Antibacterial profile and antiproliferative activities over human tumor cells of new silver(I) complexes containing two distinct trifluoromethyl uracil isomers.

New silver(I) complexes of 5-(trifluoromethyl)uracil (5TFMU) and 6-(trifluoromethyl)uracil (6TFMU) isomers were synthesized, characterized, and evaluated as antibacterial and antiproliferative agents. Based on elemental and thermogravimetric analyses, the Ag-5TFMU and Ag-6TFMU species are formulated as AgC5H2F3N2O2 and Ag2C5HF3N2O2, respectively. Infrared and 13C solid-state nuclear magnetic resonance spectroscopies suggest coordination of the trifluoromethyluracil isomers to silver by both nitrogen and oxygen atoms. Confirmation of their structure and connectivity was achieved, in the absence of single crystals of suitable quality, by state-of-the-art structural powder diffraction methods. In Ag-5TFMU, the organic ligand is tridentate and two distinct metal coordination environments are found (linear AgN2 as well as C2v AgO4 geometries), whereas Ag-6TFMU contains a complex polymeric structure with tetradentate dianionic 6TFMU moieties and five distinct AgX2 (X = N, O) fragments, further stabilized by ancillary (longer) Ag…O contacts. These species presented modest activity over Gram-positive and Gram-negative bacterial strains, whereas Ag-6TFMU was active over a set of tumor cells, with the best activity over prostate (PC-3) and kidney cell lines and selectivity indices of 4.6 and 1.3, respectively. On the other hand, Ag-5TFMU was active over all considered tumor cells except MCF-7 (breast cancer). The best activity was found for PC-3 cells, but no selectivity was observed. The Ag-5TFMU and Ag-6TFMU species also reduced the proliferation of tongue squamous cell carcinoma cell lines SCC - 4 and SCC-15. Preliminary biophysical assays by circular dichroism suggest that the Ag-5TFMU complex interacts with DNA by intercalation, an effect not seen in Ag-6TFMU.

Citrus wastewater as a source of value-added products: Quali-quantitative analysis and in vitro screening on breast cancer cell lines.

Citrus wastewater from industries is a source of bioactive compounds whose recovery could be a useful approach to convert processing waste into potential resources to be exploited in food, pharmaceutical, and chemical companies. Citrus wastewater, obtained from the industrial processing of Citrus sinensis, was freeze-dried and qualitative/quantitative evaluated using HPLC/MS Q-TOF analysis. Antiproliferative activity was investigated on MDA-MB-231 (triple-negative breast cancer cell line), MCF-7 (breast cancer cell line), and its multidrug-resistant variant MCF-7R. Fraction 8 emerged for its cytotoxicity toward MCF-7R cells. Its main component, the polymethoxylated flavone nobiletin (80%), is likely involved in increasing the number of G1-phase MCF-7R cells without inducing cell death. Notably, fraction 8 sensitizes MCF7-R cells to the antiproliferative effects of doxorubicin, thus contributing to overcoming MCF7-R multidrug resistance. Our studies highlighted the possibility of applying a sustainable strategy for citrus wastewater recycling to recover functional compounds as useful adjuvants for the prevention and treatment of malignancies.

Chemical composition and biological activities of nine essential oils obtained from Algerian plants.

The essential oils (EOs) from nine species (Artemisia campestris, A. herba-alba, Juniperus foetidissima, Laurus nobilis, Mentha pulegium, M. spicata, Rosmarinus officinalis, Salvia officinalis, and Thymus vulgaris) of the Algerian flora have been hydrodistilled, analysed, and tested for their antioxidant and antiproliferative properties. A. campestris EO showed a higher content of terpene hydrocarbons; A. herba-alba EO was mainly rich in their oxygenated derivatives. Sesquiterpenes were the most abundant compounds in J. foetidissima EO, while oxygenated monoterpenes and phenylpropanoids prevailed in L. nobilis EO. The other EOs were rich in oxygenated monoterpenes, with quality-quantitative differences. T. vulgaris and L. nobilis performed better in all the antioxidant assays, respectively with IC50 values ranging from 0.0002 and 0.0012 mg/mL in the CUPRAC assay to 2.83 and 3.50 mg/mL in the FRAP assay. T. vulgaris was also the only EO exhibiting an antiproliferative activity towards the human breast (MCF-7) and lung (A549) cancer cell lines.

