Physicochemical Characterization of Chrysin‐Derivative‐Loaded Nanostructured Lipid Carriers with Special Reference to Anticancer Activity

Homologues long‐chain chrysin derivatives (LCD, C _n: 8–18) were synthesized and incorporated into nanostructured lipid carriers (NLC) with the aim to treat human neuroblastoma. Mutual miscibility and attractive interactions among the NLC components, namely tripalmitin (TP), cetyl palmitate (CP), oleic acid (OA), and the chrysin (CHR) derivatives (LCD) at the air–water interface were assessed by the Langmuir monolayer approach. Optimum combination for the NLC formulations was found to be 2:2:1 (M/M/M) for TP/CP/OA, respectively. NLC formulations, both in the absence and presence of LCD, were characterized by combined dynamic light scattering, electron microscopy, atomic force microscopy, and differential scanning calorimetry. The size and zeta potential of the NLC formulations were found in the range 200–350 nm and ?12 to ?18 mV, respectively. Encapsulation efficiency and release kinetics of CHR and LCD when loaded into NLC were also evaluated. LCD exhibited maximum incorporation, drug‐loading capacity, and sustained release because of its enhanced hydrophobicity. Superior incorporation efficiency and sustained‐release profile of LCD were able to enhance their anticancer activity against human neuroblastoma cell lines, compared to CHR, making them promising agents in combating cancer.     

Oxidative Desulfurization of Model Diesel Using a Fenton‐Like Catalyst in the Ionic Liquid [Dmim]BF4

A Fenton‐like catalyst prepared from tetrabutylammonium chloride and ferric trichloride was characterized by Fourier transform infrared, UV‐vis and Raman spectroscopy. The catalyst (C₄H₉)₄NFeCl₄ (TBAFeCl₄) in an extraction and catalytic oxidative desulfurization (ECODS) system containing H₂O₂ and the ionic liquid (IL) 1‐decyl‐3‐methylimidazolium tetrafluoroborate ([Dmim]BF₄) exhibited high catalytic activity for the removal of dibenzothiophene (DBT) in model diesel. Desulfurization with the Fenton‐like catalyst TBAFeCl₄ in ECODS involves the structural distortion of DBT via polarization of the IL and its subsequent oxidation. The catalytic system could be recycled multiple times without significant decrease in desulfurization activity due to the high stability of the system.     

Development of a conjugated polyaniline incorporated electrospun poly(vinylidene fluoride‐co‐hexafluoropropylene) composite membrane electrolyte for high performance dye‐sensitized solar cells

Different weight percentage (2, 3, 4, and 5 wt %) of polyaniline (PANI) were incorporated into electrospun poly(vinylidene fluoride‐co‐hexafluoropropylene) (PVdF‐HFP) composite membranes (esCPMs). The regular morphology, molecular structure, crystallinity, porosity, electrolyte uptake, and leakage of the composite membranes were examined. The esCPMs were activated in liquid electrolyte containing 0.5 M LiI, 0.05 M I₂, and 0.5 M 4‐tert‐butylpyridine and 0.5 M 1‐butyl‐3‐methylimidazoliun iodide in acetonitrile to afford electrospun PVdF‐HFP/PANI composite membrane electrolytes (esCPMEs). The influence of different wt % of PANI on the esCPMEs was studied by electrochemical impedance measurements and Tafel polarization studies. The photovoltaic performance of a dye‐sensitized solar cell assembled using 3 wt % PANI incorporated esCPME exhibits a higher power conversion efficiency of 7.20% than that assembled using esPME (η = 6.42%). © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42777.     

