Human Breast Adenocarcinoma Cell Research Articles

Synthesis, Characterization, and Biological Investigation of Antimony(III) Halide Complexes With Different Coordination Architectures Constructed From Thiophene Thiosemicarbazones

ABSTRACTIn this study, we report the synthesis, characterization, and biological investigation of antimony(III) halide complexes with various coordination architectures constructed from thiophene thiosemicarbazones. Antimony(III) thiophene‐2‐carbaldehyde thiosemicarbazone complexes (1, 2, 4, and 5) exhibit a square pyramidal geometry, with ligands coordinated to the central antimony atom in two distinct binding modes. In contrast, antimony(III) 2‐acetylthiophene thiosemicarbazone complexes (3, 6, and 7) adopt a seesaw geometry. These complexes (1–7) represent the first reported examples of antimony(III) halide thiosemicarbazone compounds. The unique coordination environments observed in these complexes are of significant importance within the realm of antimony chemistry. These synthesized complexes exhibit different coordination geometries as well as potential biological activities. The antiproliferative activity against the human breast adenocarcinoma (MCF‐7) cell line and antimicrobial activity against Gram‐positive and Gram‐negative bacteria were assessed. Antimony(III) thiophene‐2‐carbaldehyde thiosemicarbazone complexes (1, 2, 4, and 5) showed significant antiproliferative activity with IC50 values ranging from 8.5 to 19.1 μM, while antimony(III) 2‐acetylthiophene thiosemicarbazone complexes (3, 6, and 7) had higher IC50 values. Additionally, the antimony complexes demonstrated selective antimicrobial activity against Gram‐negative bacteria.

Boron Salicylate Ester Compounds as Boron Therapeutics. Their Synthesis, Structural Characterizations and Anticancer Effects against MDA-MB-231.

The element boron forms a wide range of borate minerals with different properties. Borate minerals make it possible to design boron-containing molecules with new biological properties in terms of their chemical structure and properties. It is known that boron compounds have antioxidant, anti-inflammatory, anti-tumor and anti-cancer properties. This makes boron compounds important for the future development of boron chemotherapeutics, boron supplements and new drugs. Reliable scientific studies on boron compounds will facilitate the clear presentation of their functions in its biological applications and metabolism. In this study, boron monoester and boron diester structures were synthesized with salicylic acid ligand. To stabilize boron ester structures, Na+, K+, Mg2+, Ca2+ cations were used as counter-ions. Structural properties of the synthesized substances, molecules obtained by crystallization/precipitation from aqueous solutions in solid state, elemental analysis, melting point determination, infrared spectroscopy analysis (FT-IR), thermal analysis (TGA/DTA), mass analysis (GC-MS) and single crystal analysis. Structural properties were tried to be explained by structure analysis (SC-XRD) methods. Additionally, the anticancer potential of boron salicylate esters against the MDA-MB-231 human breast adenocarcinoma cell line was examined. The K-B salicylate diester molecule was found to have the most potential potency with the lowest IC50 value against the MDA-MB-231 cell line. The anticancer potential of boron salicylate esters can be further investigated with other cancer models with the combination of anticancer drugs. It is also thought that the mechanism of action of these molecules may help reveal their further applications.

Engineering Microgel Packing to Tailor the Physical and Biological Properties of Gelatin Methacryloyl Granular Hydrogel Scaffolds.

Granular hydrogel scaffolds (GHS) are fabricated via placing hydrogel microparticles (HMP) in close contact (packing), followed by physical and/or chemical interparticle bond formation. Gelatin methacryloyl (GelMA) GHS have recently emerged as a promising platform for biomedical applications; however, little is known about how the packing of building blocks, physically crosslinked soft GelMA HMP, affects the physical (pore microarchitecture and mechanical/rheological properties) and biological (in vitro and in vivo) attributes of GHS. Here, the GHS pore microarchitecture is engineered via the external (centrifugal) force-induced packing and deformation of GelMA HMP to regulate GHS mechanical and rheological properties, as well as biological responses in vitro and in vivo. Increasing the magnitude and duration of centrifugal force increases the HMP deformation/packing, decreases GHS void fraction and median pore diameter, and increases GHS compressive and storage moduli. MDA-MB-231 human triple negative breast adenocarcinoma cells spread and flatten on the GelMA HMP surface in loosely packed GHS, whereas they adopt an elongated morphology in highly packed GHS as a result of spatial confinement. Via culturing untreated or blebbistatin-treated cells in GHS, the effect of non-muscle myosin II-driven contractility on cell morphology is shown. In vivo subcutaneous implantation in mice confirms a significantly higher endothelial, fibroblast, and macrophage cell infiltration within the GHS with a lower packing density, which is in accordance with the in vitro cell migration outcome. These results indicate that the packing state of GelMA GHS may enable the engineering of cell response in vitro and tissue response in vivo. This research is a fundamental step forward in standardizing and engineering GelMA GHS microarchitecture for tissue engineering and regeneration.

