were conducted to analyze manna composition, including total phenolic contents using the Folin-Ciocalteu method and LC-MS. Gallic acid and catechin were detected in both extracts, in addition to tiliroside presence in ethanol extract, which added more value to the phenolic content of ethanol extract. Cytotoxic activities of Gaz alafi were evaluated against breast cancer cell lines and compared to normal cell lines and doxorubicin using the MTT assay. Antimicrobial properties were assessed against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, and Candida albicans using the dilution method of the micro-titer plate. Serum levels of IFN-γ, interleukin-2 (IL-2), interleukin-4 (IL-4), and interleukin-10 (IL-10) were measured using ELISA. The effect of extracts on splenocyte proliferation was evaluated using the lymphocytes proliferation assay. Macrophage function was evaluated using the nitro blue tetrazolium assay, whereas pinocytosis was evaluated using the neutral red uptake assay. Ten days after tumor inoculation, changes in tumor size, survival rates, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine were measured.ResultsThe growth of cancer cells was inhibited by Gaz alafi ethanol extract. An alteration in IFN- γ, IL-2, and IL-4 levels toward antiproliferation immune response were reported for both extracts. The aqueous extract efficiently stimulated lymphocyte proliferation, phagocytosis, and pinocytosis, followed by the ethanol extracts with moderate activity. After treating the mice with ethanol extracts, a significant reduction in tumor size and several undetected tumors were recorded.ConclusionsGaz alafi extracts (aqueous and ethanol) are promising sources for anticancer and immunostimulatory agents. Further studies are needed to fully identify the chemical composition of Gaz alafi extracts.

Eucommia ulmoides Oliver bark is a potential medicinal plant-based feedstock for bioactive products and possesses the effective functions of antioxidant and antitumor. Network pharmacology was employed to reveal the oxidative and free radical damage and cancer-related potential compounds of Eucommia ulmoides Oliver in this study. The result showed that quercetin might be the key compound to resist these two types of diseases. Then, the effect of steam explosion on the release of bioactive compounds and the antioxidative and antiproliferative properties of the extract from Eucommia ulmoides Oliver bark were investigated. Results showed that steam explosion at 0.7 MPa for 30 min significantly enhanced the total phenolic, total flavonoids, and quercetin content of Eucommia ulmoides Oliver bark. Reducing power and 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging activity of the steam-exploded extracting solution were 1.72 and 2.76 times of native. The antiproliferative activity to CT26 and HepG2 of the extract from steam-exploded Eucommia ulmoides Oliver bark (SEU) was higher than those of native-exploded Eucommia ulmoides Oliver bark (NEU). All these results suggested that steam explosion could be applied to release the bioactive compounds, thus enhanced the antioxidative and antiproliferative activities of medicinal and edible plant-based sources.

Abstract Background AdipoR2, which belongs to the seven-transmembrane-domain receptor family, has been shown to play an important role in the development of human tumours, but the underlying mechanisms are poorly understood. In this study, we found that AdipoR2 expression correlates with glioma grade. In addition, we also investigated the mechanisms behind the antiproliferative effects of AdipoR2 in U251 cells (a human glioma cell line) using colony formation and WST-8 growth assays. Methods The U251 cell line was cultured in vitro. Western blotting was used to detect the expression of relevant proteins. Quantitative RT-PCR was used to detect AdipoR1 and AdipoR2 expression. Flow cytometry was used to detect cell cycle assay results. The gene expression profiles of glioma samples from the CGGA database were analysed by MATLAB and GSEA software. Results The AMPK/mTOR pathway plays a central role in the regulation of cell proliferation, differentiation and migration and may promote tumorigenesis. Therefore, we can control cancer progression by modulating the AMPK/mTOR pathway. However, there is no information on the relationship between AdipoR and AMPK/mTOR in central nervous system tumours such as GBM. In this study. We found 648 upregulated genes and 436 downregulated genes correlated with AdipoR2 expression in 158 glioma samples. GSEA suggested that AdipoR2 is a cell cycle-associated gene. The results of the flow cytometry analysis indicated that AdipoR2 induced G0/G1 cell cycle arrest in U251 cells. Furthermore, we identified the AMPK/mTOR signalling axis to be involved in AdipoR2-induced cell cycle arrest. Conclusions Our results suggest that AdipoR2 may represent a novel endogenous negative regulator of GBM cell proliferation. These findings also suggest that AdipoR2 may be a promising therapeutic target in GBM patients.

In this paper, we investigate the structural and biological features of G-quadruplex (G4) aptamers as promising antiproliferative compounds affecting the STAT3 signalling pathway. Targeting the STAT3 protein through high-affinity ligands to reduce its levels or activity in cancer has noteworthy therapeutic potential. T40214 (STAT) [(G3C)4] is a G4 aptamer that can influence STAT3 biological outcomes in an efficient manner in several cancer cells. To explore the effects of an extra cytidine in second position and/or of single site-specific replacements of loop residues in generating aptamers that can affect the STAT3 biochemical pathway, a series of STAT and STATB [GCG2(CG3)3C] analogues containing a thymidine residue instead of cytidines was prepared. NMR, CD, UV, and PAGE data suggested that all derivatives adopt dimeric G4 structures like that of unmodified T40214 endowed with higher thermal stability, keeping the resistance in biological environments substantially unchanged, as shown by the nuclease stability assay. The antiproliferative activity of these ODNs was tested on both human prostate (DU145) and breast (MDA-MB-231) cancer cells. All derivatives showed similar antiproliferative activities on both cell lines, revealing a marked inhibition of proliferation, particularly at 72 h at 30 µM. Transcriptomic analysis aimed to evaluate STAT’s and STATB’s influence on the expression of many genes in MDA-MB-231 cells, suggested their potential involvement in STAT3 pathway modulation, and thus their interference in different biological processes. These data provide new tools to affect an interesting biochemical pathway and to develop novel anticancer and anti-inflammatory drugs.

Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound LHQ490 potently inhibited FGFR2 kinase activity with an IC 50 of 5.2 nM, and was >61-, >34-, and >293-fold selective against FGFR1, FGFR3, and FGFR4, respectively. LHQ490 also exhibited high selectivity in a panel of 416 kinases. Cell-based studies revealed that LHQ490 efficiently suppressed the proliferation of BaF3-FGFR2 cells with an IC 50 value of 1.4 nM, and displayed >70- and >714-fold selectivity against BaF3-FGFR1 and the parental BaF3 cells, respectively. More importantly, LHQ490 potently suppressed the FGFR2 signaling pathways, selectively inhibited FGFR2-driven cancer cell proliferation, and induced apoptosis of FGFR2-driven cancer cells. Taken together, this study provides a potent and highly selective FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents. [Display omitted] • 34 new FGFR2 inhibitors were designed, synthesized and evaluated. • LHQ490 selectively inhibited FGFR2 kinase activity with an IC 50 of 5.2 nM. • LHQ490 selectively suppressed the proliferation of FGFR2-driven cancer cells. [ABSTRACT FROM AUTHOR]

A marine specimen of the Red Sea soft coral Dendronephthya sp. was extracted with a mixture of n-hexane, diethyl ether, and methanol. One new cytotoxic steroid dendronestadione (1), five known steroids: dendronesterones A-C (2–4), dendrotriol (5), and cholesterol (6) along with 4-oxo-pentanoic acid (7) and a polyhydroxy alkane hexitol (8) were isolated from the Dendronephthya sp. extract. The chemical structures of the isolated metabolites were elucidated by the application of several spectroscopic techniques (1D, 2D NMR, IR, and UV) and mass spectrometry. The antiproliferative effect of the isolated compounds was assessed against a panel of human cancer cell lines including HepG2, HT-29, and PC. The obtained results indicated that compounds 1–4 (dendronesterones A–C) exhibited a higher cytotoxic effect than that of the other co-isolated ones. Among all examined dendronesterones, dendronesterone C showed the highest IC50 values of 19.1 ± 1.81, 32.4 ± 2.84, and 7.8 ± 0.80 µM against the three cancer cells under investigation. Interestingly, all isolated ketosteroids showed potent effects against prostate cancer cells. These findings highlight the role of ketosteroids as an antiproliferative agent against the examined cells in this study.

Comprehensive Summary: Metallodrugs with fine‐tuned coordination between metals and bioactive ligands can achieve cytotoxic effects in cancer therapy and have been considered as a new approach for drug design. However, it has yet to be elucidated whether these metallodrugs target epitranscriptomic proteins for gene expression regulation. This report describes a rhein‐based Rh(III)‐arene complex, Rh1, that exhibited promising antiproliferative effects in several tumor cell lines. Rh1 induced cell death through the autophagy, cell cycle arrest, and accumulation of intracellular reactive oxygen species (ROS). In addition, Rh1 upregulated the global N6‐methyladenosine (m6A) levels in A549 cells in the fat mass‐ and obesity‐associated protein (FTO)‐dependent manner. Collectively, the metal‐based FTO inhibitor Rh1 effectively suppressed tumor cell proliferation and modulated the abundance of cellular m6A, highlighting the potential of metal‐based agents to target and regulate epitranscriptomics for tumor suppression. [ABSTRACT FROM AUTHOR]

Novel 4-amino-thieno[2,3-d]pyrimidine-6-carboxylates substituted at the second position were prepared by cyclocondensation of 2-amino-3-cyano-thiophene and aryl nitriles in an acidic medium. The design of the target compounds was based on structural optimization. The derivatives thus obtained were tested in vitro against human and mouse cell lines. The examination of the compound effects on BLAB 3T3 and MFC-10A cells showed that they are safe, making them suitable for subsequent experiments to establish their antitumor activity. The photoirritancy factor of the compounds was calculated. Using the MTT test, the antiproliferative activity to MCF-10A, MCF-7 and MDA-MB-231 cell lines was estimated. The best antiproliferative effect in respect to the MCF-7 cell line revealed compound 2 with IC50 4.3 ± 0.11 µg/mL (0.013 µM). The highest selective index with respect to MCF-7 cells was shown by compound 3 (SI = 19.3), and to MDA-MB-231 cells by compound 2 (SI = 3.7). Based on energy analysis, the most stable conformers were selected and optimized by means of density functional theory (DFT). Ligand efficiency, ligand lipophilicity efficiency and the physicochemical parameters of the target 4-amino-thienopyrimidines were determined. The data obtained indicated that the lead compound among the tested substances is compound 2. [ABSTRACT FROM AUTHOR]

Protein hydrolysates from various sources, including tuna cooking juice, soy protein isolate, sodium caseinate, wheat gluten and skin gelatin from porcine, tilapia, halibut and milkfish were analyzed to screen their antiproliferative activities against the human oral squamous carcinoma cell line, HSC-3. The soy protein isolate was selected for further investigations based on its hydrolysates with bromelain (SB) and thermolysin (ST), showing the greatest inhibition of cell growth. The SB and ST hydrolysates showed antiproliferative activities up to 35.45–76.39% against HSC-3 cells at 72 h, and their IC50 values were 0.74 and 0.60 mg/mL, respectively. SB and ST induced cell cycle arrest in the S phase through a pathway independent of p21 and p27 protein expression. Further, ST induced the apoptosis of HSC-3 cells by downregulating expression of Bcl-2, PARP, caspase 3 and caspase 9, but an upregulating expression of p53 and cleaved caspase 3. Unlike ST, SB may induce necrosis on HSC-3 cells. Thus, soybean hydrolysates may be a good source for providing antiproliferative peptides against HSC-3, while SB and ST may have the potential to be developed as functional foods. [ABSTRACT FROM AUTHOR]

Cedrus atlantica is a tree species found in Morocco with many clinical benefits in genitourinary, musculoskeletal, and skin systems. Previous studies have reported that extracts of Cedrus atlantica have antioxidant, antimicrobial, and anticancer properties. However, its role in colorectal cancer (CRC) remains unclear. The present study investigated the effects and underlying mechanisms of Cedrus atlantica extract (CAt) using HT‐29 (human colorectal adenocarcinoma) and CT‐26 CRC cell lines. The 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay was performed to measure cell viability. Flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL) assay were used to study the cell cycle and cell apoptosis, respectively. The expression of cell cycle and apoptosis‐associated proteins was detected by western blotting or immunohistochemical (IHC) staining. CAt showed significant inhibitory effects on the proliferation of HT‐29 and CT‐26 cells, and combined with the clinical drug, 5‐fluorouracil (5‐FU), exhibited synergistic effects. CAt induced cell cycle arrest at the G0/G1 phase through the upregulation of p53/p21 and the downregulation of cyclin‐dependent kinases (CDKs)/cyclins. In addition, CAt‐treated cells exhibited chromatin condensation, DNA fragmentation, and apoptotic bodies, which are typical characteristics of apoptosis activated via both the extrinsic (Fas ligand (FasL)/Fas/caspase‐8) and intrinsic (Bax/caspase‐9) pathways. Importantly, CAt suppressed tumor progression and prolonged the life span of mice within a well‐tolerated dose. Therefore, our findings provide novel insights into the use of CAt for the treatment of CRC. [ABSTRACT FROM AUTHOR]