Ruthenium complexes with abiraterone acetate as antiproliferative agents.

This study is dedicated to the development of multimodal anticancer agents. We have obtained ruthenium complexes conjugated with the steroid-type antitumor drug abiraterone acetate in order to take advantage of the dual antitumor properties of both ruthenium and abiraterone. The compounds exhibit good antiproliferative activity against cancer cells, with selectivity over primary fibroblasts. Real-time cell analysis revealed that compound dichlorido(η66-p-cymene)(abiraterone acetate)ruthenium(II) had pronounced antiproliferation activity compared to abiraterone acetate. Flow cytometric studies on the mechanism of cell death have revealed that the most active compound induces apoptosis more effectively than abiraterone acetate. Our findings demonstrate the potential of this novel dual-action compound as promising candidates for further development as anticancer agents.

Design and synthesis of triazolopyridine derivatives as potent JAK/HDAC dual inhibitors with broad-spectrum antiproliferative activity.

A series of triazolopyridine-based dual JAK/HDAC inhibitors were rationally designed and synthesised by merging different pharmacophores into one molecule. All triazolopyridine derivatives exhibited potent inhibitory activities against both targets and the best compound 4-(((5-(benzo[d][1, 3]dioxol-5-yl)-[1, 2, 4]triazolo[1, 5-a]pyridin-2-yl)amino)methyl)-N-hydroxybenzamide (19) was dug out. 19 was proved to be a pan-HDAC and JAK1/2 dual inhibitor and displayed high cytotoxicity against two cancer cell lines MDA-MB-231 and RPMI-8226 with IC50 values in submicromolar range. Docking simulation revealed that 19 fitted well into the active sites of HDAC and JAK proteins. Moreover, 19 exhibited better metabolic stability in vitro than SAHA. Our study demonstrated that compound 19 was a promising candidate for further preclinical studies.

Polymethoxylated flavone variations and in vitro biological activities of locally cultivated Citrus varieties in China.

Citrus peels are rich in polymethoxylated flavones (PMFs), which have beneficial health and pharmacological properties. In this study, the profiles, variations, and biological activities of PMFs in the peel extracts of 27 Citrus varieties (eight species) native to China were investigated. UPLC-QTOF-MS/MS analysis revealed that mandarin accumulated more diversity and higher detectable PMF contents. Wangcangzhoupigan (ZPG) possessed the highest antioxidant capacity. Gailiangcheng (GLC) and Bingtangcheng (BTC), sweet oranges showed excellent inhibitory effects against pancreatic lipase and α-glucosidase, respectively. Most citrus extracts effectively inhibited the production of ROS and pro-inflammatory cytokines, while increasing the accumulation of anti-inflammatory cytokines. In addition, Limeng (LM), Cupig-oushigan (GSG), and Yanxiwanlu (YXWL) showed anti-proliferative effects against DU145 and PC3 cancer cells. This study provides a comprehensive PMF profile and biological activities of various citrus species and will benefit future functional citrus breeding practices aimed at designing plants rich in total or specific PMFs for health benefits.

Copper and Manganese Complexes of Pyridinecarboxaldimine Induce Oxidative Cell Death in Cancer Cells.

Leveraging the versatile redox behavior of transition metal complexes with heterocyclic ligands offers significant potential for discovering new anticancer therapeutics. This study presents a systematic investigation of a pyridinecarboxaldimine ligand (PyIm) with late 3d-transition metals inhibiting cancer cell proliferation and the mechanism of action. Synthesis and thorough characterization of authentic metal complexes of redox-active late 3d-transition metals enabled the validation of antiproliferative activity in liver cancer cells. Notably, (PyIm)2Mn(II) (1) and (PyIm)2Cu(II) (5) complexes exhibited a good inhibitory profile against liver cancer cells (EC50: 4.0 µM for 1 and 1.7 µM for 5) with excellent selectivity over normal kidney cells (Selectivity index, SI = 17 for 5). Subsequently, evaluation of these complexes in cancers cell lines from four different sites of origin (liver, breast, blood, and bone) demonstrated a predominant selectivity to liver and a moderate selectivity to breast cancer and leukemia cells over the normal kidney cells. The mechanism of action studies highlighted no expected DNA damage in cells, rather, the enhancement of extracellular and intracellular reactive oxygen species (ROS) resulting in mitochondrial damage leading to oxidative cell death in cancer cells. Notably, these complexes potentiated the antiproliferative effect of commercially used cancer therapeutics (cisplatin, oxaliplatin, doxorubicin, and dasatinib) in liver cancer cells. These findings position redox-active metal complexes for further evaluation as promising candidates for developing anticancer therapeutics and combination therapies.