Copper(II), zinc(II) and cadmium(II) complexes with the O-picolyl ether of chiral α-aminooxime of natural (+)-limonene: synthesis, structures, luminescence and cytotoxicity

Copper(II), zinc(II) and cadmium(II) complexes, [CuLCl2], [ZnLCl2] and [CdLCl2], with a new derivative of chiral α-aminooxime of natural (+)-limonene bearing a pycolyl group (L) were synthesized. The complexes are mononuclear, the L molecules act as N,N,N-tridentate chelating ligands. The computations support the fact that the N,N,N–chelation by a metal ion is thermodynamically preferred over the N,N–chelation for all complexes. The ligand L and the complexes [ZnLCl2] and [CdLCl2] exhibit fluorescence, with the emission spectra depending on the excitation wavelength. L emits in close to white region, while the Zn(II) and Cd(II) complexes demonstrate blue emission. Due to chelation-induced fluorescence enhancement effect, the fluorescence quantum yield increases when going from L to [ZnLCl2] and [CdLCl2]. The complex [CdLCl2] displays cytotoxicity against the HepG2 cell line (IC50 = 14.3 ± 1.5 μM), which is almost twice as high as that of cisplatin. The human breast adenocarcinoma cell line (MCF-7) is more sensitive to [CuLCl2] (IC50 = 43.4 ± 0.4 μM) than to [CdLCl2].

A broad-spectrum biological activities of Heracleum humile extracts: A first report of the antiviral, anti-cancer and chemical properties

The current work focused on researching the bioactive potential of ethyl acetate (EA), methanol (MeOH), and water extract of H. humile plant, specifically ethyl acetate, methanol extracts were acquired with maceration method, and water extract was obtained by the infusion method. The highest total phenolic ingredient was determined in the water extract, while the highest total flavonoid ingredient was found in the MeOH extract. The water extract displayed the most potent antioxidant activity in the assays used. The ethyl acetate extract showed the highest enzyme inhibition activity in Butyrylcholinesterase inhibition (BChE) and amylase assay. Antibacterial efficiency was analyzed using microdilution analysis. The minimum inhibitory concentration (MIC) amounts ranged from 125 to 500 μg/mL except for water extract. The antiviral potential of the extracts was assessed against Bovine herpes virus 1 (BoHV-1) (Cooper strain). Methanol extract showed more potent antiviral effect. Selectivity indices were calculated for ethyl acetate and methanol extract as 3.32 and 13.39, respectively. All extracts displayed Deoxyribonucleic Acid (DNA) protection activity at approximately 25%–35%. For cell viability evaluation, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) test was performed against triple-negative human breast adenocarcinoma cells (MDA-MB-231) and Michigan Cancer Foundation-7 (MCF-7) cells. The most effective results were found in ethyl acetate extract at 48h. The 50% inhibitor concentrations (IC50) were determined for MDA-MB-231 and MCF-7 as 116.7 μg/mL and 247.9 μg/mL, respectively. Based on the bioactive compound content results, extracts of H. humile include valuable compounds that possess significant biological properties. In conclusion, these extracts could offer promising novel plant-derived therapeutics.

The antioxidant and selective apoptotic activities of modified auraptene-loaded graphene quantum dot nanoparticles (M-AGQD-NP)