One new clerodane-type furanoditerpenoid tinosinoid A (1) and nine new nor-clerodane analogs tinosinoids B–J (2−10) have been isolated from the stems of Tinospora sinensis. The structures of the new compounds with absolute configurations have been elucidated by spectroscopic means, including MS, NMR and ECD techniques, as well as chemical correlation. Compound 1 is a rare sulfur-containing clerodane diterpenoid incorporating a 2-mercaptoethanol unit via a thioether bond, while compounds 4/5 and 9 represent two pairs of unusual equilibrium regioisomers through an interesting intramolecular transesterification. Our bioassays established that 1 and 8 displayed moderate antiproliferative effects against two human tumor cell lines, and 9 and 10 showed significant α-glucosidase inhibitory activities. A kinetics study revealed that compound 10 was a noncompetitive α-glucosidase inhibitor, and its possible binding mode to the enzyme was further probed by molecular docking experiments. [ABSTRACT FROM AUTHOR]

SK2, a nitrated [6,6,6]tricycle derivative with an n-butyloxy group, showed selective antiproliferation effects on oral cancer but not on normal oral cells. This investigation assessed for the first time the synergistic antiproliferation potential of cisplatin/SK2 in oral cancer cells. Cell viability assay at 24 h showed that a low dose of combined cisplatin/SK2 (10 μM/10 μg/mL) provided more antiproliferation than cisplatin or SK2 alone. Cisplatin/SK2 triggered also more apoptosis inductions in terms of subG1 accumulation, annexin V, pancaspase, and caspase 3/8/9 measurements. Moreover, cisplatin/SK2 provided more oxidative stress and DNA damage in oral cancer cells than independent treatments. Oxidative stress inhibitors rescued the cisplatin/SK2-induced antiproliferation and oxidative stress generation. Moreover, cisplatin/SK2 induced more antiproliferation, apoptosis, oxidative stress, and DNA damage in oral cancer cells than in normal oral cells (S-G). In conclusion, low-dose cisplatin/SK2 combined treatment promoted selective and synergistic antiproliferation in oral cancer cells depending on oxidative-stress-associated responses. [ABSTRACT FROM AUTHOR]

Cancer progression is linked to abnormal epigenetic alterations such as DNA methylation and histone modifications. Since epigenetic alterations, unlike genetic changes, are heritable and reversible, they have been considered as interesting targets for cancer prevention and therapy by dietary compounds such as luteolin. In this study, epigenetic modulatory behaviour of luteolin was analysed on HeLa cells. Various assays including colony forming and migration assays, followed by biochemical assays of epigenetic enzymes including DNA methyltransferase, histone methyl transferase, histone acetyl transferase, and histone deacetylases assays were performed. Furthermore, global DNA methylation and methylation-specific PCR for examining the methylation status of CpG promoters of various tumour suppressor genes (TSGs) and the expression of these TSGs at transcript and protein level were performed. It was observed that luteolin inhibited migration and colony formation in HeLa cells. It also modulated DNA methylation at promoters of TSGs and the enzymatic activity of DNMT, HDAC, HMT, and HAT and reduced the global DNA methylation. Decrease in methylation resulted in the reactivation of silenced tumour suppressor genes including FHIT, DAPK1, PTEN, CDH1, SOCS1, TIMPS, VHL, TP53, TP73, etc. Hence, luteolin-targeted epigenetic alterations provide a promising approach for cancer prevention and intervention. [ABSTRACT FROM AUTHOR]

Among all cancers, the global incidence rate of breast cancer is the highest. Novel chemotherapeutic agents are needed to improve the existing chemotherapy outcomes and to reduce the toxic side effects. 10-hydroxy- 2-decenoic acid (10-H2DA), a royal jelly acid, had been reported to have anti-inflammatory, anti-tumor, and antimetastasis activities. This study aimed to investigate anti-proliferative efficacy and the underlying mechanisms of 10-H2DA co-treatment with doxorubicin (DXR), a chemotherapeutic compound, in MCF-7 breast cancer cells. MTS assay was conducted to determine cell viability. Cell cycle progression and cell apoptosis were detected by flow cytometry. Pivotal protein expressions were determined by Western blot. Results revealed that the 125 µg/ml 10- H2DA co-treatment with the 0.54 µg/ml DXR synergistically and significantly inhibited cancer cell growth up to 79%, compared with the medium control (p < 0.05); it was 1.6-fold higher than the DXR treatment alone. The underlying mechanisms involved extensive suppression of oncoprotein c-MYC/BAX and activation of tumor suppressor The two mechanisms led to G1/S cell cycle arrest, cell apoptosis, and shortened lifespan. The activations of HO-1/BAX and p53/BAX while suppressing NRF2/BAX expression suggested induction of cell ferroptosis. Our findings suggest that the 10-H2DA in adjunct to the DXR is a promising novel candidate for breast cancer treatment via extensive decrease in C-MYC/BAX, increase in p53/BAX, cell cycle arrest, and cell apoptosis. Further in vivo mechanistic studies are necessary to validate its benefits. [ABSTRACT FROM AUTHOR]

Aloysia citrodora (Verbenaceae) is traditionally used to treat various diseases, including bronchitis, insomnia, anxiety, digestive, and heart problems. In this study, this plant's antioxidant and anti-proliferation effects were evaluated. In addition to volatiles extraction, different solvent extracts were prepared. The GC-MS, LC-MS analysis and the Foline-Ciocalteu (F-C) method were used to investigate the phytochemical components of the plant. MTT assay was used to measure the antiproliferative ability for each extract. Antioxidant activity was determined using the 2,2-diphenylpicrylhydrazyl (DPPH) assay. In in vivo anti-proliferation experiments, Balb/C mice were inoculated with tumor cells and IP-injected with ethyl acetate extract of A. citrodora. After treatment, a significant reduction in tumor size (57.97%) and undetected tumors (44.44%) were obtained in treated mice, demonstrating the antiproliferative efficacy of the ethyl acetate extract. Besides, ethanol extract revealed the most potent radical scavenging effect. The findings of this study displayed that A. citrodora has promising cytotoxic and antioxidant activities. Still, further testing is required to investigate the extract's chemical composition to understand its mechanisms of action. [ABSTRACT FROM AUTHOR]