Phosphoinositide 3-Kinase Inhibitors from Gladiolus segetum Ker-Gawl Corms Supported by Network Pharmacology.

Gladiolus segetum Ker-Gawl corms total extract exhibited remarkable in vitro anti-proliferative effects against panel of cancer cell lines; including human colon carcinoma (Caco-2), human breast cancer (MCF7) and hepatocellular carcinoma (HepG2) cell lines with IC50 values of 7.4, 9.1 and 11.2 µg/ml, respectively. The total ethanolic extract of G. segetum Ker-Gawl corms was subjected to untargeted metabolomics profiling using LC-HR-ESI-MS, which revealed the presence of various clusters of phytoconstituents as triterpenes, anthraquinones, flavonoids and phenolic derivatives. Network pharmacology study was performed for all identified compounds, the formed networks identified 73 intersected genes. The diagrammatic illustration of the top pathways revealed that phosphoinositide 3-kinase (PI3K) gene is the effective dominant gene in the top four KEGG pathways. Upon molecular docking and molecular dynamics investigation, kaempferol-3-O-glucopyranoside was suggested to be key anticancer metabolite. Interestingly, cytotoxic investigation of this compound revealed potential activity against the tested cancer cell lines (Caco-2, MCF7 and HepG2) with IC50 values of 6.2, 8.5 and 9.3 µg/ml, respectively. The present study highlighted the potential of G. segetum Ker-Gawl as a promising source of interesting anticancer scaffolds.

Diterpenoids with Potent Anti-Psoriasis Activity from Euphorbia helioscopia L.

Psoriasis, an immune-mediated inflammatory skin disorder, seriously affects the quality of life of nearly four percent of the world population. Euphorbia helioscopia L. is the monarch constituent of Chinese ZeQi powder preparation for psoriasis, so it is necessary to illustrate its active ingredients. Thus, twenty-three diterpenoids, including seven new ones, were isolated from the whole herb of E. helioscopia L. Compounds 1 and 2, each featuring a 2,3-dicarboxylic functionality, are the first examples in the ent-2,3-sceo-atisane or the ent-2,3-sceo-abietane family. Extensive spectroscopic analysis (1D, 2D NMR, and HRMS data) and computational methods were used to confirm their structures and absolute configurations. According to the previous study and NMR data from the jatropha diterpenes obtained in this study, some efficient 1H NMR spectroscopic rules for assigning the relative configurations of 3α-benzyloxy-jatroph-11E-ene and 7,8-seco-3α-benzyloxy-jatropha-11E-ene were summarized. Moreover, the hyperproliferation of T cells and keratinocytes is considered a key pathophysiology of psoriasis. Anti-proliferative activities against induced T/B lymphocytes and HaCaT cells were tested, and IC50 values of some compounds ranged from 6.7 to 31.5 µM. Compounds 7 and 11 reduced the secretions of IFN-γ and IL-2 significantly. Further immunofluorescence experiments and a docking study with NF-κB P65 showed that compound 13 interfered with the proliferation of HaCaT cells by inhibiting the NF-κB P65 phosphorylation at the protein level.

2-Arylbenzofurans from the stems and leaves of Artocarpus tonkinensis and their potential antiproliferative activities.

Phytochemical study on the stems and leaves of Artocarpus tonkinensis led to the isolation of a new 2-arylbenzofuran, artocartone (1), as well as seven known 2-arylbenzofurans (2-8). The chemical structure of 1 was established by means of comprehensive spectroscopic analyses and the known compounds were determined by comparing their MS and NMR data with those reported data in literature. The antiproliferative activities of all isolates 1-8 against five human cancer cell lines: HL-60, SMMC-7721, A-375, MCF-7 and SW480 in vitro were evaluated. As a result, compounds 1- 8 displayed notable antiproliferative activities against various human cancer cell lines with IC50 values in the range of 0.28 ± 0.05-26.89 ± 0.18 µM.