BackgroundPancreatic and Gastric cancers are very aggressive and deadly types of cancer that require effective treatment strategies to stop their progression. Nano-drug delivery systems, like those using Auraptene-loaded GQD nanoparticles, play a crucial role in addressing this need by delivering targeted and controlled treatments to cancer cells, making treatment more effective, and reducing side effects. The study focused on investigating the effects of Auraptene, an efficient anticancer compound when loaded into Graphene Quantum Dots (GQDs) on types of human cancer cells.MethodsTo create auraptene-loaded graphene quantum dot nanoparticles (AGQD-NP) (Unmodified and modified types) a combination of hydrothermal and high-energy homogenization methods was used. The nanoparticles were characterized by conducting DLS (Dynamic light scattering), FTIR (Fourier-transform infrared spectroscopy), FESEM (Field Emission Scanning Electron microscopy), and zeta potential analysis. bioactivity of AGQD-NP was assessed through tests, including antioxidant capacity measured by ABTS and DPPH scavenging abilities well as cytotoxicity tested using MTT assay on both human cancer cell lines and normal human vascular endothelial cells.ResultsThe modified AGQD-NP (M-AGQD-NP) demonstrated antioxidant properties by neutralizing free radicals. They also displayed selective toxicity, towards human gastric adenocarcinoma cell-line (AGS) and human pancreatic adenocarcinoma (PANC) cancer cells with IC50 values recorded at 78.8 µg/mL and 89.72 µg/mL respectively. The specific targeting of gastric cancer cells was evident from the differing IC50 values compared to the Human breast adenocarcinoma cell line (MCF-7), Human hepatocellular carcinoma cell line (Hella), and normal vascular endothelial cells (Huvec). Additionally, the induced apoptotic death, in the human pancreatic adenocarcinoma (PANC) cancer cells was confirmed through AO/PI staining and Annexin-based flow cytometry revealing increased expression levels of P53, Caspase3, BAX, and Caspase8.ConclusionIn summary, the M-AGQD-NP have shown encouraging effects displaying antioxidant capabilities and a specific focus, on pancreatic and gastric cancer cells. These findings indicate uses for AGQD-NP as an efficient apoptosis inducer in cancer treatment. Additional In-vivo researches are required to validate their effectiveness, in living organisms.

PH‐responsive bionanocomposite pectin grafted with dimethylaminoethyl methacrylate and acrylic acid copolymer along with silver nanoparticles for breast cancer drug delivery

AbstractIn this study, we developed a pH‐responsive hydrogel membrane composed of pectin, dimethylaminoethyl methacrylate (DMAEMA), and acrylic acid (AA) through a free radical‐triggered graft copolymerization method. Freshly formed silver nanoparticles (AgNPs) produced from the reduction reaction were embedded in the produced hydrogel. Pectin‐grafted dimethylaminoethyl methacrylate and acrylic acid copolymer [poly (DMAEMA‐co‐AA)‐g‐pectin] and its bionanocomposite with AgNPs were confirmed by Fourier‐transform infrared spectroscopy (FT‐IR), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). The swelling behavior of poly (DMAEMA‐co‐AA)‐g‐pectin in solutions with diverse pH values was assessed. For use as a controlled drug delivery agent, the hydrogel was loaded with 5‐fluorouracil (5‐FU). The incorporation of AgNPs had a great impact on the entrapment efficiency of 5‐FU. At pH 7.4, nearly 48% of the 5‐FU was released in vitro from the polymeric nanocomposite within 24 h. Moreover, poly (DMAEMA‐co‐AA)‐g‐pectin and poly (DMAEMA‐co‐AA)‐g‐pectin/AgNPs presented high cytocompatibility toward normal skin fibroblast cells (BJ1), and the drug delivery system strongly inhibited human Caucasian breast adenocarcinoma cells (MCF‐7). These results demonstrated that these poly (DMAEMA‐co‐AA)‐g‐pectin/AgNPs are an excellent candidate for use in anticancer drug delivery systems.Highlights Free radical polymerization of nanocomposites incorporated with nanoparticles. Nanoparticles improve the bionanocomposites' drug loading. The developed bionanocomposites exhibit control drug release. The novel bionanocomposites acts as an excellent anticancer drug carrier.

Antiproliferative and Pro-apoptotic Activities of Tournefortia mutabilis vent. Leaves on the Human Breast Adenocarcinoma Cell Line (MCF-7)

Background: Breast cancer is the most common cancer among women worldwide, impacting not only the patients but also their families and communities. Tournefortia mutabilis vent. is a plant endemic to Mexico, traditionally used in Zapotec medicine for the treatment of cancer. Objectives: This study aims to evaluate the effects of the chloroformic extract of T. mutabilis vent. leaves on cell proliferation and cell death in MCF-7 cells. Methods: The effect of the extract on MCF-7 cell proliferation was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet staining. Apoptosis was evaluated through fluorescein diacetate/propidium iodide staining and caspase-3, -6, and -9 activity assays. Results: The half-maximal inhibitory concentration (IC50) of the T. mutabilis vent. extract on MCF-7 cell proliferation at 48 hours and 72 hours after treatment was 86.4 µg/mL and 2.74 µg/mL, respectively. We observed that the extract and its semi-purified fractions induced cell death through the activation of caspases 3, -6, and -9. Conclusions: Tournefortia mutabilis vent. is a potential source of compounds with antiproliferative and pro-apoptotic activities on the MCF-7 cell line, primarily through the intrinsic pathways of apoptosis.