Objective: To investigate the cytotoxic activity and molecular mechanism(s) of two Thai noni juice (TNJ) products ethanolic extracts against cholangiocarcinoma (CCA) cell lines and non-cancerous cells, and to explore phenolic acid compositions of TNJ products. Methods: Phenolic acid profiles of TNJ Chiangrai (TNJ-Cr) and TNJ Buasri (TNJ-Bs) ethanolic extracts were determined by HPLC. The cytotoxicity of TNJ ethanolic extracts on cancer and non-cancerous cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and trypan blue assays. Mechanism(s) underlying the anti-CCA activity of TNJ ethanolic extracts were determined by cell cycle, apoptosis, and reactive oxygen species (ROS) generation assays. The expression levels of proteins involved in apoptosis and ERK signaling were evaluated by Western blot analysis. Results: Phenolic acid profiles of both TNJ ethanolic extracts showed that the p-hydroxybenzoic, vanillic, and protocatechuic acids were the major phenolic acids in TNJ products. Cytotoxicity assays revealed that the TNJ-Cr and TNJ-Bs ethanolic extracts reduced viability of CCA cell lines through induction of apoptosis by up-regulation of p53 and Bax proapoptotic proteins. Both TNJ ethanolic extracts promoted ROS generation by activating the ERK1/2 signaling in well-differentiated CCA cells KKU-213B. Meanwhile, TNJ ethanolic extracts did not induce ROS production in poorly differentiated CCA cells KKU-100. Both TNJ ethanolic extracts showed no toxicity to human peripheral blood mononuclear cells. Conclusions: TNJ ethanolic extracts could inhibit CCA cell proliferation by inducing ROS generation and apoptosis and may be applicable for combination therapies in CCA treatment.

Phenformin has been recognized as a drug with anti‐ proliferative potential. Due to its excellent pharmaceutical parameters, its structure was modified based on the principle of intermediate derivatization, and the influence of different substituents of phenformin and its position on the benzene ring on its antiproliferative activity was discussed. In this study, 15 phenformin derivatives with different substituents were synthesized by inserting electron‐withdrawing or electron‐donating groups on the different positions of phenyl side of phenformin, and screened for their antiproliferative activities. It was found that the introduction of electron‐donating substituents slightly improves the antiproliferative activity of phenformin, however, the introduction of −Cl and −OCF3 substituents significantly increased the antiproliferative activity of phenformin with N‐l‐(2‐chloro) phenethylbiguanide (2B), the best antiproliferative activity compound. Western blot assay and the molecular docking studies demonstrated that 2B activates AMPK. [ABSTRACT FROM AUTHOR]

The diastereoselective domino‐Knoevenagel‐IMHDA reactions of 5,6‐dihydro‐2H‐pyran derivatives containing an o‐formylaryl amine or ether moiety were performed with active methylene reagents. In the spiro heterocyclic products representing a novel skeleton, a tetrahydroquinoline or chroman unit is fused with two pyran rings and the bridgehead carbon atoms are chirality centers formed diastereoselectively. Depending on the substitution pattern, a domino Knoevenagel‐[1,5]‐hydride shift‐cyclization sequence was identified as a competing pathway, which resulted in the formation of tetrahydroquinoline derivatives with a 5,6‐dihydro‐2H‐pyran‐3‐yl substituent. The relative configurations of the products were determined by means of the characteristic NOE correlations and single crystal X‐ray diffraction analysis. Antiproliferative activity assays of two products against A2780 and WM35 human cancer cell lines showed low micromolar IC50 values down to 2.99 μM. [ABSTRACT FROM AUTHOR]

Red yeast rice (RYR), commonly known as angkak, is a functional food fermented by rice using Monascus mushrooms. It has a pigment and flavonoid content that is useful as an antioxidant and plays a role in preventing cancer or tumors. This analysis aims to test the antiproliferation activity of commercial RYR fractions of water and ethyl acetate against Miyazaki Canine Mammary Gland Tumor-Bambang 2 (MCM-B2) breast tumor cells. Research on RYR antiproliferation of cancer-sustaining MCM-B2 cells has not been previously released. In the preliminary study, the antiproliferation bioactivity was measured using the brine shrimp lethality test. The outcome of the brine shrimp lethality test showed that ethyl acetate and water fraction cytotoxicity were more than 1000 ppm and 337.07 ppm, respectively, at a lethal concentration of 50. Antiproliferative activity analyses were performed using direct hemocytometer counting. The antiproliferation activity data collected were analyzed using one-way ANOVA and Duncan continuous testing. The outcome showed that the water and ethyl acetate RYR antiproliferation activity against MCM B2 cancer cells correlated positively with the increasing concentration of each fraction. Ethyl acetate and water fractions at concentrations of 350 ppm may inhibit the growth of MCM-B2 cancer cells in vitro, reaching 42.63 percent and 39.84 percent, respectively, not significantly different (P < 0.05) with a positive doxorubicin control of 41.24 percent. In conclusion, the ethyl acetate and water fraction of RYR have potent antiproliferation activity against MCM-B2 breast tumor cells.

Background and Aim: Tumor disorder is one of the degenerative diseases that affected human and animals and recently is tend to increase significantly. The treatment of tumor diseases can be performed through surgical, chemotherapy, radiotherapy, biological substances, and herbs medicine. Typhonium flagelliforme leaves extract known to have an antiproliferation activity, while interferons (IFNs) one of the cytokines that first used as an antiviral agent was also known to have antitumor activity. Nowadays, the treatment of tumors using a traditional way, including the use of herbal substances, becomes popular. Some limitations of the antitumor activity due to resistant development of the cell to some substances were one of the problems on why the treatment of cancer was unsuccessful. This study aimed to elaborate the synergistic effect on the antiproliferation and anti-angiogenesis activities of the combinations between T. flagelliforme leaves ethanol extract and canine natural (natural canine IFN [nCaIFN]) and recombinant (recombinant canine IFN [rCaIFN]) IFNs on tumor-derived cell lines to find the new potential antitumor substances. Materials and Methods: The extraction of T. flagelliforme leaves was performed using the maceration method and followed by phytochemical screening assays. According to the result of LC50 by the brine shrimp lethality test, the dose used for T. flagelliforme extract was 120 ppm while the dose of IFNs was 102 U/ml. The tumor-derived cell lines (canine squamous cell carcinoma [CSCC], canine mammary gland benign mixed tumor/MCM-IPB-B3, and feline squamous cell carcinoma [FSCC]) and normal rabbit endothelial cells were cultured and maintained on Dulbecco's Modified Eagle's Medium DMEM/Ham-F12 medium supplemented with 10% fetal calf serum, antibiotic, and antifungal. The antiproliferation activity was assayed by calculated the total cell number after treated with the tested substances. The antiangiogenesis assay was performed using in vitro method on rabbit normal endothelial cells and in ovo using chicken chorioallantoic membrane (CAM). Results: The phytochemical screening test of the T. flagelliforme leaves ethanol extract indicated that the compound consisted of flavonoid, steroid, and tannin. The antiproliferation activity was increased in the combination of substances compared to the single exposure of each substance on all tested tumor-derived cell lines. There was no significantly different on the antiproliferation activity between a combination of T. flagelliforme with nCaIFN or rCaIFN in every single tested cell lines, but the comparison of this activity among the three tumor-derived cell lines seem that the antiproliferation activity is more effective on CSCC cell lines compared to the canine mammary gland benign mixed tumor and FSCC cell lines. A similar pattern of synergistic effect was also detected on the anti-angiogenesis activity in vitro using rabbit endothelial cells as well as in ovo assays. The most effective of the in vitro and in ovo anti-angiogenesis activity was observed on the combination substances between T. flagelliforme extract and rCaIFN compared to other treatments. Conclusion: There was a synergistic effect on the antiproliferation and antiangiogenesis activities of the combination between T. flagelliforme and canine IFNs (natural and recombinant) and this result could be developed as another alternative on the cancer treatments.