Comprehensive phenolic profiling and biological evaluation of Centaurea glastifolia L. (Asteraceae).

The present investigation focused on the comprehensive analysis of the phenolic profile of Centaurea glastifolia L. (Asteraceae) and the assessment of its diverse biological activities. Utilising LC-MS/MS, the phytochemical composition of the 70% methanol extract of Centaurea glastifolia (CG-ME) was thoroughly elucidated, revealing the presence of 30 distinct phytochemical compounds. Notably, major phenolic constituents identified in the extract included quinic acid, chlorogenic acid, luteolin-7-O-glucoside, kaempferol-3-O-glucoside, luteolin, and apigenin-7-O-glucoside. The antioxidant, antibacterial, antiproliferative, and cytotoxic activities of CG-ME were investigated. The CG-ME exhibited a moderate capacity for scavenging DPPH radicals (IC50: 50.05 ± 1.58 µg/mL) and FRAP (63.96 ± 0.39 mg TE/g extract), indicating a moderate level of antioxidant activity. Moreover, CG-ME demonstrated significant antiproliferative effects (GI50: 1.10 and 1.30 µg/mL) on cancer cells (C6 and HTC cancer cell lines, respectively) while displaying low cytotoxicity towards normal cells (LC50: >1000 µg/mL). In terms of antibacterial activity, CG-ME was found to be inactive against tested both Gram-positive and Gram-negative bacterial strains (MIC > 500 µg/mL). The extracts had a promising antiproliferative effect on C6, HeLa, and HT29 cancer cell lines with a less cytotoxic effect (10.5-14.2%) against normal cells.

Exosomal Delivery Enhances the Antiproliferative Effects of Acid-Hydrolyzed Apiaceae Spice Extracts in Breast Cancer Cells.

Breast cancer remains a leading cause of death worldwide. The Apiaceae plant family includes many culinary spices that have been shown to have medicinal properties. Many phytochemicals exhibit potent bioactivities but often suffer from poor uptake and oral bioavailability. Bovine milk and colostrum exosomes are a compelling drug delivery platform that could address this issue; these natural nanoparticles can be loaded with hydrophilic and lipophilic small molecules and biologics, resulting in lower doses needed to inhibit cancer growth. Ethanolic extracts of eight Apiaceae spices were examined for phytochemical content and antiproliferative potential. Acid hydrolysis (AH) was employed to remove glycosides, asses its impacts on extract efficacy, and evaluate its effects on exosome loading and subsequent formulation efficacy. Antiproliferative activity was assessed through MTT assays on T-47D, MDA-MB-231, and BT-474 breast cancer cells; all extracts exhibited broad antiproliferative activity. AH enhanced the bioactivity of cumin, caraway, and fennel in T-47D cells. Celery, cumin, anise, and ajwain showed the highest activity and were assayed in exosomal formulations, which resulted in reduced doses required to inhibit cellular proliferation for all extracts except AH-cumin. Apiaceae spice extracts demonstrated antiproliferative activities that can be improved with AH and further enhanced with exosomal delivery.

Molecular docking and DFT study of antiproliferative ribofuranose nucleoside derivatives targeting EGFR and VEGFR2in cancer cells.

Antimetabolites are the most effective chemotherapeutics for treating cancer. They have exerted their anticancer effects by interfering with DNA synthesis. Recently, interest in modified nucleoside analogues has grown due to their superior efficiency. Nucleoside analogue derivatives have emerged as crucial candidates for cancer treatment due to their ability to target the cells responsible for cancer within the body specifically. The ability of nucleoside analogues derivatives to target specific molecular pathways has reduced toxicity and increased efficiency compared to traditional chemotherapy drugs. Nucleoside analogues have interfered with physiological nucleosides and induced cytotoxicity in cancerous cells. In this investigation, derivatives of ribofuranose nucleoside analogues have been designed. Density functional theory (DFT) calculations have been performed at the B3LYP/6-311 G(d,p) level. The designed molecules have been characterized by UV/Vis spectroscopy using the CPCM model in DMSO solvent, and molecular structural parameters, such as HOMO/LUMO and MEPS, have been determined. Derivative d1m has exhibited a high energy gap and low absorption energy compared to the other derivatives. Molecular docking of the designed molecules (d1o-d2m) has been performed with the EGFR and VEGFR2 proteins. d2o has shown good binding energy with the EGFR protein, while d1o has shown good results with VEGFR2. Global chemical parameters and NBO analysis have been conducted to investigate the derivatives charge transfer properties and chemical reactivity. NBO analysis has provided information about the donor and acceptor parts within a molecule, while global chemical parameters have given insights into the reactivity, stability, and solubility of the molecules. It has been found that the derivatives are more chemically reactive, thermodynamically stable, and have better binding affinity than the parent molecule. Based on the analysis, the drug interaction with the cancer-causing protein makes it more effective for cancer treatment.

