Higher Antiproliferative Effect Research Articles

Biological Activities of Ethanol Extracts of Hericium erinaceus Obtained as a Result of Optimization Analysis.

Mushrooms are one of the indispensable elements of human diets. Edible mushrooms stand out with their aroma and nutritional properties. In this study, some biological activities of the wild edible mushroom Hericium erinaceus were determined. In this context, firstly, the most suitable extraction conditions of the fungus in terms of biological activity were determined. First, 64 different experiments were performed with the Soxhlet device under 40-70 °C extraction temperature, 3-9 h extraction time, and 0.5-2 mg/mL extraction conditions. As a result, a total antioxidant status (TAS) analysis was performed, and the extraction conditions were optimized so that the objective function was the maximum TAS value. The data obtained from the experimental study were modeled with artificial neural networks (ANNs), one of the artificial intelligence methods, and optimized with a genetic algorithm (GA). All subsequent tests were performed using the extract obtained under optimum extraction conditions. The antioxidant capacity of the mushroom was assessed using Rel assay kits and the DPPH and FRAP techniques. The agar dilution method was used to measure the antimicrobial activity. The anti-Alzheimer activity was assessed based on the activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The antiproliferative activity was assessed against the A549 cancer cell line. The total phenolic content was measured using the Folin-Ciocalteu reagent. The measurement of total flavonoids was conducted using the aluminum chloride test. LC-MS/MS equipment was used to screen for the presence of standard chemicals. The optimum extraction conditions were found to be a 60.667 °C temperature, 7.833 h, and 1.98 mg/mL. It was determined that the mushroom has high antioxidant potential. It was determined that the substance was successful at combating common bacterial and fungal strains when used at dosages ranging from 25 to 200 µg/mL. The high antiproliferative effect of the substance was attributed to its heightened concentration. The anti-AChE value was found to be 13.85 μg/mL, while the anti-BChE value was confirmed to be 28.00 μg/mL. The phenolic analysis of the mushroom revealed the presence of 13 chemicals. This investigation found that H. erinaceus exhibits robust biological activity when extracted under appropriate circumstances.

Autophagy regulation and redox perturbation by transcrocetin suppress the growth of endometriosis

Until non-hormonal therapeutic targets for endometriosis are suggested, we focused on mitochondrial function and autophagy regulation in the disease. Transcrocetin is a carotenoid and retinoic acid with high antioxidant potency and antiproliferative effects in several diseases. In this study, we demonstrated the therapeutic mechanisms of transcrocetin in endometriosis using the End1/E6E7 and VK2/E6E7 cell lines. Transcrocetin suppressed the viability and proliferation of these cell lines and did not affect the proliferation of normal uterine stromal cells. p21 Waf1/Cip1 as a cell cycle regulator and target of p53, were increased by transcrocetin and caused the G1 arrest via inhibition of cyclin-dependent kinase activity, which might further cause cell death. Furthermore, we confirmed endoplasmic reticulum stress and calcium ion dysregulation in the cytosol and mitochondrial matrix, disrupting the mitochondrial membrane potential. Mitochondrial bioenergetics were suppressed by transcrocetin, and oxidative phosphorylation-related gene expression was downregulated. Moreover, the proliferation of End1/E6E7 and VK2/E6E7 cells was regulated by transcrocetin-induced oxidative stress. Finally, we verified the impairment of autophagic flux following pre-treatment with chloroquine. Therefore, transcrocetin may be a potent therapeutic alternative for endometriosis.

Novel family of [RuCp(N,N)(P)]+ compounds with simultaneous anticancer and antibacterial activity: Biological evaluation and solution chemistry studies