Breast cancer is the second most common cancer in women. Several studies have been conducted on natural materials to see the ability of its activity as a new anticancer compound. The purpose of this study was to determine the cytotoxic activity of Gendola leaf (Basella rubra Linn.) extracts and fractions, in inhibiting proliferation and inducing apoptosis of T47D breast cancer cells. The design of this study was experimental laboratory research using the in-vitro method. Cytotoxic and anti-proliferation tests on T47D cancer were using the MTT method, and the apoptosis test was using the flow cytometry method. Cytotoxic of extracts and fractions of n-hexane Gendola leaves were tested with a concentration series of 1000; 500; 250; 125; 62.5 μg/mL and doxorubicin was studied a series concentration of 0.5; 0.25; 0.125; 0.0625; 0.03125 μg/mL for 24 hours. Antiproliferation test used n-hexane fraction with a concentration series of 1IC50, ½IC50, ¼IC50, and ⅛IC50 with an incubation time of 24 and 48 hours. Apoptosis test utilized n-hexane fraction with a concentration series of 1IC50, ½IC50 with an incubation time of 24 hours. The results showed that the ethanol extract had IC50 424 μg/mL, n-hexane fraction 292 μg/mL. The n-hexane fraction had an anti-proliferation effect at a concentration of 1IC50 within 32 hours but was unable to induce T47D cell apoptosis. These results indicate that the n-hexane fraction of Gendola leaf has a cytotoxic effect, which can inhibit proliferation, that is unable to induce apoptosis but induce necrosis of T47D breast cancer cells.

A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps, which produce the final products, derivatives 17a–17j, in a moderate yield. The principles of cheminformatics and computational chemistry were applied in order to study the relationship between the physicochemical properties of the 3,9-disubstituted acridines and their biological activity at a cellular and molecular level. The selected 3,9-disubstituted acridine derivatives were studied in the presence of DNA using spectroscopic (UV-Vis, circular dichroism, and thermal denaturation) and electrophoretic (nuclease activity, relaxation and unwinding assays for topoisomerase I and decatenation assay for topoisomerase IIα) methods. Binding constants (2.81–9.03 × 104 M−1) were calculated for the derivatives from the results of the absorption titration spectra. The derivatives were found to have caused the inhibition of both topoisomerase I and topoisomerase IIα. Molecular docking simulations suggested a different way in which the acridines 17a–17j can interact with topoisomerase I versus topoisomerase IIα. A strong correlation between the lipophilicity of the derivatives and their ability to stabilize the intercalation complex was identified for all of the studied agents. Acridines 17a–17j were also subjected to in vitro screening conducted by the Developmental Therapeutic Program of the National Cancer Institute (NCI) against a panel of 60 cancer cell lines. The strongest biological activity was displayed by aniline acridine 17a (MCF7–GI50 18.6 nM) and N,N-dimethylaniline acridine 17b (SR–GI50 38.0 nM). The relationship between the cytostatic activity of the most active substances (derivatives 17a, 17b, and 17e–17h) and their values of KB, LogP, ΔS°, and δ was also investigated. Due to the fact that a significant correlation was only found in the case of charge density, δ, it is possible to assume that the cytostatic effect might be dependent upon the structural specificity of the acridine derivatives.

Polyphenols are a broad group of bioactive phytochemicals with powerful antioxidant, anti-inflammatory, immunomodulatory, and antiviral activities. Numerous studies have demonstrated that polyphenol extracts obtained from natural sources can be used for the prevention and treatment of cancer. Pomegranate peel extract is an excellent source of polyphenols, such as punicalagin, punicalin, ellagic acid, and caffeic acid, among others. These phenolic compounds have antineoplastic activity in in vitro models of cervical cancer through the regulation of cellular redox balance, induction of apoptosis, cell cycle arrest, and modulation of different signaling pathways. The current review summarizes recent data from scientific reports that address the anticancer activity of the predominant polyphenol compounds present in PPE and their different mechanisms of action in cervical cancer models.

Cacalol (C), a sesquiterpene isolated from Psacalium decompositum , has demonstrated anti-inflammatory and antioxidant activities. Its cytotoxic, antiproliferative, and pro-apoptotic effects have been previously shown in an in vitro breast cancer model. A derivative, cacalol acetate (CA), shows potential in regulating these processes, which has not been previously reported. This study focused on an in vitro cervical cancer model, assessing CA's antiproliferative, pro-apoptotic, cytostatic, and anti-migratory activities using the HeLa cell line. The natural anticancer agent indole-3-carbinol (I3C) was used as a control for comparison. CA demonstrated significant antitumor activities, including inhibiting cell growth, inducing apoptosis, arresting cells in the G2 phase of the cell cycle, and inhibiting cell migration. These effects were notably greater compared to I3C. I3C, while following a similar trend, did not induce Cas-3 expression, suggesting a different apoptotic pathway. Neither CA nor I3C increased p62 and LC3B levels, indicating they do not stimulate autophagy marker expression. Both compounds inhibited HeLa cell migration and induced cell cycle arrest. Despite both holding promise as anticancer agents for cervical cancer, CA's lower cytotoxicity and stronger regulation of tumor phenotypes make it a more promising agent compared to I3C., Competing Interests: The authors declare no conflicts of interest.