Molecular Mechanism of Action of 2‐Ferrocenyl‐1,1‐diphenylbut‐1‐ene on HL‐60 Leukemia Cells

The aim of this work was to investigate the mechanism of action of 2‐ferrocenyl‐1,1‐diphenylbut‐1‐ene ( 1 ) on HL‐60 human leukemia cells. While inactive against noncancerous cells, 1 provoked a concentration‐dependent decrease in viable tumor cells, primarily via apoptosis, as evidenced by analysis of cell morphology, activation of caspases 3 and 7, increased DNA fragmentation, and externalization of phosphatidylserine. Necrosis was observed only at the highest tested concentration (4 μM ). Compound 1 interfered with the cell cycle, causing an accumulation of cells in the G₁/G₀ phase. Interaction of 1 with dsDNA and ssDNA was observed by differential pulse voltammetry and confirmed by hyperchromicity in the UV/Vis spectra of dsDNA, with an interaction constant of 2×10⁴ M ^?1. Both the organic analogue 1,1,2‐triphenylbut‐1‐ene ( 2 ) and ferrocene were inactive against cancer and noncancer cell lines and did not react with DNA. These results reinforce the idea that the hybrid strategy of conjugating ferrocene to the structure of tamoxifen derivatives is advantageous in finding new substances with antineoplastic activity.     

Synthesis,Characterization and Evaluation of Surface and Thermal Properties of 3‐Cyclohexyloxy‐2‐Hydroxypropyl Pyridinium and Imidazolium Surface‐Active Ionic Liquids

In this work, 1‐halo‐3‐(cyclohexyloxy)propan‐2‐ol ( 3a/3b ) were reacted with N‐methylimidazole ( 4 ) or pyridine ( 5 ) to yield the respective 3‐(3‐(cyclohexyloxy)‐2‐hydroxypropyl)‐1‐methyl‐1H‐imidazol‐3‐ium ( 6a/6b ) or pyridinium ( 7a/7b ) surface‐active ionic liquids (SAIL). The self‐aggregation behavior of these ionic liquids (IL) was evaluated by conductometric and tensiometric methods. The thermal stability and size of the micelles were determined by thermogravimetric analysis and dynamic light scattering studies, respectively. The investigated IL were found to exhibit very low cytotoxicity as evaluated by MTT (3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide) assay on the C6 glioma cell line, indicating that the investigated SAIL can be considered for biological applications like drug and gene delivery. The conventional IL 3‐methyl‐1‐octyl imidazolium bromide ( C ₈ mimBr ) was used for comparison in property evaluations.     

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

A series of chalcone conjugates featuring the imidazo[2,1‐b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF‐7, A549, HeLa, DU‐145 and HT‐29). These new hybrid molecules have shown promising cytotoxic activity with IC₅₀ values ranging from 0.64 to 30.9 μM . Among them, (E)‐3‐(6‐(4‐fluorophenyl)‐2,3‐bis(4‐methoxyphenyl)imidazo[2,1‐b]thiazol‐5‐yl)‐1‐(pyridin‐2‐yl)prop‐2‐en‐1‐one ( 11 x ) showed potent antiproliferative activity with IC₅₀ values ranging from 0.64 to 1.44 μM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate ( 11 x ) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell‐cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase‐3, DNA fragmentation analysis, and Annexin V–FITC assay. Moreover, molecular docking studies indicated that this conjugate ( 11 x) interacts and binds efficiently with the tubulin protein.     

Structure–Activity Relationship of Tumor‐Selective 5‐Substituted 2‐Amino‐3‐carboxymethylthiophene Derivatives

Methyl‐2‐amino‐5‐[2‐(4‐methoxyphenethyl)]thiophene‐3‐carboxylate ( 8 c ) is the prototype of a well‐defined class of tumor‐selective agents. Compound 8 c preferentially inhibited the proliferation of a number of tumor cell lines including many human T‐lymphoma/leukemia cells, but also several prostate, renal, central nervous system and liver tumor cell types. Instead, a broad variety of other tumor cell lines including B‐lymphomas and HeLa cells were not affected. The tumor selectivity (TS; selectivity index or preferential suppression of CEM lymphoma (IC₅₀=0.90 μM ) versus HeLa tumor cell carcinoma (IC₅₀=39 μM )) amounted up to ～43 for 8 c . At higher concentrations, the compound proved cytotoxic rather than cytostatic. The antiproliferative potency and selectivity of 8 c could be preserved by replacing the ethyl linker between the 2‐amino‐3‐carboxymethylthiophene and the substituted aryl by a thioalkyl but not by an oxyalkyl nor an aminoalkyl. Among >50 novel 8 c derivatives, the 5‐(4‐ethyl‐ and 4‐isopropylarylmethylthio)thiophene analogues, methyl‐2‐amino‐5‐((4‐ethylphenylthio)methyl)thiophene‐3‐carboxylate ( 13 m ) and methyl‐2‐amino‐5‐((4‐isopropylphenylthio)methyl)thiophene‐3‐carboxylate ( 13 n ), were more potent (IC₅₀: 0.3–0.4 μM ) and selective (TS: 100–144) anti‐T‐lymphoma/leukemia agents than the prototype compound.     