A family of ten novel ruthenium(II)-cyclopentadienyl organometallics of general formula [Ru(η5-C5H5)(N,N)(PPh2(C6H4COOR)][CF3SO3] (1–10) in which (N,N) = 4,4′-R′-2,2′-bipyridyl (R = –H or –CH2CH2OH; R’ = –H, –CH3, –OCH3, –CH2OH, and –CH2-biotin) was prepared from [Ru(η5-C5H5)(PPh2(C6H4COOH))2Cl]. All compounds were fully characterized by means of several spectroscopic and analytical techniques, and the molecular structures of [Ru(η5-C5H5)(PPh2(C6H4COOH))2Cl], 1, 3 and 4 have been additionally studied by single-crystal X-ray diffraction. The anticancer activity of all compounds was evaluated in sensitive and multidrug-resistant counterpart cell lines from human colorectal cancer (Colo 205 and Colo 320) and non-small cell lung cancer NSCLC (A549, NCI–H460 versus NCI–H460/R) as well. Notably, compounds 6 and 7 (R CH2CH2OH and (N,N) = bipy or Me2bipy, respectively) showed antiproliferative effect against both cell lines with high intrinsic selectivity towards cancer cells. The antibacterial activity of all compounds was also evaluated against both Gram negative and Gram positive strains, and some compounds in the series showed potent antibacterial activity against Staphylococcus aureus strains, including the methicillin-resistant MRSA strains.Solution speciation studies revealed that the complexes bearing the PPh2(C6H4COO−) ligand are neutral at physiological pH (7.4) in contrast with their ethylene glycol derivatives that have a permanent positive charge. While all compounds are lipophilic, the difference in the distribution coefficient for neutral and charged complexes is around one order of magnitude. Complexes 6 and 7 exhibited excellent biological activity and were selected for further studies. Spectrofluorometric methods were used to investigate their interaction with biomolecules such as human serum albumin (HSA) and calf thymus DNA (ct-DNA). For these complexes, binding site II of HSA is a possible binding pocket through non-covalent interactions. The release of ethidium from the DNA adduct by the charged complexes proves their interaction with DNA in contrast to the neutral ones.In conclusion, Ru(II)-cyclopentadienyl complexes with 2,2′-bipyridyl-derivatives and an ethylene glycol moiety tethered to the phenylphosphane co-ligand are very promising from a therapeutic perspective, in particular complexes 6 and 7 that display remarkable antibacterial activity with a high anti-proliferative effect against colon and non-small cell lung cancers, both clinically challenging neoplasias in need of effective solutions.

DNA/BSA binding studies and in vitro anticancer and antibacterial studies of isoelectronic Cu(I)- and Ag(I)-pyridinyl Schiff base complexes incorporating triphenylphosphine as co-ligands

Four mononuclear Ag(I) and Cu(I) Schiff base complexes of the type [M(L)(PPh3)2]X [where M = Ag+ or Cu+, L = (E)-N-(2-fluorophenyl)-1-(pyridin-2-yl)methanimine (fpm) or (E)-1-(pyridin-2-yl)-N-(p-tolyl)methanimine (ptm) and X = NO3–] have been synthesized and characterized by various spectroscopic and analytical techniques. The analysis shows that the complexes are four-coordinates formed via the nitrogen atoms of a bidentate fpm or ptm ligands and two phosphorus atoms from the triphenylphosphine co-ligands. Two of the complexes were structurally characterized by single crystal X-ray diffraction revealing a distorted trigonal pyramidal geometry around the Ag(I) or Cu(I) center. The binding affinity of the complexes with calf thymus-DNA (CT-DNA) and bovine serum albumin (BSA) was determined using UV–visible spectroscopy. The interaction of the complexes with CT-DNA revealed the strong stacking interaction between the aromatic chromophore of the complexes and the base pairs of the CT-DNA. The study of the complexes with BSA showed moderate affinity to BSA, suggesting that complexes 1–4 can be delivered and dispositioned in vivo. Invitro anticancer activity of the synthesized complexes was evaluated against non-cancerous human embryonic kidney 293 (HEK293), cervical cancer cell (HELA), breast cancer cell (MDA-MB231) and malignant human melanoma cell (A375). High antiproliferative effects of the complexes on HELA (with EC50 values between 1.82±1.23 and 10.66±2.87 μM better than cisplatin with EC50 > 50 μM) and MDA-MB231(≈2 to 7-fold effective than cisplatin) were recorded. Further, the invitro antibacterial activity of the synthesized compounds was evaluated against S. aureus, E. coli, S. typhi and P. aeruginosa using the disc diffusion method from which the Cu(I) complexes showed better inhibitory effects than the Ag(I) complexes.