Cherry kernels are a by-product of cherries that are usually discarded, leading to waste and pollution. In this study, the chemical composition of 21 batches of cherry kernels from two different cherry species was analyzed using untargeted metabolomics. The in vitro antioxidant activity, cellular antioxidant activity, and antiproliferative activity of these kernel extracts were also determined, and a correlation analysis was conducted between differential compounds and biological activity. A total of 49 differential compounds were screened. The kernels of Prunus tomentosa were found to have significantly higher total phenol, total flavonoid content, and biological activity than those of Prunus pseudocerasus ( P  < 0.05). Correlation analysis showed that flavonoids had the greatest contribution to biological activity. The study suggests that both species of cherry kernel, particularly Prunus tomentosa , could be a potential source of bioactive compounds that could be used in the pharmaceutical, cosmetic, and food industries., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

In the last decade, biological processes involving halogen bond (HaB) as a leading interaction attracted great interest. However, although bound iodine atoms are considered powerful HaB donors, few iodinated new drugs were reported so far. Recently, iodinated 4,4'-bipyridines showed interesting properties as HaB donors in solution and in the solid state. In this paper, a study on the inhibition activity of seven halogenated 4,4'-bipyridines against malignant melanoma (MM) cell proliferation is described. Explorative dose/response proliferation assays were first performed with three 4,4'-bipyridines by using four MM cell lines and the normal BJ fibroblast cell line as control. Among them, the A375 MM cell line was the most sensitive, as determined by MTT assays, which was selected to evaluate the antiproliferative activity of all 4,4'-bipyridines. Significantly, the presence of an electrophilic iodine impacted the biological activity of the corresponding compounds. The 3,3',5,5'-tetrachloro-2-iodo-4,4'-bipyridine showed significant antiproliferation activity against the A375 cell line, and lower toxicity on BJ fibroblasts. Through in silico studies, the stereoelectronic features of possible sites determining the bioactivity were explored. These results pave the way for the utilization of iodinated 4,4'-bipyridines as templates to design new promising HaB-enabled inhibitors of MM cell proliferation., (© 2024 Wiley-VCH GmbH.)

Two influential market groups can take action to reduce the risk that nuclear dual-use technologies end up in the wrong hands. Financial institutions, such as banks and insurance companies, and large manufacturers that integrate dual-use technologies into more complex goods both can encourage other companies to adopt stricter compliance programs to reduce the risks of nuclear proliferation. The authors describe ways to create financial incentives for risk reduction along the whole nuclear supply chain. [ABSTRACT FROM AUTHOR]

Background: Bauhinia strychnifolia Craib is an herb in Thai traditional medicine. Its decoction is traditionally used as an anticancer, antidiarrheal, and hangover remedy for centuries. Several studies described bioactivities of its organic solvent extracts, however, only few demonstrated the usefulness of the decoction. Here, we aimed to determine the bioactivities of Bauhinia strychnifolia Craib root and stem aqueous extracts in gut and liver perspective. Methods: To achieve the goal, we performed MTT test, microscopic analyses, disc diffusion assay, broth microdilution assay, free radicals scavenging assays, and LC-MS analysis. Results: We found that the extracts inhibited the growth of human hepatocellular carcinoma (HepG2) and colon adenocarcinoma (HT-29) cell lines. Moreover, they also inhibited the growth of gram-positive bacteria Staphylococcus aureus and Bacillus cereus but not inhibited the growth of gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa. Furthermore, the extracts exhibited moderate antioxidant activity and increased GSH production in HepG2 cell line when compared with untreated. Our LC-MS analysis confirmed the existence of anticancer and antioxidant; 3,5,7,3′,5′-pentahydroxyflavanonol-3-O-α-L-rhamnopyranoside and β-sitosterol, in the extracts. Conclusion: The results from our study supported that the administration of Bauhinia strychnifolia Craib root and stem decoction would really aid colon or liver cancer patients and detoxify the alcoholic drunkard as it is claimed in Thai traditional medicine. [ABSTRACT FROM AUTHOR]

Two new prenylated coumarins, 3'-hydroxytoddanone (1), and isotoddalolactone (2), along with four known analogues (3–6) were isolated from the roots of Zanthoxylum nitidum. Their chemical structures were elucidated based on extensive spectroscopic interpretation and HR-ESI-MS analysis. The absolute configuration of compound 2 was determined by comparing experimental ECD spectrum with that calculated by the time-dependent density functional theory (TDDFT) method. Compounds 4–6 were isolated from the Zanthoxylum genus for the first time. The two new compounds were tested for antiproliferative activities in vitro on the HL-60, K562 and THP-1 cell lines. Compounds 1 and 2 exhibited moderate cell growth inhibitory activities in vitro against human leukemic HL-60 cell lines, with IC50 values of 32.64 and 33.15 µM, respectively. [ABSTRACT FROM AUTHOR]

In our study, some newly synthesized aryl-substituted pyrazole derivatives mimicking cis-diphenylethylene scaffold of two apoptotic inducing agents celecoxib and combretastatin A-4 were found to have strong antiproliferative as well as antiinflammatory activities. Among these coxib–combretastatin hybrids, two lead compounds 8 and 6c simultaneously inhibited prostaglandin E2 (PGE2) production in LPS-activated murine macrophage RAW 264.7 cells and suppressed cell cycle progression of MCF7 cells at G2/M or G0/G1 phases, but only compound 8 induced apoptosis via caspase-3 activation. Both the lead compounds showed good docking energies with both protein targets COX-2 and tubulin in the molecule interaction modeling. The cis-diphenylethylene scaffold of celecoxib or combretastatin A-4 as well as functional groups such as the ethyl ester group and the sulfonamide could be considered as potential key features for the dual activity of studied compounds meanwhile the trimethoxybenzene remained the crucial characterization of the newly derived compounds of combretastatins. [ABSTRACT FROM AUTHOR]

A series of novel pyrrole fused benzoxazinones/quinoxalinones has been evaluated for antiproliferative activity against breast cancer cell line, MCF7 and treatment‐resistant triple‐negative breast cancer cell line MDA‐MB‐231. Among which pyrroloquinoxalinones exhibited higher cytotoxicity. Furthermore, they showed insignificant cellular cytotoxicity in normal human cell HEK293T when treated with their respective IC50 concentrations. In silico molecular docking, study suggests that the inhibitory mechanism of pyrroloquinoxalinones probably mediated via modulation of breast cancer targets such as VEGFR2 and EGFR. The stability of target protein (VEGFR2 and EGFR)‐ligand (pyrroloquinoxalinones) interactions was validated by Molecular dynamic simulation (50 ns). Additionally, pyrrolobenzoxazinones/quinoxalinones were evaluated for in vitro antibacterial activity against Gram‐positive and Gram‐negative bacterial strains. All the compounds exhibited significant antibacterial activity (IC50 0.034–15.4 μM) towards the tested bacterial strains. These findings indicate that pyrrolobenzoxazinones/quinoxalinones are valuable scaffolds for the development of potent anticancer and antibacterial compounds. [ABSTRACT FROM AUTHOR]