Discovery of Non‐ATP‐Competitive Inhibitors of Polo‐like Kinase 1

Polo‐like kinase 1 (Plk1) is an evolutionarily conserved serine/threonine kinase, and its N‐terminal kinase domain (KD) controls cell signaling through phosphorylation. Inhibitors of Plk1 are potential anticancer drugs. Most known Plk1 KD inhibitors are ATP‐competitive compounds, which may suffer from low selectivity. In this study we discovered novel non‐ATP‐competitive Plk1 KD inhibitors by virtual screening and experimental studies. Potential binding sites in Plk1 KD were identified by using the protein binding site detection program Cavity. The identified site was subjected to molecular‐docking‐based virtual screening. The activities of top‐ranking compounds were evaluated by in vitro enzyme assay with full‐length Plk1 and direct binding assay with Plk1 KD. Several compounds showed inhibitory activity, and the most potent was found to be 3‐((2‐oxo‐2‐(thiophen‐2‐yl)ethyl)thio)‐6‐(pyridin‐3‐ylmethyl)‐1,2,4‐triazin‐5(4H)‐one (compound 4 ) with an IC₅₀ value of 13.1±1.7 μm . Our work provides new insight into the design of kinase inhibitors that target non‐ATP binding sites.     

Mono‐, Di‐ and Tetra‐Cationic Surfactants as Carbon Steel Corrosion Inhibitors

Corrosion inhibition of three new synthesized cationic surfactants, N‐(2‐(((Z)‐4‐(pyridin‐4‐yl)but‐3‐en‐1‐yl)amino)ethyl)‐N‐(2‐((E)‐(pyridin‐4‐ylmethylene)amino)ethyl)dodecan‐1‐aminium bromide I(4N), N¹,N²‐didodecyl‐N¹‐((Z)‐4‐(pyridin‐4‐yl)but‐3‐en‐1‐yl)‐N²‐(2‐((E)‐(pyridin‐4‐ylmethylene)amino)ethyl)ethane‐1,2‐diaminium bromide II(4N) and 1‐dodecyl‐4‐((E)‐((2‐(dodecyl(2‐(dodecyl((Z)‐4‐(1‐dodecylpyridin‐1‐ium‐4‐yl)but‐3‐en‐1‐yl)ammonio)ethyl)ammonio)ethyl)imino)methyl)pyridin‐1‐ium bromide IV(4N) on carbon steel was investigated by weight loss, electrochemical impedance spectroscopy and polarization measurements. Results show that the synthesized cationic surfactants inhibit corrosion of carbon steel in 1 M HCl. The inhibitive action occurs by virtue of adsorption on the metal surface following a Langmuir adsorption isotherm model. Polarization curves reveal that the investigated cationic surfactants can be classified as mixed inhibitor types. The variations in the corrosion inhibition efficiency between three cationic surfactants are correlated with their chemical structures, with more hydrophobic surfactants yielding higher inhibition efficiency.     

Interleukin-4 Aggravates LPS-Induced Striatal Neurodegeneration In Vivo via Oxidative Stress and Polarization of Microglia/Macrophages

The present study investigated the effects of interleukin (IL)-4 on striatal neurons in lipopolysaccharide (LPS)-injected rat striatum in vivo. Either LPS or PBS as a control was unilaterally injected into the striatum, and brain tissues were processed for immunohistochemical and Nissl staining or for hydroethidine histochemistry at the indicated time points after LPS injection. Analysis by NeuN and Nissl immunohistochemical staining showed a significant loss of striatal neurons at 1, 3, and 7 days post LPS. In parallel, IL-4 immunoreactivity was upregulated as early as 1 day, reached a peak at 3 days, and was sustained up to 7 days post LPS. Increased levels of IL-4 immunoreactivity were exclusively detected in microglia/macrophages, but not in neurons nor astrocytes. The neutralizing antibody (NA) for IL-4 significantly protects striatal neurons against LPS-induced neurotoxicity in vivo. Accompanying neuroprotection, IL-4NA inhibited activation of microglia/macrophages, production of reactive oxygen species (ROS), ROS-derived oxidative damage and nitrosative stress, and produced polarization of microglia/macrophages shifted from M1 to M2. These results suggest that endogenous IL-4 expressed in LPS-activated microglia/macrophages contributes to striatal neurodegeneration in which oxidative/nitrosative stress and M1/M2 polarization are implicated.     