Fluorinated High-Valent Sn(IV) Porphyrins Show Remarkable Photodynamic Activity in Cancer Cells.

In recent years, Sn(IV) porphyrins have proven to be excellent choice as photosensitizers for photodynamic therapy. This work reports the synthesis, characterization and photodynamic activity of four high-valent fluorinated Sn(IV) porphyrins having different numbers of F-atoms in the peripheral of meso-phenyl groups viz. (Dichloro)meso-tetrakis(4-fluorophenylporphyrinato)stannic(IV), [Sn(IV)FTPP(Cl)2] or Sn1; (Dichloro)meso-tetrakis(2,4-difluorophenylporphyrinato)stannic(IV), [Sn(IV)2,4-FTPP(Cl)2] or Sn2; (Dichloro)meso-tetrakis(2,6-difluorophenylporphyrinato)stannic(IV), [Sn(IV)2,6-FTPP(Cl)2] or Sn3 and (Dichloro)meso-tetrakis(4-trifluoromethylphenylporphyrinato)stannic(IV), [Sn(IV)CF3TPP(Cl)2] or Sn4. The solid-state structure of Sn1 has been determined by single crystal X-ray diffraction analysis. The increasing number of F-atoms attached to the meso-phenyl positions of the porphyrin framework results in increase of their lipophilicity, singlet oxygen quantum yield (ΦΔ) and photocytotoxicity in A549 (human lung adenocarcinoma cells), MCF-7 and MDA-MB-231 (human breast adenocarcinoma) cells. Sn4 predominantly localize in the mitochondria of A549 cells. The light-induced cell death by the Sn(IV) porphyrins in A549 cells occur primarily via apoptosis.

Preparation, Characterization, DFT Calculations, biological evaluations and Molecular docking studies of benzimidazolium-based n-heterocyclic carbenes and selenium-adducts

This study involves designing through DFT, synthesis, and characterization of three benzimidazolium salts (AL1-AL3) and their corresponding selenium adducts (AC1-AC3). The compounds were characterized theoretically as well as experimentally through FT-IR and 1H &13C NMR. Theoretical calculations were performed using the B3LYP/6–31 G (d, p) levels of theory to determine various optical and chemical properties of the designed molecules. The HOMO/LUMO energies and their energy gaps were also calculated to assess the structure–activity relationships. In vitro testing against the Human breast Adenocarcinoma cell line (MCF-7) was conducted using the MTT assay and 5-Fluorouracil (standard) was used for the comparison of results. The ligand AL3 showed maximum inhibitory potential (66.51 ± 0.82) even approaching the standard 5FU while the complex AC3 showed maximum viability with the least inhibition value as (21.7 ± 0.73) against MCF7 cell line. The antioxidant potential for scavenging DPPH radicals was also assessed, revealing that AL1 has the greatest potential, with a value of 62.01 ± 0.9. The interactions of the complexes with various proteins were also assessed via molecular docking studies, revealing strong binding energies and ligand affinities towards angiogenic factors such as VEGF-A, EGF, HIF, and COX-1. This suggests that the anticancer activities of the complexes AC1-AC3 may be attributed to their potent anti-angiogenic effects. Moreover, selenium-NHC adducts exhibited more significant anticancer potential as compared to their ligands. Furthermore, the antibacterial and antifungal potential of compounds AC1-AC3 was assessed. Notably, the ligand AL2 exhibited significant antibacterial activity against E. coli, as evidenced by a zone of inhibition (ZI) value of 17.5 ± 0.29 mm, whereas AL3 demonstrated the highest activity against P. multocida showing the ZOI value of 18.5 ± 0.38. Among all the synthesized compounds, AL1 displayed the most significant antifungal activity against F. avenaceum (27 ± 0.51 mm), surpassing even the standard drug gentamycin (13 ± 0.23 mm), which was tested under the same conditions. However, its corresponding Se-NHC, AC1, adduct was found to be inactive. Overall, AL3 and its corresponding Se-NHC adduct (AC3), demonstrated superior biological potential against the majority of the tested strains.