Cytotoxic and antiproliferative effects of hellebrin on breast and lung cancer cells

This study aimed to investigate the impact of hellebrin on human lung cancer cell (H1299) and breast cancer cell (MCF-7) lines over time. The viability of various concentrations of hellebrin (100 nM-400 nM) on two cancer cell lines was measured using the MTT method. The cellular proliferation over time was examined using xCELLigence real-time cell analysis (RTCA). The results showed a significant decrease in cell viability with increasing concentrations of hellebrin in both cancer cell lines compared to the control group (p˂0.0001). While the viability of both cancer cells decreased after a certain period of hellebrin application, the viability of the control groups increased over time. These findings indicate that hellebrin has high antiproliferative and cytotoxic effects on breast and lung cancer cells. Consequently, this study suggests that hellebrin may have potential as a treatment for other cancers, especially lung cancer, and further in vitro and in vivo experiments are needed to investigate this possibility.

A sequential recovery extraction and biological activity of water-soluble sulfated polysaccharides from the polar red macroalgae Sarcopeltis skottsbergii

Algal biomass is comprised of a variety of biochemical components that make it a viable raw material for use in a variety of applications using a biorefining process. From the residual supernatant generated by high-pressure homogenization for the extraction of the R-phycoerythrin pigment, two soluble polysaccharides (neutral and acid fractions) were obtained. The composition of total carbon (C), hydrogen (H), nitrogen (N), and sulfur (S), gas chromatography–mass spectrometry (GC–MS), Fourier transform infrared (FTIR-ATR) spectroscopy, antioxidant capacity (ABTS) and antiproliferative in vitro and in vivo activities were evaluated. The two polysaccharides, which had a relatively high sulfate content, exhibited significant antioxidant activity in superoxide radical assay (ABTS) and high anti-proliferative effects on G-361, U-937, HCT-116 cancer cells. High selectivity index (>3) was observed for the acid extract on G-361 and U-937 cell lines, but a significant inhibitory effect on the growth of 1064sK healthy fibroblast cells was measured too. On the other hand, neutral fraction polysaccharides, with the lowest sulfate content and relatively lower radical scavenging rates, showed scarce antitumor activity, a high selectivity index on G-361 melanoma cancer cells and non-toxicity on healthy cells. This differential behavior was verified by testing toxicity and lethality of both polysaccharide extracts in and in vivo zebrafish embryo acute toxicity test. Following this method, the LC50 of the neutral fraction resulted much higher (1.477 mg mL−1, p ≈ 0.0000) than that of the acid fraction (0.080 mg mL−1, p ≈ 0.0000) at 72 h post-fertilization. During this period, a slight growth delay and/or rare teratogenic effects were also induced by these fractions at concentrations lower than their LC50. Overall, this study indicates that the antitumor, antioxidant and toxicity effects of polysaccharides may be related to the combined effects of sulfate and galactose contents from the residual supernatant bioprocess. The nutraceutical potential of the acid fractions is thus finally discussed.

Development of heterodimeric estrogen receptor alpha antagonists to target simultaneously the ligand and coactivator binding site.

One-third of breast cancer patients will develop recurrent cancer within 15 years of endocrine treatment. Notably, tumor growth in a hormone-refractory state still relies on the interaction between estrogen receptor alpha (ERα) and upregulated coactivators. Herein, we suggest that simultaneous targeting of the primary ligand binding site (LBS) and the coactivator binding site (CABS) at ERα represents a promising alternative therapeutic strategy to overcome mutation-driven resistance in breast cancer. We synthesized two series of compounds that connect the LBS-binder (E)-3-{4-[8-fluoro-4-(4-hydroxyphenyl)-2,3-dihydrobenzo[b]oxepin-5-yl]phenyl}acrylic acid 8 with the coactivator binding site inhibitors (CBIs) 4,6-bis(isobutyl(methyl)amino)pyrimidine or 3-(5-methoxy-1H-benzo[d]imidazol-2-yl)propanoic acid via covalent linkage. The most active benzoxepine-pyrimidine conjugate 31 showed strong inhibition of estradiol-induced transactivation (IC50 = 18.2 nM (ERα) and 61.7 nM (ERβ)) in a luciferase reporter gene assay as well as high antiproliferative effects in MCF-7 (IC50 = 65.9 nM) and tamoxifen-resistant MCF-7/TamR (IC50 = 88.9 nM) breast cancer cells. All heterodimers exhibited two- to sevenfold higher antagonism at ERα (compared with ERβ) and were superior to the acrylic acid precursor 8 in terms of ER antagonism and antiproliferative activity. It was demonstrated on the example of31 that the compounds did not influence the ERα content in MCF-7 cells and therefore act as pure antiestrogens without downregulating potency. Possible interactions of the CBI at the receptor surface, which enhanced the biological activities, were evaluated using molecular docking studies.