Anti‐HIV‐1 Peptide Derivatives Based on the HIV‐1 Co‐receptor CXCR4

The human immunodeficiency virus type 1 (HIV‐1) uses CD4 and the co‐receptor CCR5 or CXCR4 in the process of cell entry. The negatively charged extracellular domains of CXCR4 (CXCR4‐ED) interact with positive charges on the V3 loop of gp120, facilitating binding via electrostatic interactions. The presence of highly conserved positively charged residues in the V3 loop suggests that CXCR4‐ED‐derived inhibitors might be broadly effective inhibitors. Synthetic peptide derivatives were evaluated for anti‐HIV‐1 activity. The 39‐mer extracellular N‐terminal region (NT) was divided into three fragments with 10‐mer overlapping sites ( N1 – N3 ), and these linear peptides were synthesized. Peptide N1 contains Met 1–Asp 20 and shows significant anti‐HIV‐1 activity. Extracellular loops 1 and 2 (ECL1 and 2) were mimicked by cyclic peptides C1 and C2 , which were synthesized by chemoselective cyclization. Cyclic peptides C1 and C2 show higher anti‐HIV‐1 activity than their linear peptide counterparts, L1 and L2 . The cytotoxicities of C1 and C2 are lower than those of L1 and L2 . These results indicate that Met 1–Asp 20 segments of the NT and cyclic peptides of ECL1 and ECL2 are potent anti‐HIV‐1 drug candidates.     

Antimicrobial properties and thermal stability of polycarbonate modified with 1‐alkyl‐3‐methylimidazolium tetrafluoroborate ionic liquids

Four water immiscible ionic liquids (ILs): 1‐hexyl‐3‐methylimidazolium tetrafluoroborate, 1‐heptyl‐3‐methylimidazolium tetrafluoroborate, 1‐octyl‐3‐methylimidazolium tetrafluoroborate and 1‐dodecyl‐3‐methylimidazolium tetrafluoroborate have been synthesized. Polycarbonate (PC) films containing ILs were prepared by solvent casting from methylene chloride solutions. Scanning electron microscopy measurements showed the high homogeneity of PC/IL films with the IL content up to 4 wt %. The tendency to IL aggregation was observed for polymeric films with higher IL content (5%). PC/IL composites were found to have the reduced thermal decomposition temperature under both an air and a nitrogen atmosphere in comparison with the neat PC. The effect of IL content on the antimicrobial activity of PC films against Escherichia coli bacteria was studied. Pronounced antimicrobial efficacy was revealed for PC/IL films for all studied ILs starting from 3 wt % of IL. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40050.     

Research on the preparation and antibacterial properties of 2‐N‐thiosemicarbazide‐6‐O‐hydroxypropyl chitosan membranes with iodine

The 2‐N‐thiosemicarbazide‐6‐O‐hydroxypropyl chitosan (ATU‐HPCS) was prepared by chitosan grafted hydroxypropyl and thiosemicarbazide through the method of “amino protection‐graft‐deprotection,” while the ATU‐HPCS gel membranes were obtained from gelatin and polyvinyl pyrrolidone as additives, and the ATU‐HPCS membranes with iodine (ATU‐HPCS‐I₂‐M) were prepared by adding the ethanol solution of iodine in the ATU‐HPCS gel membranes. The ATU‐HPCS‐I₂‐M were characterized to evaluate their potential applications as antibacterial materials. The iodine releasing rule of ATU‐HPCS‐I₂‐M showed a sustained‐release effect of iodine, the maximum emission was approximately 0.80%. The inhibition zone diameters of ATU‐HPCS‐I₂‐M against Staphylococcus aureus (as Gram‐positive bacteria) and Escherichia coli (as Gram‐negative bacteria) were both greater than 15 mm, it demonstrated significant antibacterial activity compared with the ATU‐HPCS gel membranes. The double effects of the biocompatibility of chitosan and the sustained‐release of iodine provided an ideal healing environment for wound surface. These properties have made ATU‐HPCS‐I₂‐M highly potential as a novel natural macromolecule antimicrobial material preventing the bacteria from burns, surgery wounds, etc. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40535.     