Design, Synthesis, and Anticancer and Antibacterial Activities of Quinoline-5-Sulfonamides.

A series of new unique acetylene derivatives of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonamide 3a-f and 6a-f were prepared by reactions of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonyl chlorides with acetylene derivatives of amine. A series of new hybrid systems containing quinoline and 1,2,3-triazole systems 7a-h were obtained by reactions of acetylene derivatives of quinoline-5-sulfonamide 6a-d with organic azides. The structures of the obtained compounds were confirmed by 1H and 13C NMR spectroscopy and HR-MS spectrometry. The obtained quinoline derivatives 3a-f and 6a-f and 1,2,3-triazole derivatives 7a-h were tested for their anticancer and antimicrobial activity. Human amelanotic melanoma cells (C-32), human breast adenocarcinoma cells (MDA-MB-231), and human lung adenocarcinoma cells (A549) were selected as tested cancer lines, while cytotoxicity was investigated on normal human dermal fibroblasts (HFF-1). All the compounds were also tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis. Only the acetylene derivatives of 8-hydroxyquinoline-5-sulfonamide 3a-f were shown to be biologically active, and 8-hydroxy-N-methyl-N-(prop-2-yn-1-yl)quinoline-5-sulfonamide (3c) showed the highest activity against all three cancer lines and MRSA isolates. Its efficacies were comparable to those of cisplatin/doxorubicin and oxacillin/ciprofloxacin. In the non-cancer HFF-1 line, the compound showed no toxicity up to an IC50 of 100 µM. In additional tests, compound 3c decreased the expression of H3, increased the transcriptional activity of cell cycle regulators (P53 and P21 proteins), and altered the expression of BCL-2 and BAX genes in all cancer lines. The unsubstituted phenolic group at position 8 of the quinoline is the key structural fragment necessary for biological activity.

Therapeutic Senolysis of Axitinib-Induced Senescent Human Lung Cancer Cells.

Tyrosine kinase inhibitors (TKIs) inhibit receptor-mediated signals in cells. Axitinib is a TKI with high specificity for vascular endothelial growth factor receptors (VEGFRs). We determined whether axitinib could induce senescence in human cancer cells and be lysed by the senolytic drug ABT-263. Human lung and breast adenocarcinoma cell lines were used. These cells were cultured with axitinib or a multi-target TKI lenvatinib. The expression of β-galactosidase, VEGFRs, Ki-67, reactive oxygen species (ROS) of cancer cells, and their BrdU uptake were evaluated by flow cytometry. The mRNA expression of p21 and IL-8 was examined by quantitative PCR. The effects of TKIs on phosphorylation of Akt and Erk1/2, as downstream molecules of VEGFR signaling, were examined by immunoblot. The in vivo anti-cancer effect was examined using a xenograft mice model. Axitinib, but not lenvatinib, induced cellular senescence (increased cell size and enhanced expression of β-galactosidase) in all adenocarcinoma cell lines. Axitinib-induced senescence was unrelated to the expression of VEGFRs on cancer cells. ROS were involved in axitinib-induced senescence. Axitinib-induced senescent lung adenocarcinoma A549 cells were drastically lysed by ABT-263. In A549-xenografted mice, combination therapy with axitinib and ABT-263 significantly suppressed tumor growth with the induction of apoptotic cancer cells.

Combining In Vitro, In Vivo, and Network Pharmacology Assays to Identify Targets and Molecular Mechanisms of Spirulina-Derived Biomolecules against Breast Cancer.

The current research employed an animal model of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland carcinogenesis. The estrogen receptor-positive human breast adenocarcinoma cell line (MCF-7) was used for in vitro analysis. This was combined with a network pharmacology-based approach to assess the anticancer properties of Spirulina (SP) extract and understand its molecular mechanisms. The results showed that the administration of 1 g/kg of SP increased the antioxidant activity by raising levels of catalase (CAT) and superoxide dismutase (SOD), while decreasing the levels of malonaldehyde (MDA) and protein carbonyl. A histological examination revealed reduced tumor occurrence, decreased estrogen receptor expression, suppressed cell proliferation, and promoted apoptosis in SP protected animals. In addition, SP disrupted the G2/M phase of the MCF-7 cell cycle, inducing apoptosis and reactive oxygen species (ROS) accumulation. It also enhanced intrinsic apoptosis in MCF-7 cells by upregulating cytochrome c, Bax, caspase-8, caspase-9, and caspase-7 proteins, while downregulating Bcl-2 production. The main compounds identified in the LC-MS/MS study of SP were 7-hydroxycoumarin derivatives of cinnamic acid, hinokinin, valeric acid, and α-linolenic acid. These substances specifically targeted three important proteins: ERK1/2 MAPK, PI3K-protein kinase B (AKT), and the epidermal growth factor receptor (EGFR). Network analysis and molecular docking indicated a significant binding affinity between SP and these proteins. This was verified by Western blot analysis that revealed decreased protein levels of p-EGFR, p-ERK1/2, and p-AKT following SP administration. SP was finally reported to suppress MCF-7 cell growth and induce apoptosis by modulating the PI3K/AKT/EGFR and MAPK signaling pathways suggesting EGFR as a potential target of SP in breast cancer (BC) treatment.