Iron oxide nanoparticles derived from Polyalthia korintii (Dunal) Benth. & Hook. F leaves extract exhibits biological and dye degradation potentials.

Green synthesis of iron oxide nanoparticles using plant extracts is of tremendous interest owing to its cost effectiveness, ecofriendly and high efficiency compared to physical and chemical approaches. In the current study, we describe a green approach for producing iron oxide nanoparticles utilizing Polyalthia korintii aqueous leaf extract (PINPs). The prepared PINPs were assessed of their biological and dye degradation potentials. The physico-chemical characterization of PINPs using UV-Visible spectrophotometer, Fourier Transform Infrared Spectroscopy, X-Ray Diffraction studies, Field emission Scanning Electron Microscopy and Energy Dispersive X-ray spectroscopy analysis confirmed the synthesized sample comprised of iron oxide entity, predominantly spherical with the size range of 40-60 nm. Total Phenolic Content of PINPs is 59.36 ± 1.64 µg GAE/mg. The PINPs exhibited 89.78 ± 0.07% DPPH free radical scavenging and 28.7 ± 0.21% ABTS cation scavenging activities. The antibacterial activities were tested against different gram-positive and gram-negative bacteria and PINPs were more effective against Enterococcus faecalis and Klebsiella pneumoniae. Cytotoxicity of PINPs against K562 and HCT116 were measured and IC50 values were found to be 84.99 ± 4.3 µg/ml and 79.70 ± 6.2 µg/ml for 48 h respectively. The selective toxicity of PINPs was demonstrated by their lowest activity on lymphocytes, HEK293 cells, and erythrocytes. The toxicity (LC 50 values) against first, second, third and fourth instar larvae of Culex quinquefasciatus was 40 ± 1.5 mg/mL, 45 ± 0.8 mg/mL, 99 ± 2.1 mg/mL and 120 ± 3.5 mg/mL respectively. Finally, PINPs were utilized to as a catalyst for removal of textile dyes like Methylene blue and methyl orange in a fenton-like reaction. The results showed 100% dye degradation efficiency in a fenton like reaction within 35 min. Thus, the green synthesized PINPs exhibit antioxidant, antibacterial, antiproliferative, larvicidal and dye degradation potentials, indicating their suitability for biological and environmental applications.

Anticancer dinuclear Ir(III) complex activates Nrf2 and interferes with NAD(H) in cancer cells.

Dinuclear complex [Ir2(µ-L1)(η5-Cp*)2Cl2](PF6)2 (1) exhibits low micromolar cytotoxic activity in vitro in various human cancer cells (GI50 = 1.7-3.0 µM) and outperformed its mononuclear analogue [Ir(η5-Cp*)Cl(L2)]PF6 (2; GI50 > 40.0 µM); Cp* = pentamethylcyclopentadienyl, L1 = 4-chloro-2,6-bis[5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl]pyridine, L2 = 5-(pyridin-2-yl)-1,3,4-thiadiazol-2-amine. Compound 1 upregulated the Keap1/Nrf2 oxidative stress-protective pathway in the treated MV4-11 acute myeloid leukemia cells. In connection with the redox-mediated mode of action of 1, its NADH-oxidizing activity was detected in solution (1H NMR), while NAD+ remained intact (with formate as a hydride source). Surprisingly, only negligible NADH oxidation was detected in the presence of the reduced glutathione and ascorbate. Following the results of in-solution experiments, NAD(H) concentration was assessed in 1-treated MV4-11 cancer cells. Besides the intracellular NADH oxidation in the presence of 1, the induced oxidative stress also led to a decrease of NAD+, resulting in depletion of both NAD+/NADH coenzymes. The discussed findings provide new insight into the biochemical effects of catalytic anticancer compounds that induce cell death via a redox-mediated mode of action.