Two new series of aminoquinoline based derivatives (thiazolyl pyrazolines and pyrazolyl thiazolidinones) were designed and synthesized. The in vitro antiporliferative activity of the target compounds was assessed against two different cancer types; (MCF‐7) breast cancer cell line and (HCT116) colorectal carcinoma cell line, using MTT assay technique. The 4‐methyl thiazolyl pyrazoline derivative 4 b showed potent anticancer activity on HCT116 with IC50 value of 3.07 μM. The promising derivative exhibited dual kinase EGFR/HER2 inhibitory activity with IC50 values of 0.06/0.08 μM versus 0.04/0.05 μM for erlotinib and lapatinib, respectively, as detected by EGFR and HER2 kinase assays. Moreover, the flow cytometry analysis of HCT116 cells treated with 4 b revealed that the derivative was capable of arresting the cell cycle at G1 phase and inducing late cellular apoptosis. Molecular docking of 4 b showed that the synthesized compound exhibited promising binding energy scores of −15.0774 and −16.9040 kcal/mol into EGFR and HER2 active sites, respectively. Finally, the pharmacokinetics and physicochemical parameters of 4 b showed its promising drug‐like properties. [ABSTRACT FROM AUTHOR]

The new copper(II) complex dichloridobis(4‐{[3‐(pyridin‐2‐yl‐κN)‐1H‐pyrazol‐1‐yl‐κN2]methyl}benzoic acid)copper(II) methanol sesquisolvate hemihydrate, [CuCl2L2]·1.5CH3OH·0.5H2O, (1), has been synthesized from CuCl2·2H2O and the ligand 4‐{[3‐(pyridin‐2‐yl)‐1H‐pyrazol‐1‐yl]methyl}benzoic acid (L, C15H11N3O2). The complex was characterized by elemental analysis, Fourier transform IR spectroscopy, electrospray ionization mass spectrometry and single‐crystal X‐ray diffraction. Two chloride ligands and two bidentate L ligands coordinate the CuII centre in 1 in a Jahn–Teller‐distorted octahedral geometry of rather unusual configuration: a chloride substituent and a pyrazole N atom of an N,N′‐chelating ligand occupy the more distant axial positions. Classical O—H...O hydrogen bonds and O—H...Cl interactions link neighbouring complex molecules and cocrystallized methanol molecules into chains that propagate parallel to the b direction. The title compound shows intriguing bioactivity: the effects of 1 on the enzymatic activity of protein tyrosine phosphatase 1B (PTP1B) and on the viability of human breast cancer cells of cell line MCF7 were evaluated. Complex 1, with an IC50 value of 0.51 µM, can efficiently inhibit PTP1B activity. An enzyme kinetic assay suggests that 1 inhibits PTP1B in a noncompetitive manner. A fluorescence titration assay indicates that 1 has a strong affinity for PTP1B, with a binding constant of 4.39 × 106M−1. Complex 1 may also effectively decrease the viability of MCF7 cells in an extent comparable to that of cisplatin (IC50 = 6.3 µM). The new copper complex therefore represents a promising PTP1B inhibitor and an efficient antiproliferation reagent against MCF7 cells. [ABSTRACT FROM AUTHOR]

Two new imidazophenanthroline derivatives, namely 2‐(4‐bromo‐(2,1,3)‐benzothiadiazol‐7‐yl)‐1H‐imidazo[4,5‐f][1,10]phenanthroline (btdip), 2‐(dibenzofuran‐3‐yl)‐1H‐imidazo[4,5‐f][1,10]phenanthroline (dbfip) and their octahedral nickel complexes [Ni(phen)2(btdip)]2+ (1) and [Ni(phen)2(dbfip)]2+ (2) have been synthesized and characterized by CHN analysis, ESI‐MS, NMR and UV‐vis spectra. Their DNA binding abilities were spectrophotometrically, hydrodynamically and electrophoretically studied and found that while btdip binds DNA externally, dbfip binds in the grooves and both of their nickel complexes also bind DNA through grooves giving severe DNA damage in the presence of peroxide. The compounds were screened against four different human cancer cell lines using MTT assay method. The results obtained showed that both ligands are active against DLD‐1, and further dbfip is found to be more active than positive control drugs against DLD‐1 and HepG2 cell lines. The complex 2 has more antiproliferative effect than 1 against MCF‐7 and HepG2 cells. On the other hand, complex 2 was found to have more toxic effect on HepG2 cells than the standard drugs cisplatin and ploxal‐S. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT), also known as suppression of androgen activity, is a first‐line treatment option for patients with prostate cancer (PC). ADT became ineffective after several years of treatment due to the development of castration‐resistant prostate cancer (CRPC), which resulted in more deaths in PC patients, but it is still androgen receptor (AR) dependent. Under these conditions, the U.S. Food and Drug Administration (FDA) approved enzalutamide for the treatment of patients with metastatic CRPC (mCRPC) and, more recently, nonmetastatic CRPC (nmCRPC). Despite the fact that this drug has extended overall and progression‐free survival in a wide range of CRPC patients, more research is needed to better understand the mechanisms of resistance challenges and analogues chemical lead structures as next generation AR antagonists. In this regard, we discovered simple and easily synthesizable new pharmacophore, 4,4‐dimethylimidazolidin‐2‐one, based derivatives MDV1‐MDV8 for potent AR antagonists; here, the thiohydantoin pharmacophore in enzalutamide is replaced by 4,4‐dimethylimidazolidin‐2‐one. The antiproliferative activities of these molecules have been assessed against androgen dependent PC cell line (LNCaP). The structure‐activity relationship of these molecules, as well as their relationship with enzalutamide, is investigated. Among the reported molecules, MDV4 showed significantly improved in vitro activity with the IC50 value of 780.85 nM. [ABSTRACT FROM AUTHOR]

Chemotherapy is a palliative treatment for unresectable patients with cholangiocarcinoma (CCA). However, drug resistance is a major cause of the failure of this treatment. Derrischalcone (DC), a novel chalcone isolated from Derris indica fruit, has been shown pharmacologically active; though, the effect of DC on CCA is unknown. The present study investigated the cytotoxic, antiproliferative, anti-migration, and anti-invasion effects and underlying mechanisms of DC on CCA KKU-M156 and KKU-100 cells. Cytotoxicity and apoptosis were evaluated by acridine orange and ethidium bromide fluorescent staining. Reactive oxygen species (ROS) was measured by dihydroethidium assay. Cell proliferation and reproductive cell death were assessed by sulforhodamine B staining and colony-forming assay. Migration and invasion were determined by wound healing and transwell chamber assays. Protein expressions associated with cell death, proliferation, migration, and invasion were analyzed by western immunoblotting. We found that DC induced cytotoxicity and apoptosis in association with ROS formation and oxidative stress. Treatment with N-acetylcysteine suppressed ROS formation and attenuated DC-induced cytotoxic and apoptotic effects. DC increased the expression of p53, p21, Bax, and cytochrome c proteins in association with cell death. DC-induced antiproliferation, colony formation, anti-migration, and anti-invasion were associated with the suppression of Akt/mTOR/cyclin D1 and FAK signaling pathways. These findings suggest that the multi-targeting strategies with DC may be a novel treatment for cancer therapy. [ABSTRACT FROM AUTHOR]

