Novel Bis(2-cyanoacrylamide) Linked to Sulphamethoxazole: Synthesis, DNA Interaction, Anticancer, ADMET, Molecular Docking, and DFT Studies.

In the light of advancement and potential extensive use of medication design and therapy, new bis(cyanoacrylamides) incorporating sulphamethoxazole derivatives (7 a-7 f) were synthesized and confirmed by different spectral tools. In vitro anticancer activity towards different human cancer cells (HCT116, MDA-MB-231 and A549) was assessed using MTT assay. Among all derivatives, 4C- and 6C-spacer derivatives (7 e and 7 f) had the most potent growth inhibitory activities against HCT116 cells with IC50 values of 39.7 and 28.5 µM, respectively. 7 e and 7 f induced apoptosis and suppressed migration of HCT116 cells. These compounds also induced a significant increase in caspase-3 and CDH1 activities, and a downregulation of Bcl2 using ELISA. pBR322 DNA cleavage activities of cyanoacrylamides were determined using agarose gel electrophoresis. Furthermore, 7 e and 7 f showed good DNA and BSA binding affinities using different spectroscopic techniques. Furthermore, molecular docking for 7 e and 7 f was performed to anticipate their binding capabilities toward various proteins (Bcl2, CDH1 and BSA). The docking results were well correlated with those of experimental results. Additionally, density functional theory and ADMET study were performed to evaluate the molecular and pharmacokinetic features of 7 e and 7 f, respectively. Thus, this work reveals promising antitumor lead compounds that merit future research and activity enhancement.

Yttrium Oxide nanoparticles induce cytotoxicity, genotoxicity, apoptosis, and ferroptosis in the human triple-negative breast cancer MDA-MB-231 cells.

BACKGROUND: Triple-negative breast cancer (TNBC) is a lethal mammary carcinoma subtype that affects females and is associated with a worse prognosis. Chemotherapy is the only conventional therapy available for patients with TNBC due to the lack of therapeutic targets. Yttrium oxide (Y2O3) is a rare earth metal oxide, whose nanoparticle (NPs) formulations are used in various applications, including biological imaging, the material sciences, and the chemical synthesis of inorganic chemicals. However, the biological activity of Y2O3-NPs against TNBC cells has not been fully explored. The current study was conducted to assess Y2O3-NPs' anticancer activity against the human TNBC MDA-MB-231 cell line. METHODS: Transmission electron microscopy (TEM), X-ray diffraction, Zeta potential, and dynamic light scattering (DLS) were used to characterize the Y2O3-NPs. SRB cell viability, reactive oxygen species (ROS) measurement, single-cell gel electrophoresis (comet assay), qPCR, flow cytometry, and Western blot were employed to assess the anticancer activity of the Y2O3-NPs. RESULTS: Our results indicate favorable physiochemical properties of Y2O3-NPs (with approximately average size 14 nm, Zeta Potential about - 53.2 mV, and polydispersity index = 0.630). Y2O3-NPs showed a potent cytotoxic effect against MDA-MB-231 cells, with IC50 values of 74.4 µg/mL, without cytotoxic effect on the normal retina REP1 and human dermal fibroblast HDF cell lines. Further, treatment of MDA-MB-231 cells with IC50 Y2O3-NPs resulted in increased oxidative stress, accumulation of intracellular ROS levels, and induced DNA damage assessed by Comet assay. Upon Y2O3-NPs treatment, a significant increase in the early and late phases of apoptosis was revealed in MDA-MB-231 cells. qPCR results showed that Y2O3-NPs significantly upregulated the pro-apoptotic genes CASP3 and CASP8 as well as ferroptosis-related gene heme oxygenase-1 (HO-1), whereas the anti-apoptotic gene BCL2 was significantly downregulated. CONCLUSION: This study suggests that Y2O3-NPs are safe on normal REP1 and HDF cells and exhibited a potent selective cytotoxic effect against the TNBC MDA-MB-231 cells through increasing levels of ROS generation with subsequent DNA damage, and induction of apoptosis and ferroptosis.