Synthetic Strategies towards the Generation of Penicillin-Containing Hybrids in the Search for Anticancer Activity.

An extended library of hybrids that combined a penicillin derivative with a peptoid moiety was designed and synthetized using either a solid-phase or a mixed solid-phase/solution-phase strategy. The library was further evaluated for antiproliferative activity. While none of the different synthesized compounds showed significant cytotoxicity against a normal cell line, tumor cell results drew several conclusions, when comparing with our reference, the highly active triazolylpeptidyl penicillin derivative, TAF7f. Thus, when the 1,2,3-triazole group was exchanged by its "retro-inverse" analogue, no change was noted in the activity of the hybrids; however, better performance was generally obtained if the triazole is replaced by a glycine moiety. Additionally, the absence of hydrogen bond donor groups decreased the compounds activity, which could explain that, in general, this set of derivatives were less active than their peptide-containing analogues. From this study, is indisputable that, regardless of the type of chain (peptide, peptoid or mixture) attached to penicillin, an isobutyl side chain placed in the position closest to penicillin and a benzyl in the next position are determinant for the activity.

Comprehensive phytochemical profiling and biological activities of Hodgsonia heteroclita subsp. indochinensis seed extracts.

Hodgsonia heteroclita subsp. indochinensis, a member of the Cucurbitaceae family, is utilized in traditional medicinal remedies based on indigenous wisdom. This study aimed to comprehensively identify and analyze the bioactive phytoconstituents within H. heteroclita subsp. indochinensis seeds. Seeds were sequentially extracted with n-hexane, ethyl acetate, and methanol. Liquid chromatography-mass spectrometry analysis detected ferulic acid, salicylic acid, cucurbitacin E, stigmasterol glucoside, and ß-sitosterol glucoside in all extracts. The total phenolic content in the HH(S)-EtOAc and HH(S)-MeOH was 14.22 ± 1.58 and 12.98 ± 1.03 mg gallic acid equivalent/g, respectively. Consequently, the HH(S)-EtOAc demonstrated antioxidant activity with an IC50 of 1.10 ± 0.28 mg/mL, while the HH(S)-MeOH displayed strong antioxidant potential with an IC50 of 0.04 ± 0.00 mg/mL according to an ABTS assay. Antibacterial evaluations of both the HH(S)-hexane and HH(S)-EtOAc revealed significant activity against Staphylococcus aureus (zone of inhibition (ZOI): 13.67 ± 2.31 and 11.67 ± 1.53 mm, respectively) but limited activity against Escherichia coli (ZOI: 7.33 ± 0.58 and 7.67 ± 0.58 mm, respectively). Additionally, the extracts exhibited low minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values, ranging from 62.50 to 250 mg/mL. The antiproliferative activity of seed extracts was assessed against two breast cancer cell lines (MCF-7 and MDA-MB-231), normal breast cells (MCF10A), and human embryonic kidney (HEK) 293T cells, through MTT and clonogenic assays. The results revealed IC50 values exceeding 400 µg/mL, indicating that the extracts are safe. Furthermore, all seed extracts (50 µg/mL) exhibited potent anti-inflammatory activity, evident by their substantial inhibition of nitric oxide production (p < 0.001) and inducible nitric oxide synthase (iNOS) gene expression (p < 0.05) in LPS-induced RAW264.7. These findings demonstrate the potential for H. heteroclita subsp. indochinensis seed extracts in the development of functional foods, nutraceuticals, and dietary supplements due to their diverse bioactive compounds and substantial biological activities, particularly their anti-inflammatory effects.

A Benzimidazole-Based N-Heterocyclic Carbene Derivative Exhibits Potent Antiproliferative and Apoptotic Effects against Colorectal Cancer.