Dual functionality of pyrimidine and flavone in targeting genomic variants of EGFR and ER receptors to influence the differential survival rates in breast cancer patients

Abstract Breast cancer ranks as one of the most prevalent forms of cancer and stands as the primary global cause of mortality among women. Overexpression of EGFR and ER receptors or their genomic alterations leads to malignant transformation, disease aggression and is linked to poor patient survival outcomes. The clinical breast cancer patient’s genomic expression, survival analysis, and computational drug-targeting approaches were used to identify best-hit phytochemicals for therapeutic purposes. Breast cancer patients have genomic alterations in EGFR (4%, n = 5699) and ER (9%, n = 8461), with the highest proportion being missense mutations. No statistically significant difference was observed in the patient survival rates between the altered and unaltered ER groups, unlike EGFR, with the lowest survival rates in the altered group. Computational screening of natural compound libraries (7711) against each EGFR (3POZ) and ER (3ERT) receptor shortlists the best-hit 3 compounds with minimum docking score (ΔG = −7.9 to −10.8), MMGBSA (−40.16 to −51.91 kcal/mol), strong intermolecular H-bonding, drug-like properties with least kd, and ki. MD simulation studies display stable RMSD, RMSF, and good residual correlation of best-hit common compounds (PubChem ID: 5281672 and 5280863) targeting both EGFR and ER receptors. In vitro, studies revealed that these common drugs exhibited a high anti-proliferative effect on MCF-7 and MDA-MB-231 breast cancer cells, with effective IC50 values (15–40 μM) and lower free energy, kd, and ki (5281672 > 5280863 > 5330286) much affecting HEK-293 non-cancerous cells, indicating the safety profile. The experimental and computational correlation studies suggest that the highly expressed EGFR and ER receptors in breast cancer patients having poor survival rates can be effectively targeted with best-hit common potent drugs with a multi-target therapeutic approach. Insight Box: The findings of this study provide valuable insights into the genomic/proteomic data, breast cancer patient’s survival analysis, and EGFR and ER receptor variants structural analysis. The genetic alterations analysis of EGFR and ER/ESR1 in breast cancer patients reveals the high frequency of mutation types, which affect patient’s survival rate and targeted therapies. The common best-hit compounds affect the cell survival patterns with effective IC50, drug-like properties having lower equilibrium and dissociation constants demonstrating the anti-proliferative effects. This work integrates altered receptor structural analysis, molecular interaction-based simulations, and ADMET properties to illuminate the identified best hits phytochemicals potential efficacy targeting both EGFR and ER receptors, demonstrating a multi-target therapeutic approach.

The Extraction and High Antiproliferative Effect of Anthocyanin from Gardenblue Blueberry.

Blueberries are rich in flavonoids, anthocyanins, phenolic acids, and other bioactive substances. Anthocyanins are important functional components in blueberries. We collected 65 varieties of blueberries to investigate their nutritional and functional values. Among them, Gardenblue had the highest anthocyanin content, with 2.59 mg/g in fresh fruit. After ultrasound-assisted solvent extraction and macroporous resin absorption, the content was increased to 459.81 mg/g in the dried powder. Biological experiments showed that Gardenblue anthocyanins (L1) had antiproliferative effect on cervical cancer cells (Hela, 51.98 μg/mL), liver cancer cells (HepG2, 23.57 μg/mL), breast cancer cells (MCF-7, 113.39 μg/mL), and lung cancer cells (A549, 76.10 μg/mL), and no apparent toxic effects were indicated by methyl thiazolyl tetrazolium (MTT) assay, especially against HepG2 cells both in vitro and in vivo. After combining it with DDP (cisplatin) and DOX (doxorubicin), the antiproliferative effects were enhanced, especially when combined with DOX against HepG2 cells; the IC50 value was 0.02 μg/mL. This was further evidence that L1 could inhibit cell proliferation by inducing apoptosis. The detailed mechanism might be L1 interacting with DNA in an intercalation mode that changes or destroys DNA, causing apoptosis and inhibiting cell proliferation. The findings of this study suggest that L1 extract can be used as a functional agent against hepatoma carcinoma cells.