Novel eco-friendly [1,2,4]triazolo[3,4-a]isoquinoline chalcone derivatives efficiency against fungal deterioration of ancient Egyptian mummy cartonnage, Egypt.

Fungal deterioration is one of the major factors that significantly contribute to mummy cartonnage damage. Isolation and molecular identification of thirteen fungal species contributing to the deterioration of ancient Egyptian mummy cartonnage located in El-Lahun regions, Fayoum government, Egypt was performed. The most dominant deteriorated fungal species are Aspergillus flavus (25.70%), Aspergillus terreus (16.76%), followed by A. niger (13.97%). A newly synthesized series of tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline chalcone derivatives were synthesized and evaluated for their antifungal activities in vitro against the isolated deteriorated fungal species (Aspergillus flavus, A. niger, A. terreus, Athelia bombacina, Aureobasidium iranianum, Byssochlamys spectabilis, Cladosporium cladosporioides, C. ramotenellum, Penicillium crustosum, P. polonicum, Talaromyces atroroseus, T. minioluteus and T. purpureogenus). The most efficient chalcone derivatives are new chalcone derivative numbers 9 with minimum inhibitory concentration (MIC) ranging from 1 to 3 mg/mL followed by chalcone derivatives number 5 with MIC ranging from 1 to 4 mg/mL.

Novel Tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline Chalcones Suppress Breast Carcinoma through Cell Cycle Arrests and Apoptosis.

Chalcones are interesting anticancer drug candidates which have attracted much interest due to their unique structure and their extensive biological activity. Various functional modifications in chalcones have been reported, along with their pharmacological properties. In the current study, novel chalcone derivatives with the chemical base of tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-arylprop-2-en-1-one were synthesized, and the structure of their molecules was confirmed through NMR spectroscopy. The antitumor activity of these newly synthesized chalcone derivatives was tested on mouse (Luc-4T1) and human (MDA-MB-231) breast cancer cell lines. The antiproliferative effect was evaluated through SRB screening and the MTT assay after 48 h of treatment at different concentrations. Interestingly, among the tested chalcone derivatives, chalcone analogues with a methoxy group were found to have significant anticancer activity and displayed gradient-dependent inhibition against breast cancer cell proliferation. The anticancer properties of these unique analogues were examined further by cytometric analysis of the cell cycle, quantitative PCR, and the caspases-Glo 3/7 assay. Chalcone methoxy derivatives showed the capability of cell cycle arrest and increased Bax/Bcl2 mRNA ratios as well as caspases 3/7 activity. The molecular docking analysis suggests that these chalcone methoxy derivatives may inhibit anti-apoptotic proteins, particularly cIAP1, BCL2, and EGFRK proteins. In conclusion, our findings confirm that chalcone methoxy derivatives could be considered to be potent drug candidates against breast cancer.

Hantzsch-Like Synthesis, DNA Photocleavage, DNA/BSA Binding, and Molecular Docking Studies of Bis(sulfanediyl)bis(tetrahydro-5-deazaflavin) Analogs Linked to Naphthalene Core.

The cyclocondensation reaction of aldehydes with dimedone and bis(6-aminopyrimidin-4-one) in acetic acid led to the formation of the corresponding bis(pyrimido[4,5-b]quinoline-4,6-diones) which are known as bis(sulfanediyl)bis(tetrahydro-5-deazaflavin) analogs in a single step. Also, bis(pyrimido[4,5-b]quinoline-4,6-diones) which are linked to naphthyl core via phenoxymethyl linkage is prepared. The interactions of the synthesized compounds with DNA and bovine serum albumin (BSA) were studied. Gel electrophoresis assay was used to show the capability of the compounds to photocleave the supercoiled pBR322 plasmid DNA in UV-A (365 nm). Besides, the most photocleavable compound, bis(tetrahydropyrimido[4,5-b]quinoline-4,6-dione) linked to pyridin-3-yl at position-5 exhibits good binding affinities toward CT-DNA and BSA as supported by UV/VIS spectral studies. In addition to the experimental findings, a molecular docking simulation was performed to collect detailed binding data for this compound to both biomolecules.