Structural Design,Synthesis and Structure–Activity Relationships of Thiazolidinones with Enhanced Anti‐Trypanosoma cruzi Activity

Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti‐Trypanosoma cruzi thiazolidinones ( 4 a – p ). (2‐[2‐Phenoxy‐1‐(4‐bromophenyl)ethylidene)hydrazono]‐5‐ethylthiazolidin‐4‐one ( 4 h ) and (2‐[2‐phenoxy‐1‐(4‐phenylphenyl)ethylidene)hydrazono]‐5‐ethylthiazolidin‐4‐one ( 4 l ) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 μM , while they did not display host cell toxicity up to 200 μM . Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti‐T. cruzi thiazolidinones ( 4 a – p ) led to the identification of compounds with enhanced potency and selectivity compared to first‐generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death.     

Modification of sulfonated poly(ether ether ketone) membranes by impregnation with the ionic liquid 1‐butyl‐3‐methylimidazolium tetrafluoroborate for proton exchange membrane fuel cell applications

Sulfonated poly(ether ether ketone) (SPEEK) membranes were modified by impregnation with the ionic liquid (IL) 1‐butyl‐3‐methylimidazolium tetrafluoroborate (BMI.BF₄) by immersion into an IL aqueous solution for different periods of time. The modified membranes were investigated by thermogravimetric analyses (TGA), differential scanning calorimetry (DSC), ion exchange capacity (IEC), and conductivity. The SPEEK membrane immersed into the IL aqueous solution for 2 min showed greater dimensional and thermal stability than the pristine SPEEK membrane, and achieved higher decomposition temperatures. It also presented a higher conductivity value (1.0 mS cm^?1), indicating that BMI.BF₄ is a promoter of proton conductivity. The membrane electrode assembly (MEA) produced reached maximum values of power density of 0.13 W cm^?2 and current density of 0.54 A cm^?2 during fuel cell operation. The results indicate that the SPEEK membrane modified by immersion for 2 min is promising for use in a proton exchange membrane fuel cell. Its performance yielded values very close to those obtained with Nafion, which reaches maximum values of power density of 0.19 W cm^?2 and current density of 0.77 A cm^?2. POLYM. ENG. SCI. 56:1037–1044, 2016. © 2016 Society of Plastics Engineers     

Metabolism of 25-Hydroxy-Vitamin D in Human Macrophages Is Highly Dependent on Macrophage Polarization

Macrophages synthesize active vitamin D (1,25-dihydroxy-vitamin D) and express the vitamin D receptor in the nucleus; however, vitamin D metabolism in relation to macrophage polarization and function is not well understood. We studied monocyte-derived macrophages (MDMs) from human buffy coats polarized into M0, M1 (LPS + IFNγ), M2a (IL4 + IL13) and M2c (IL10) macrophage subtypes stimulated with 25-hydroxy-vitamin D (1000 and 10,000 nanomolar). We measured vitamin D metabolites (25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, 24,25-dihydroxy-vitamin D and 3-epi-25-hydroxy-vitamin D) in cell media with liquid chromatography-mass spectrometry-mass spectrometry. The mRNA expression (CYP27B1, CYP24A1 and CYP24A1-SV) was measured with qPCR. We found that reparative MDMs (M2a) had significantly more 1,25-dihydroxy-vitamin D compared to the other MDMs (M0, M1 and M2c). All MDMs were able to produce 3-epi-25-hydroxy-vitamin D, but this pathway was almost completely attenuated in inflammatory M1 MDMs. All MDM subtypes degraded vitamin D through the 24-hydroxylase pathway, although M1 MDMs mainly expressed an inactive splice variant of CYP24A1, coding the degrading enzyme. In conclusion, this study shows that vitamin D metabolism is highly dependent on macrophage polarization and that the C3-epimerase pathway for vitamin D is active in macrophages.     