Novel tetraaza macrocyclic Schiff base complexes of bivalent zinc: microwave-assisted green synthesis, spectroscopic characterization, density functional theory calculations, molecular docking studies, in vitro antimicrobial and anticancer activities.

In the present manuscript, novel macrocyclic Schiff base complexes [Zn(N4MacL1)Cl2-Zn(N4MacL3)Cl2] were synthesized by the reaction of ZnCl2 and macrocyclic ligands (N4MacL1-N4MacL3) derived from diketone and diamines under microwave irradiation method and conventional method. The structures of the obtained complexes were identified by various spectrometric methods such as Fourier transformation infra-red (FT-IR), nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HR-MS), powder X-ray diffraction, molar conductivity, and UV-vis. The structures of the synthesized compounds were optimized by using the def2-TZV/J and def2-SVP/J Coulomb fitting basis sets at B3LYP level in density functional theory (DFT) calculations. The macrocyclic Schiff base complexes exhibited higher activities against Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus), Gram-negative bacteria (Escherichia coli and Xanthomonas campestris), and fungal strains (Fusarium oxysporum and Candida albicans) in comparison to macrocyclic Schiff base ligands. Furthermore, the newly synthesized macrocyclic compounds were assessed for their anticancer activity against three cell lines: A549 (human alveolar adenocarcinoma epithelial cell line), HT-29 (human colorectal adenocarcinoma cell line), and MCF-7 (human breast adenocarcinoma cell line) using the MTT assay. The obtained results showed that the macrocyclic complex [Zn(N4MacL3)Cl2] displayed the highest cytotoxic activity (2.23 ± 0.25µM, 6.53 ± 0.28µM, and 7.40 ± 0.45µM for A549, HT-29, and MCF-7 cancer cell lines, respectively). Additionally, molecular docking investigations were conducted to elucidate potential molecular interactions between the synthesized macrocyclic compounds and target proteins. The results revealed a consistent agreement between the docking calculations and the experimental data.

Rutaecarpine-inspired scaffold-hopping strategy and Ullmann cross-coupling based synthetic approach: Identification of pyridopyrimidinone-indole based novel anticancer chemotypes

Natural products as starting templates have shown historically major contribution to development of drugs. Inspired by the structure–function of an anticancer natural alkaloid Rutaecarpine, the Scaffold-hopped Acyclic Analogues of Rutaecarpine (SAAR) with ‘N’-atom switch (1°-hop) and ring-opening (2°-hop) were investigated. A new synthetic route was developed for an effective access to the analogues, i.e. 2-indolyl-pyrido[1,2-a]pyrimidinones, which involved preparation of N-Boc-N’-phthaloyltryptamine/mexamine-bromides and pyridopyrmidinon-2-yl triflate, a nickel/palladium-catalysed Ullmann cross-coupling of these bromides and triflate, deprotection of phthalimide followed by N-aroylation, and Boc-deprotection. Fourteen novel SAAR-compounds were prepared, and they showed characteristic antiproliferative activity against various cancer cells. Three most active compounds (11a, 11b, and 11c) exhibited good antiproliferative activity, IC50 7.7–15.8 µM against human breast adenocarcinoma cells (MCF-7), lung cancer cells (A549), and colon cancer cells (HCT-116). The antiproliferative property was also observed in the colony formation assay. The SAAR compound 11b was found to have superior potency than original natural product Rutaecarpine and an anticancer drug 5-FU in antiproliferative activities with relatively lower cytotoxicity towards normal breast epithelial cells (MCF10A) and significantly higher inhibitory effect on cancer cells’ migration. The compound 11b was found to possess favourable in silico physicochemical characteristics (lipophilicity-MLOGP, TPSA, and water solubility-ESOL, and others), bioavailability score, and pharmacokinetic properties (GI absorption, BBB non-permeant, P-gp, and CYP2D6). Interestingly, the compound 11b did not show any medicinal chemistry structural alert of PAINS and Brenk filter. The study represents for the first time the successful discovery of new potent anticancer chemotypes using Rutaecarpine natural alkaloid as starting template and reaffirms the significance of natural product-inspired scaffold-hopping technique in drug discovery research.