Anticancer activity of novel 3-(furan-2-yl)pyrazolyl and 3-(thiophen-2-yl)pyrazolyl hybrid chalcones: Synthesis and in vitro studies.

Twelve novel chalcone derivatives were prepared using the Claisen-Schmidt condensation reaction. The reaction of 4-acetyl-5-furan/thiophene-pyrazole derivatives 5 with the corresponding aldehydes 6 afforded the targeted chalcone derivatives 7a-l in good yields. The newly synthesized chalcones were fully characterized by spectrometric and elemental analyses. The in vitro anticancer activities of the novel compounds 7a-l were evaluated against four human cancer cell lines: HepG2 (human hepatocellular carcinoma), MCF7 (human Caucasian breast adenocarcinoma), A549 (lung carcinoma), and BJ1 (normal skin fibroblasts). Compound 7g emerged as the most promising compound, with IC50 = 27.7 µg/ml against A549 cells compared to the reference drug doxorubicin (IC50 = 28.3 µg/ml), and IC50 = 26.6 µg/ml against HepG2 cells compared to the reference drug doxorubicin (IC50 = 21.6 µg/ml). The gene expression and DNA damage values and the DNA fragmentation percentages for compound 7g were determined on the lung and liver cell lines. The expression levels of the AMY2A and FOXG1 genes increased significantly (p < 0.01) in the negative samples of lung cancer cells compared with treated cells. Also, the expression values of the PKM and PSPH genes improved significantly (p < 0.01) in the negative samples compared with treated samples of liver cancer cells. The DNA damage values increased significantly (p < 0.01) in treated lung cell line samples (7g) and the positive control. The results showed a significant decrease (p < 0.05) in DNA damage values in the negative samples of liver cancer cells compared to those treated with 7g. However, the DNA fragmentation values increased significantly (p < 0.01) in the treated lung and liver cell line samples compared with the negative control.

Novel [l,2,4]triazolo[3,4-a]isoquinoline chalcones as new chemotherapeutic agents: Block IAP tyrosine kinase domain and induce both intrinsic and extrinsic pathways of apoptosis.

Two novel chemotherapeutic chalcones were synthesized and their structures were confirmed by different spectral tools. Theoretical studies such as molecular modeling were done to detect the mechanism of action of these compounds. In vitro cytotoxicity showed a strong effect against all tested cell lines (MCF7, A459, HepG2, and HCT116), and low toxic effect against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies. Real-time PCR demonstrated that the two compounds upregulated gene expression of (BAX, p53, casp-3, casp-8, casp-9) genes and decreased the expression of anti-apoptotic genes bcl2, CDK4, and MMP1. Flow-cytometry indicated that cell cycle arrest of A459 was induced at the G2/M phase and the apoptotic percentage increased significantly compared to the control sample. Cytochrome c oxidase and VEGF enzyme activity were detected by ELISA assay. SEM tool was used to follow the morphological changes that occurred on the cell surface, cell granulation, and average roughness of the cell surface. The change in the number and morphology of mitochondria, cell shrinkage, increase in the number of cytoplasmic organelles, membrane blebbing, chromatin condensation, and apoptotic bodies were observed using TEM. The obtained data suggested that new chalcones exerted their pathways on lung carcinoma through induction of two pathways of apoptosis. Graphical abstract Novel chalcones were prepared and confirmed by different spectral tools. Docking simulations were done to detect the mechanism of action. In vitro cytotoxicity indicated a strong effect against different cancer cell lines and low toxic effects against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies that include Real-time PCR, Flow-cytometry, Cytochrome c oxidase, and ELISA assay. SEM and TEM tool were used to follow the morphological changes occurred on the cell surface.

Computational studies and sever apoptotic bioactivity of new heterocyclic cyanoacrylamide based p-fluorophenyl and p-phenolic compounds against liver carcinoma (Hepg2).