Design and optimization various formulations of PEGylated niosomal nanoparticles loaded with phytochemical agents: potential anti-cancer effects against human lung cancer cells.

Phytochemicals and their derivatives are good options to improve treatment efficiency in cancer patients. Artemisinin (ART) and metformin (MET) are widely used phytochemicals to treat various types of cancers. However, their application because of their dose-dependent side effects, and poor bioavailability brings several challenges. Niosome is a novel nanocarrier that is the best choice to encapsulate both lipophilic and hydrophilic drugs. In this study, we synthesized and characterized various formulations of PEGylated (polyethylene glycol) niosomal nanoparticles co-loaded with ART-MET and evaluated their anticancer effect on A549 lung cancer cells. Various formulations of PEGylated noisome were prepared by the thin-film hydration method and characterized in size, morphology, release pattern, and physicochemical structure. The cytotoxic effect of the free ART-MET and optimized PEGylated niosomal nanoparticles loaded with ART-MET on A549 cells were evaluated by MTT assay. Furthermore, the Real-time PCR (RT-PCR) technique used to evaluate apoptotic and anti-apoptotic gene expression. The size, encapsulation efficiency (EE), and polydispersity index (PDI) of the optimized nanoparticles are 256nm, 95%, and 0.202, respectively. Additionally, due to the PEGylation hydrophilic character, there is a major consideration of the high impact of PEGylation on reducing niosome size. According to the results of the MTT assay, free ART-MET and ART-MET-loaded niosomal nanoparticles showed dose-dependent toxicity and inhibits the growth of A549 lung cancer cells. Furthermore, the RT-PCR results indicated that ART-MET-loaded niosomal nanoparticles have a higher anti-proliferative effect by inhibiting anti-apoptotic and inducing apoptotic gene expression in A549 lung cancer cells. Our study revealed that the simultaneous use of ART and MET in the optimized PEGylated niosomal nanoparticles delivery system could be an appropriate approach to improve the effectiveness of lung cancer treatment.

Synthesis and antiproliferative activities of steroidal lactam conjugates bearing a new nitrogen mustard

Alkylating agents are potent anticancer compounds that exert their anticancer properties through the inhibition of cell replication and transcription leading to cell death. Despite the numerous benefits, these agents also have serious drawbacks such as their high toxicity and low specificity towards cancer cells. As previously reported by our group, conjugation of alkylating agents with azasteroids can reduce their systemic toxicity and enhance their anticancer activity. In this work, novel steroidal alkylating agents bearing POPAM-OH were synthesized and their anticancer efficacy was evaluated in vitro and in vivo. All the novel hybrids demonstrated high antiproliferative effects against 5 different cancer cell lines in the low micromolar range. Treatment of SCID mice bearing SKOV-3 or PC-3 tumor xenografts with the most potent hybrid 19 led to significant reduction of tumor size (tumor inhibition TI = 95% in SKOV3 models and TI = 85.2% in PC3 models). Importantly, the acute toxicity of hybrid 19 (LD10 = 36 μΜ, LD50 = 62 μΜ) in CB17 SCID mice exhibited three-fold decrease compared to the acute toxicity of previously reported hybrids of POPAM-NH2. This is an important finding since systemic cytotoxicity is a critical limitation of alkylating agents. Collectively, the steroidal conjugates of POPAM-OH displayed significant anticancer efficacy and reduced toxicity in vitro and in vivo rendering them as good candidates for cancer therapy.

Copper(II) complexes with thioether based SNS pincer ligand: Synthesis, characterization and antiproliferative activity

In this study, the SNS pincer type 2,6-bis[[(4-bromophenyl)thio]methyl]pyridine ligand (L) (1) and its novel Cu(II) complexes ([Cu(k3-L)(X)2]·nH2O (X=Cl, SCN, ClO4)) were synthesized and characterized by using NMR, UV-Vis, FT-IR spectroscopy, mass spectrometry, molar conductivity and elemental analysis techniques. The synthesized Cu complexes exhibited a triangular bipyramidal structure. The compounds were found to have non-electrolytic behavior. The antiproliferative activities of these compounds and a positive control drug were tested in three different cancer cell lines including colon, lung and liver. The results obtained using the MTT method showed that the three metal complexes prepared from the ligand containing the pyridine nucleus were found to have higher antiproliferative effects in all tested cancer cell lines compared to the positive control drug cisplatin.