Background and Objectives: Colorectal cancer (CRC) remains a major global health issue. Although chemotherapy is the first-line treatment, its effectiveness is limited due to drug resistance developed in CRC. To overcome resistance and improve the prognosis of CRC patients, investigating new therapeutic approaches is necessary. Materials and Methods: Using human colorectal adenocarcinoma (HT29) and metastatic CRC (SW620) cell lines, the potential anticancer properties of a newly synthesized compound 1-(Isobutyl)-3-(4-methylbenzyl) benzimidazolium chloride (IMBZC) were evaluated by performing MTT cytotoxicity, cell migration, and colony formation assays, as well as by monitoring apoptosis-related protein and gene expression using Western blot and reverse transcription-quantitative polymerase chain reaction technologies. Results: Tested at various concentrations, the half-maximal inhibitory concentrations (IC50) of IMBZC on HT29 and SW620 cell growth were determined to be 22.13 µM (6.97 µg/mL) and 15.53 µM (4.89 µg/mL), respectively. IMBZC did not alter the cell growth of normal HEK293 cell lines. In addition, IMBZC inhibited cell migration and significantly decreased colony formation, suggesting its promising role in suppressing cancer metastasis. Mechanistic analyses revealed that IMBZC treatment increased the expression of pro-apoptotic proteins p53 and Bax, while decreasing the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL, thus indicating the induction of apoptosis in IMBZC-treated CRC cells, compared to untreated cells. Additionally, the addition of IMBZC to conventional chemotherapeutic drugs (i.e., 5-fluorouracil, irinotecan, and oxaliplatin) resulted in an increase in the cytotoxic potential of the drugs. Conclusions: This study suggests that IMBZC has substantial anticancer effects against CRC cells through its ability to induce apoptosis, inhibit cancer cell migration and colony formation, and enhance the cytotoxic effects of conventional chemotherapeutic drugs. These findings indicate that IMBZC could be a promising chemotherapeutic drug for the treatment of CRC. Further research should be conducted using in vivo models to confirm the anti-CRC activities of IMBZC.

Data-Driven Modelling of Substituted Pyrimidine and Uracil-Based Derivatives Validated with Newly Synthesized and Antiproliferative Evaluated Compounds.

The pyrimidine heterocycle plays an important role in anticancer research. In particular, the pyrimidine derivative families of uracil show promise as structural scaffolds relevant to cervical cancer. This group of chemicals lacks data-driven machine learning quantitative structure-activity relationships (QSARs) that allow for generalization and predictive capabilities in the search for new active compounds. To achieve this, a dataset of pyrimidine and uracil compounds from ChEMBL were collected and curated. A workflow was developed for data-driven machine learning QSAR using an intuitive dataset design and forwards selection of molecular descriptors. The model was thoroughly externally validated against available data. Blind validation was also performed by synthesis and antiproliferative evaluation of new synthesized uracil-based and pyrimidine derivatives. The most active compound among new synthesized derivatives, 2,4,5-trisubstituted pyrimidine was predicted with the QSAR model with differences of 0.02 compared to experimentally tested activity.

Enhanced Anticancer Activity of 7MeERT over Ertredin: A Comparative Study on Cancer Cell Proliferation and NDUFA12 Binding.

We have previously identified Ertredin (3-(2-amino-5-bromophenyl) quinoxalin-2(1H)-one) as a compound that suppresses 3D spheroid formation and tumorigenesis in NIH3T3 cells induced by Epidermal Growth Factor Receptor variant III (EGFRvIII) transduction. One of its targets has been shown to be NDUFA12 (NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex Subunit 12), a component protein of oxidative phosphorylation complex I. In this report, we compared the growth inhibitory activity of Ertredin with its methylated analogue 7MeERT (3-(2-amino-5-bromophenyl)-7-methylquinoxalin-2(1H)-one) on human cancer cells. 7MeERT induced the inhibition of the proliferation of various cancer cells similarly to Ertredin and showed higher activity in glioblastoma cells, A431 cells overexpressing EGFR (wild type), and multiple myeloma cells. Molecular docking analysis and a Cellular Thermal Shift Assay (CETSA) suggested that 7MeERT binds to NDUFA12 similarly to Ertredin. The binding of 7MeERT and Ertredin to NDUFA12 in glioblastoma was further supported by the inhibition of the oxygen consumption rate. These results suggest that 7MeERT also binds to NDUFA12, inhibits oxidative phosphorylation, and has a higher anti-cancer cell growth inhibitory activity than Ertredin.