Design of Polymeric Nanoparticles for Theranostic Delivery of Capsaicin as Anti-Cancer Drug and Fluorescent Nitrogen-Doped Graphene Quantum Dots.

In recent years, multifunctional nanocarriers that provide simultaneous drug delivery and imaging have attracted enormous attention, especially in cancer treatment. In this research, we designed a biocompatible fluorescent multifunctional nanocarrier for the co-delivery of capsaicin (CPS) and nitrogen-doped graphene quantum dots (N-GQDs) using the pH sensitive amphiphilic block copolymer (poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone), PEtOx-b-PCL). The effects of the critical formulation parameters (the amount of copolymer, the concentration of poly(vinyl alcohol) (PVA) as a stabilizing agent in the inner aqueous phase, and volume of the inner phase) were evaluated to achieve optimal nanoparticle properties using Central Composite Design (CCD). The optimized nanoparticles demonstrated a desirable size distribution (167.8±1.4nm) with a negative surface charge (-19.9±0.4) and a suitable loading capacity for capsaicin (70.80±0.05%). The CPS & N-GQD NPs were found to have remarkable toxicity on human breast adenocarcinoma cell line (MCF-7). The solid fluorescent signal was acquired from cells containing multifunctional nanoparticles, according to the confocal microscope imaging results, confirming the significant cellular uptake. This research illustrates the enormous potential for cellular imaging and enhanced cancer therapy offered by multifunctional nanocarriers that combine drug substances with the novel fluorescent agents. This article is protected by copyright. All rights reserved.

Novel hybrid benzoisothiazole-1,2,3-triazole-4-carboxamides with sub-micromolar toxicity towards human breast carcinoma cells and high affinity to DNA

A pharmacophore hybridization strategy to combine biologically active scaffolds was implemented for design and synthesis of benzoisothiazole-1,2,3-triazole-4-carboxamide conjugates via piperazine linker. In vitro screening led to identification of the compounds 5h and 5j, with para-chlorine- or fluorine- substitution on the phenyl ring, and isopropyl or cyclopropyl substituents in position 5 of 1,2,3-triazole cycle as potent anticancer agents. These compounds demonstrated toxicity towards human breast adenocarcinoma cells of the MCF-7 line in sub-micromolar concentrations with IC50 = 0.76 ± 0.04 μM and 0.90 ± 0.02 μM, respectively, while showing no toxicity in normal cells (IC50 > 100 μM). Colony formation and proliferation of carcinoma MCF-7 cells were effectively inhibited by the derivatives 5h and 5j. These derivatives caused DNA fragmentation of the MCF-7 cells. We suggest that the DNA-damaging action of the compounds 5h and 5j may be related to their high capability of intercalating into DNA molecule that is comparable to such ability of known anticancer agent – the doxorubicin. High affinity of the compounds 5h and 5j for the DNA was confirmed using computational molecular docking in silico.

Ephrin type-A receptor 2-antisense RNA1/2 promote proliferation and migration of MDA-MB-231 cells through EPHA2-dependent Ras signaling pathway mediated by MAPK8/JNK1, MAPK9/JNK2-NFATC2/NFAT1 and JUND