Seven styrylquinolines were synthesized in this study. Two of these styrylquinolines are new and were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620, and normal cells (HaCaT). According to the results, compounds 3a and 3d showed antiproliferative activity in SW480 and SW620 cells, but their effect seemed to be caused by different mechanisms of action. Compound 3a induced apoptosis independent of ROS production, as evidenced by increased levels of caspase 3, and had an immunomodulatory effect, positively regulating the production of different immunological markers in malignant cell lines. In contrast, compound 3d generated a pro-oxidant response and inhibited the growth of cancer cells, probably by another type of cell death other than apoptosis. Molecular docking studies indicated that the most active compound, 3a, could efficiently bind to the proapoptotic human caspases-3 protein, a result that could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. The obtained results suggest that these compounds have chemopreventive potential against CRC, but more studies should be carried out to elucidate the molecular mechanisms of action of each of them in depth.

Antiproliferation effects of Clavularia-derived natural products against cancer cells have been reported on, but most studies have focused on identifying bioactive compounds, lacking a detailed investigation of the molecular mechanism. Crude extracts generally exhibit multiple targeting potentials for anticancer effects, but they have rarely been assessed for methanol extracts of Clavularia inflata (MECI). This investigation aims to evaluate the antiproliferation of MECI and to examine several potential mechanisms between oral cancer and normal cells. A 24 h MTS assay demonstrated that MECI decreased cell viability in several oral cancer cell lines more than in normal cells. N-acetylcysteine (NAC), an oxidative stress inhibitor, recovered these antiproliferation effects. Higher oxidative stress was stimulated by MECI in oral cancer cells than in normal cells, as proven by examining reactive oxygen species and mitochondrial superoxide. This preferential induction of oxidative stress was partly explained by downregulating more cellular antioxidants, such as glutathione, in oral cancer cells than in normal cells. Consequently, the MECI-generated high oxidative stress in oral cancer cells was preferred to trigger more subG1 population, apoptosis expression (annexin V and caspase activation), and DNA damage, reverted by NAC. In conclusion, MECI is a potent marine natural product showing preferential antiproliferation against oral cancer cells.

With the advancement of nanotechnology, the nano-sized particles make an imprint on our daily lives.The present investigation revealed that biomolecules present in seed exudates of Vigna radiata are responsible for the synthesis of AuNPs, confirmed by the routine characterization techniques. Anticancer efficacy showed by AuNPs might be due to the release of phytochemicals in the exudate which is being adsorbed on the surface of AuNPs referencing their anticancer efficacy against the tested breast cancer cell lines. Inhibition of clonogenicity and cell cycle arrest at G2/M phase then apoptosis of AuNPs was also observed, but found nontoxic to the human PBMC cells which further confirms its biocompatible property Among the various physicochemical study, present AuNPs shows unique information, they show photoluminescent property which may be used for bioimaging purposes. However, further molecular analysis needs to be explored to understand the underlying mechanism for therapeutic and biomedical application.

Recent evidences highlight the usefulness of small molecule (Histone deacetylase 4) HDAC4 inhibitors in the several preclinical paradigms. Major toxicity and mutagenicity issues associated with hydroxamate HDAC inhibitors, stimulated us to develop potent non‐hydroxamate inhibitors. In the present work a novel series of thiazolidinedione (TZD) derivatives with pyridine as cyclic linker and TZD ring as zinc binding group was designed and screened in a panel of isoenzymes of HDACs, wherein the most potent compounds exhibiting HDAC4 IC50‐values<5 μM were 5 v, 5 w, 5 y and 5 z (IC50=4.2±1 μM, 0.75±0.03 μM, 4.9±0.5 and 2.3±0.5 μM, respectively). The docking studies displayed the unique binding mode of this series of compound at active site of HDAC4, wherein TZD ring was indicated as zinc binding group. Further, 5 w and 5 y were found as the most potent antiproliferative agent in lymphoblastic leukemia (CCRF‐CEM) and breast cancer MDA‐MB‐231 cells. Compound 5 y was found to induce the apoptosis and DNA fragmentation of CEM cells. The western blotting analysis of 5 y also showed the presence of cleaved caspases supporting their apoptotic nature. Further, Class IIa (HDAC4) selectivity of 5 y was also supported by western blotting observations, wherein 5 y caused the accumulation of acetylated H3 but not of acetylated Tubulin. Thus, our findings endorse the further investigation of this series of compounds for their potential as targeted cancer therapeutic agents. [ABSTRACT FROM AUTHOR]

[Display omitted] • Collective fabrication of Asparagus racemosus phytochemicals on silver nanoparticles and their strong antiproliferative efficacy demonstrated. • Ar-AgNPs inhibited cell migration and induced cell death in MDA-MB-231 breast cancer cells. • The anticancer mechanism involves disruption of the secondary and tertiary structure of tubulin and disruption of microtubule assembly dynamics. Collective functionalization of therapeutic phytochemicals on metal nanoparticles enhances their stability in circulation, target-specific delivery, and therapeutic outcome. Here, we report a facile, green synthesis of silver nanoparticles using the phytochemicals of Asparagus racemosus (Ar, shatavari), a medicinal herb with reported anticancer potential. The nanoparticles (Ar-AgNPs) were found to possess strong antiproliferative, anticlonogenic, anti-migratory, and cell-death-inducing effects against the breast cancer cell line, MDA-MB-231. The nanosilver, synthesized using a green synthesis approach, was polymorphous with a size distribution between 20 and 40 nm and aggregation-resistant (zeta potential,–26.4 mV). The functionalization of the particles with Ar phytochemicals was confirmed with liquid chromatography-mass spectroscopy (LC/MS). The particles inhibited MDA-MB-231 cell proliferation with an IC 50 of 25 ± 2 µg/mL. Ar-AgNPs disrupted the structural integrity of tubulin and strongly retarded the assembly competence of the protein to form microtubules. Ar-AgNPs, however, did not show any phase-specific cell cycle arrest but showed an accumulation of dead-cell fragments as a sub-G 1 population. They nevertheless killed the cells, as verified using annexin-PI-based flow cytometry. Taken together, our findings suggest the anticancer potential of Ar-AgNPs can be attributed, at least in part, to their ability to disrupt the structural and functional integrity of tubulin. [ABSTRACT FROM AUTHOR]