ANTIPROLIFERATIVE ACTIVITIES OfEXTRACTS FROM MYCELIAL BIOMASS OFSOME MEDICINAL BASIDIOMYCETES IN HUMAN COLONCANCERCELLSCOLO 205.

Theanticancer effects ofphytohormones ofcytokinin nature are similar to those ofmedicinal mushrooms, which are able to synthesize cytokinins in large amounts. To determine theantiproliferative effect ofcrude extracts and cytokinin fractions from themycelial biomass ofseven fungi species on colon cancer cells in vitro. Cytokinin content in mycelial biomass ofGanoderma lucidum, Lentinula edodes, Trametes versicolor, Pleurotus ostreatus, Morchella esculenta, Hericium coralloides, and Fomitopsis officinalis was determined by high performance liquid chromatography mass spectrometry. Theantiproliferative effect ofthemushroom extracts on thehuman colon adenocarcinoma Colo 205cells was assessed by MTT-test. Thecontent ofcytokinins (trans-zeatin, zeatin riboside, isopentenyladenosine, isopentenyladenine and zeatin-O-glucoside) was determined in themycelial biomass ofthemedicinal macromycetes. Zeatin-type hormones prevailed in all species, though trans-zeatin was themost abundant in H.coralloides and M.esculenta. In P.ostreatus, only zeatin-O-glucoside was detected. Thelowest IC50was found forboth thecytokinin fraction (0.21μg/ml) and thecrude extract (0.17μg/ml) from mycelial biomass ofH.coralloides. F.officinalis also demonstrated high antiproliferative effect against Colo205cells: IC50was 0.9μg/ml forthecrude extract and almost twice lower forthecytokinin fraction. In thestudied concentration range (0.016-2μg/ml), thecrude extracts from G.lucidum and M.esculenta and thecytokinin fraction from L.edodes did not reach IC50values. Thepresent study showed that crude extracts and/or cytokinin fractions ofseveral medicinal Basidiomycetes species are capable to inhibit proliferation ofcolon cancer cells in vitro. Crude extract cytotoxicity ofH.coralloides, P.ostreatus and T.versicolor was higher than that ofcytokinin fraction while antiproliferative effect ofcytokinin fraction from F.officinalis was higher than that in its crude extract.

Green Synthesis of Silver Nanoparticles Using Randia aculeata L. Cell Culture Extracts, Characterization, and Evaluation of Antibacterial and Antiproliferative Activity.

The demand for metallic nanoparticles synthesized using green methods has increased due to their various therapeutic and clinical applications, and plant biotechnology may be a potential resource facilitating sustainable methods of AgNPs synthesis. In this study, we evaluate the capacity of extracts from Randia aculeata cell suspension culture (CSC) in the synthesis of AgNPs at different pH values, and their activity against pathogenic bacteria and cancer cells was evaluated. Using aqueous CSC extracts, AgNPs were synthesized with 10% (w/v) of fresh biomass and AgNO3 (1 mM) at a ratio of 1:1 for 24 h of incubation and constant agitation. UV-vis analysis showed a high concentration of AgNPs as the pH increased, and TEM analysis showed polydisperse nanoparticles with sizes from 10 to 90 nm. Moreover, CSC extracts produce reducing agents such as phenolic compounds (162.2 ± 27.9 mg gallic acid equivalent/100 g biomass) and flavonoids (122.07 ± 8.2 mg quercetin equivalent/100 g biomass). Notably, AgNPs had strong activity against E. coli, S. pyogenes, P. aeruginosa, S. aureus, and S. typhimurium, mainly with AgNPs at pH 6 (MIC: 1.6 to 3.9 µg/mL). AgNPs at pH 6 and 10 had a high antiproliferative effect on cancer cells (IC50 < 5.7 µg/mL). Therefore, the use of cell suspension cultures may be a sustainable option for the green synthesis of AgNPs.