Roles of Fatty Acids in Microglial Polarization: Evidence from In Vitro and In Vivo Studies on Neurodegenerative Diseases

Microglial polarization to the M1 phenotype (classically activated) or the M2 phenotype (alternatively activated) is critical in determining the fate of immune responses in neurodegenerative diseases (NDs). M1 macrophages contribute to neurotoxicity, neuronal and synaptic damage, and oxidative stress and are the first line of defense, and M2 macrophages elicit an anti-inflammatory response to regulate neuroinflammation, clear cell debris, and promote neuroregeneration. Various studies have focused on the ability of natural compounds to promote microglial polarization from the M1 phenotype to the M2 phenotype in several diseases, including NDs. However, studies on the roles of fatty acids in microglial polarization and their implications in NDs are a rare find. Most of the studies support the role of polyunsaturated fatty acids (PUFAs) in microglial polarization using cell and animal models. Thus, we aimed to collect data and provide a narrative account of microglial types, markers, and studies pertaining to fatty acids, particularly PUFAs, on microglial polarization and their neuroprotective effects. The involvement of only PUFAs in the chosen topic necessitates more in-depth research into the role of unexplored fatty acids in microglial polarization and their mechanistic implications. The review also highlights limitations and future challenges.     

Dicer Nuclease‐Promoted Production of Let7a‐1 MicroRNA Is Enhanced in the Presence of Tryptophan‐Containing Amphiphilic Peptides

A library of Trp‐containing amphiphilic peptides was synthesized and screened for the ability to bind to pre‐miRNA targets. Two members of this family, peptides Ac‐WKKLLKWLKKLLKLAG‐NH₂ ( 2 b ) and Ac‐WKKLLKWLKKLLDabLAG‐NH₂ ( 4 b ) were found to have nanomolar binding affinities to pre‐let7a‐1. Peptides 2 b and 4 b caused an increase in the in vitro Dicer cleavage of pre‐let7a‐1. This observation was confirmed by a cell‐based assay, the results of which show an up to 50 % increase in Dicer activity. Enhanced expression of let7a‐1 promoted by the peptides results in specific reductions of target mRNAs. The results of a microarray study show that lower amount of fluctuating genes are generated in the presence of 2 b or 4 b , relative to that from exogenous delivery of let7a‐1. Because peptides 2 b and 4 b promote enhanced formation of mature let7a‐1 only at the endogenous miRNA level, this specifically controls genes related to let7a‐1.     

2‐Anilino‐3‐Aroylquinolines as Potent Tubulin Polymerization Inhibitors

Several 2‐anilino‐3‐aroylquinolines were designed, synthesized, and screened for their cytotoxic activity against five human cancer cell lines: HeLa, DU‐145, A549, MDA‐MB‐231, and MCF‐7. Their IC₅₀ values ranged from 0.77 to 23.6 μm . Among the series, compounds 7 f [(4‐fluorophenyl)(2‐((4‐fluorophenyl)amino)quinolin‐3‐yl)methanone] and 7 g [(4‐chlorophenyl)(2‐((4‐fluorophenyl)amino)quinolin‐3‐yl)methanone] showed remarkable antiproliferative activity against human lung cancer and prostate cancer cell lines. The IC₅₀ values for inhibiting tubulin polymerization were 2.24 and 2.10 μm for compounds 7 f and 7 g , respectively, and were much lower than that of the reference compound E7010 [N‐(2‐(4‐hydroxyphenylamino)pyridin‐3‐yl)‐4‐methoxybenzenesulfonamide]. Furthermore, flow cytometric analysis revealed that these compounds arrest the cell cycle at the G₂/M phase, leading to apoptosis. Apoptosis was also confirmed by mitochondrial membrane potential, Annexin V–FITC assay, and intracellular ROS generation. Immunohistochemistry, western blot, and tubulin polymerization assays showed that these compounds disrupt tubulin polymerization. Molecular docking studies revealed that these compounds bind efficiently to β‐tubulin at the colchicine binding site.