Ephrin type-A receptor 2 (EPHA2) is a receptor tyrosine kinase that is overexpressed in a variety of cancers, including breast cancer. EPHA2 expression may be causally related to tumorigenesis; therefore, it is important to understand how EPHA2 expression is regulated. We previously reported that EPHA2 antisense RNA (EPHA2-AS), a natural antisense transcript, is an important modulator of EPHA2 mRNA levels and hence production of EPHA2 protein. EPHA2-AS encodes two splice variants, EPHA2-AS1 and EPHA2-AS2. The two variants are constitutively expressed in a concordant manner with EPHA2 mRNA in human breast adenocarcinoma cell lines and in patient samples, with the highest levels detected in the basal-like/triple-negative molecular subtype of breast cancer cells. In this study, we investigated the mechanism of EPHA2-AS1/2 in triple-negative breast cancer using MDA-MB-231 cells. We performed RNA-seq transcriptome analyses of MDA-MB-231 cells treated with AHCC®, which suppressed expression of EPHA2-AS1/2 and EPHA2 mRNA, and EPHA2-AS1/2-silenced MDA-MB-231 cells. Bioinformatics analyses identified 545 overlapping differentially expressed genes that were significantly up- or down-regulated by these treatments. Subsequent functional enrichment analyses of the overlapping genes in combination with in vitro assays indicated that EPHA2-AS1/2 may promote the proliferation and migration of MDA-MB-231 cells through the EPHA2-dependent Ras signaling pathways mediated by MAPK8/JNK1, MAPK9/JNK2-NFATC2/NFAT1 (proliferation and migration) and JUND (migration). These results thus suggest that EPHA2-AS1/2 may represent a potential molecular target for triple-negative breast cancer treatment.

Bcl-2 dependent modulation of Hippo pathway in cancer cells

IntroductionBcl-2 and Bcl-xL are the most studied anti-apoptotic members of Bcl-2 family proteins. We previously characterized both of them, not only for their role in regulating apoptosis and resistance to therapy in cancer cells, but also for their non-canonical functions, mainly including promotion of cancer progression, metastatization, angiogenesis, and involvement in the crosstalk among cancer cells and components of the tumor microenvironment. Our goal was to identify transcriptional signature and novel cellular pathways specifically modulated by Bcl-2.MethodsWe performed RNAseq analysis of siRNA-mediated transient knockdown of Bcl-2 or Bcl-xL in human melanoma cells and gene ontology analysis to identify a specific Bcl-2 transcriptional signature. Expression of genes modulated by Bcl-2 and associated to Hippo pathway were validated in human melanoma, breast adenocarcinoma and non-small cell lung cancer cell lines by qRT-PCR. Western blotting analysis were performed to analyse protein expression of upstream regulators of YAP and in relation to different level of Bcl-2 protein. The effects of YAP silencing in Bcl-2 overexpressing cancer cells were evaluated in migration and cell viability assays in relation to different stiffness conditions. In vitro wound healing assays and co-cultures were used to evaluate cancer-specific Bcl-2 ability to activate fibroblasts.ResultsWe demonstrated the Bcl-2-dependent modulation of Hippo Pathway in cancer cell lines from different tumor types by acting on upstream YAP regulators. YAP inhibition abolished the ability of Bcl-2 to increase tumor cell migration and proliferation on high stiffness condition of culture, to stimulate in vitro fibroblasts migration and to induce fibroblasts activation.ConclusionsWe discovered that Bcl-2 regulates the Hippo pathway in different tumor types, promoting cell migration, adaptation to higher stiffness culture condition and fibroblast activation. Our data indicate that Bcl-2 inhibitors should be further investigated to counteract cancer-promoting mechanisms.

Enzymatic synthesis of biocompatible polypyrrole with enhanced electrochemical properties for supercapacitors

This study focuses on the biocompatible and ecofriendly enzymatic synthesis of conductive polypyrrole (PPy) using mediators for supercapacitor electrode material. The work investigates the effects of various mediator systems on laccase-catalyzed oxidation of pyrrole and is confirmed through Fourier transform infrared spectroscopy (FTIR) and Ultraviolet (UV) visible spectroscopy. The x-ray diffraction (XRD) and transmission electron microscopy (TEM) analysis has revealed that both mediators and laccase can produce crystalline and amorphous PPy with agglomeration of globular-shaped particles. The PPy-ABTS (2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) demonstrates higher decomposition temperatures, indicating superior thermal stability up to 400 °C. Electrochemical studies such as cyclic voltammetry (CV), galvanometric charge-discharge (GCD), and electrochemical impedance spectroscopy (EIS) revealed that PPy-ABTS possesses good electrochemical properties. Compared to other laccase-mediated materials synthesized PPy in this study, PPy-ABTS exhibits higher specific capacitance values (242 F g−1 by CV at 10 mV s−1 and 153 F g−1 by GCD at 1 A g−1), with a capacitance retention of nearly 90 % after 10000 cycles. Cytotoxicity study shows that PPy-ABTS has an IC50 value of 528 μg ml−1 against human breast adenocarcinoma (MCF-7) cells, indicating its biocompatibility. Consequently, PPy-ABTS emerges as a promising electrode material for high-performance supercapacitors. Its unreported biocompatibility opens up possibilities for diverse biomedical applications.