Design, Synthesis, Characterization, Antiproliferative Activity, and In Silico Studies of Novel Alkyl Ether Derivatives Containing 1H‐1,2,4‐Triazole Ring

AbstractIn this study, starting from 1H‐1,2,4‐triazole, a new series of aliphatic ether derivatives containing phenyl and 1H‐1,2,4‐triazole groups together were synthesized using reduction and Williamson ether synthesis mechanisms, respectively. The molecular structures of the synthesized compounds were characterized by fourier‐transform infrared spectroscopy (FT‐IR), 1H and 13C nuclear magnetic resonance (1H NMR and 13C NMR), mass spectroscopy, and elemental analysis techniques. All synthesized compounds were screened against three different human cancer cell lines, including colon, lung, and liver cancer cells. Some of the compounds showed exceptionally high antiproliferative effects against all three cancer cell lines, with IC50 values much lower than the positive control drug bendamustine. In addition, molecular docking studies were performed to support the in vitro results and the interaction types and amino acids that play key roles in the binding of the compounds to enzymes were identified. Finally, the potential of these compounds to be drugs and their drug‐likeness properties were evaluated by absorption, distribution, metabolism, and excretion‐toxicity (ADMET) calculations and it was determined that the compounds could be drug candidates with the capacity to be effective and safe drugs for use in the treatment of different diseases.

Discovery and optimization of 4-anilinoquinazoline derivatives spanning ATP binding site and allosteric site as effective EGFR-C797S inhibitors

Epidermal growth factor receptor (EGFR) is an effective drug target for the treatment of non-small cell lung cancer (NSCLC). However, a tertiary point mutation (C797S) at the ATP binding pocket of the EGFR induces resistance to the third-generation EGFR inhibitors, due to the loss of covalent interaction with Cys797. Here, we designed a series of 4-anilinoquinazoline derivatives that simultaneously occupied the ATP binding pocket and the allosteric site. The newly-synthesized compounds displayed high potency against EGFR-C797S resistance mutation. Among them, compound 14d presented high anti-proliferative effect against BaF3-EGFRL858R/T790M/C797S (IC50 = 0.75 μM) and BaF3-EGFR19del/T790M/C797S (IC50 = 0.09 μM) cells. Moreover, 14d resulted in obvious inhibition activities against EGFR and its downstream signaling pathways in a dose-dependent manner in BaF3-EGFR19del/T790M/C797S cells. Finally, 14d significantly inhibited tumor growth in BaF3-EGFR19del/T790M/C797S xenograft model (30 mg/kg, TGI = 67.95%). These results demonstrated that 14d is a novel and effective EGFR-C797S inhibitor which spanning the ATP binding pocket and the allosteric site and effective both in vitro and in vivo.

Design, Synthesis and Biological Evaluation of Novel and Potent Protein Arginine Methyltransferases 5 Inhibitors for Cancer Therapy.

Protein arginine methyltransferases 5 (PRMT5) is a clinically promising epigenetic target that is upregulated in a variety of tumors. Currently, there are several PRMT5 inhibitors under preclinical or clinical development, however the established clinical inhibitors show favorable toxicity. Thus, it remains an unmet need to discover novel and structurally diverse PRMT5 inhibitors with characterized therapeutic utility. Herein, a series of tetrahydroisoquinoline (THIQ) derivatives were designed and synthesized as PRMT5 inhibitors using GSK-3326595 as the lead compound. Among them, compound 20 (IC50: 4.2 nM) exhibits more potent PRMT5 inhibitory activity than GSK-3326595 (IC50: 9.2 nM). In addition, compound 20 shows high anti-proliferative effects on MV-4-11 and MDA-MB-468 tumor cells and low cytotoxicity on AML-12 hepatocytes. Furthermore, compound 20 possesses acceptable pharmacokinetic profiles and displays considerable in vivo antitumor efficacy in a MV-4-11 xenograft model. Taken together, compound 20 is an antitumor compound worthy of further study.

An Insight into Symmetrical Cyanine Dyes as Promising Selective Antiproliferative Agents in Caco-2 Colorectal Cancer Cells.

Cancer remains one of the diseases with the highest worldwide incidence. Several cytotoxic approaches have been used over the years to overcome this public health threat, such as chemotherapy, radiotherapy, and photodynamic therapy (PDT). Cyanine dyes are a class of compounds that have been extensively studied as PDT sensitisers; nevertheless, their antiproliferative potential in the absence of a light source has been scarcely explored. Herein, the synthesis of eighteen symmetric mono-, tri-, and heptamethine cyanine dyes and their evaluation as potential anticancer agents is described. The influences of the heterocyclic nature, counterion, and methine chain length on the antiproliferative effects and selectivities were analysed, and relevant structure–activity relationship data were gathered. The impact of light on the cytotoxic activity of the most promising dye was also assessed and discussed. Most of the monomethine and trimethine cyanine dyes under study demonstrated a high antiproliferative effect on human tumour cell lines of colorectal (Caco-2), breast (MCF-7), and prostate (PC-3) cancer at the initial screening (10 µM). However, concentration–viability curves showed higher potency and selectivity for the Caco-2 cell line. A monomethine cyanine dye derived from benzoxazole was the most promising compound (IC50 for Caco-2 = 0.67 µM and a selectivity index of 20.9 for Caco-2 versus normal human dermal fibroblasts (NHDF)) and led to Caco-2 cell cycle arrest at the G0/G1 phase. Complementary in silico studies predicted good intestinal absorption and oral bioavailability for this cyanine dye.

Phytochemical Investigation of Egyptian Riverhemp: A Potential Source of Antileukemic Metabolites

As part of our research group’s continuous efforts to find alternative treatments for cancer, the aqueous ethanol extract of Sesbania sesban L. Merr. (SS, Egyptian riverhemp) demonstrated an antileukemic activity against K562 cell line. Bioguided fractionation of SS leaves hydroethanolic extract resulted in the isolation of one new compound (33) named as hederatriol 3-O-β-D-glucuronic acid methyl ester as well as 34 known compounds. Seven compounds ((34), (22), (20), (24), (21), (19), and (35)) showed high antiproliferative effects (IC50 = 22.3, 30.8, 31.3, 33.7, 36.6, 37.5, and 41.5 μM, respectively), while four compounds ((32), (5), (29), and (1)) showed milder activities (IC50 = 56.4, 67.6, 83.3, and 112.3 μM, respectively). A mechanistic study was further carried out on a molecular genetics level against several transcription factors signaling pathways that are incorporated in the incidence of cancer. The results showed that compounds (22) and (21) demonstrated a specific inhibition of Wnt pathway (IC50 = 3.8 and 4.6 μM, respectively), while compound (22) showed a specific inhibition of Smad pathway (IC50 = 3.8 μM). Compound (34) strongly altered the signaling of Smad and E2F pathways (IC50 = 5 μM). The bioactive metabolites were further investigated in silico by docking against several targets related to K562 cell line. The results showed that compounds (22) and (34) exhibited a strong binding affinity towards topoisomerase (docking score = −7.81 and −9.30 Kcal/Mole, respectively). Compounds (22) and (34) demonstrated a strong binding affinity towards EGFR-tyrosine kinase (docking score = −7.12 and −7.35 Kcal/Mole, respectively). Moreover, compound (34) showed a strong binding affinity towards Abl kinase (docking score = −7.05 Kcal/Mole).

Unveiling the Antioxidant Therapeutic Functionality of Sustainable Olive Pomace Active Ingredients.

Olive pomace (OP) is the main residue that results from olive oil production. OP is rich in bioactive compounds, including polyphenols, so its use in the treatments of diseases related to oxidative stress, such as cancer, could be considered. The present work aimed to study the biological properties of different OP extracts, obtained by ohmic heating-assisted extraction and conventional heating, using water and 50% ethanol, in the treatment and prevention of colorectal cancer through Caco-2 cell models. Additionally, an in-silico analysis was performed to identify the phenolic intestinal absorption and Caco-2 permeability. The extracts were chemically characterized, and it was found that the Ohmic-hydroethanolic (OH-EtOH) extract had the highest antiproliferative effect, probably due to its higher content of phenolic compounds. The OH-EtOH induced potential modifications in the mitochondrial membrane and led to apoptosis by cell cycle arrest in the G1/S phases with activation of p53 and caspase 3 proteins. In addition, this extract protected the intestine against oxidative stress (ROS) caused by H2O2. Therefore, the bioactive compounds present in OP and recovered by applying a green technology such as ohmic-heating, show promising potential to be used in food, nutraceutical, and biomedical applications, reducing this waste and facilitating the circular economy.