An efficient route for the preparation of new heterocyclic cyanoacrylamides based p-fluorophenyl and p-phenolic compounds was depicted. All structures were confirmed based on the different spectral tools and elemental analyses. MTT assay for the novel synthesized series was performed against four different cell lines (A549, MCF7, Hepg2, and Wi38). Among all tested groups, the p-phenolic compound 10 (207.1 µg/ml) and the corresponding p-fluorophenyl derivative 6 (325.7 µg/ml) were selected for further simulation and molecular studies against liver carcinoma. Compounds 6 and 10 were investigated theoretically to different protein sets as (cdk2, Bcl2-xl, cIAP1-BIR3, and MDM2) and they illustrated different binding affinities. The computational studies and different molecular techniques (e.g. cell cycle analysis, DPA assay, relative gene expression, and ELISA assay) were utilized in this report.

Bee venom and its active component Melittin synergistically potentiate the anticancer effect of Sorafenib against HepG2 cells.

There are current attempts to find a safe substitute or adjuvant for Sorafenib (Sorf), the standard treatment for advanced hepatocellular carcinoma (HCC), as it triggers very harsh side effects and drug-resistance. The therapeutic properties of Bee Venom (BV) and its active component, Melittin (Mel), make them suitable candidates as potential anti-cancer agents per-se or as adjuvants for cancer chemotherapy. Hence, this study aimed to evaluate the combining effect of BV and Mel with Sorf on HepG2 cells and to investigate their molecular mechanisms of action. Docking between Mel and different tumor-markers was performed. The cytotoxicity of BV, Mel and Sorf on HepG2 and THLE-2 cells was conducted. Combinations of BV/Sorf and Mel/Sorf were performed in non-constant ratios on HepG2. Expression of major cancer-related genes and oxidative stress status was evaluated and the cell cycle was analyzed. The computational analysis showed that Mel can bind to and inhibit XIAP, Bcl2, MDM2, CDK2 and MMP12. Single treatments of BV, Mel and Sorf on HepG2 showed lower IC50than on THLE-2. All combinations revealed a synergistic effect at a combination index (CI) < 1. Significant upregulation (p < 0.05) of p53, Bax, Cas3, Cas7 and PTEN and significant downregulation (p < 0.05) of Bcl-2, Cyclin-D1, Rac1, Nf-κB, HIF-1a, VEGF and MMP9 were observed. The oxidative stress markers including MDA, SOD, CAT and GPx showed insignificant changes, while the cell cycle was arrested at G2/M phase. In conclusion, BV and Mel have a synergistic anticancer effect with Sorf on HepG2 that may represent a new enhancing strategy for HCC treatment.

Attacking the mitochondria of colorectal carcinoma by novel 2-cyanoacrylamides linked to ethyl 1,3-diphenylpyrazole-4-carboxylates moiety as a new trend for chemotherapy.

A novel set of 2-cyanoacrylamides linked to ethyl 1,3-diphenylpyrazole-4-carboxylates moiety were synthesized and elucidated by different spectroscopic tools. In vitro cytotoxic assay was carried out against different cell lines (Hct116, A549, MDA-MB231, and HFB4). Ethyl 5-(2-cyano-3-(furan-2-yl)acrylamido)-1,3-diphenylpyrazole-4-carboxylate 5 achieved the potent cytotoxic effect toward all tested cancer cell lines especially colon cancer (HCT116) with IC50 value (30.6 µg/ml) relative to the lead compound 3 and the standard positive control 5-FU. Additionally, it exhibited less toxic effect toward the normal human melanocytes (HFB4) cell line. Compound 5 was theoretically investigated and compared for its binding affinity to a model of protein markers relative to the lead compound 3 using two different molecular docking programs. More investigations were performed in an attempt to find out the molecular mechanism of this novel compound inside colon cancer cells, as real time PCR analysis, Elisa assay, flow cytometry, and morphological characterizations using TEM and SEM tools.Herein, we showed that compound 5 interferes with the intrinsic pathway of apoptosis at the mitochondrial level in response to an apoptogenic stimulus as cytochromec, caspase-9 and caspases-3 which were triggered by our novel compound 5. All molecular investigations proved that intrinsic apoptotic pathway of colorectal carcinoma was strongly initiated by the effect of compound 5 through upregulation of mitochondrial apoptosis related genes as (Caspase-3, caspase-9, BAX, P53, and cytochrome-c) and down-regulated anti-apoptotic proteins (BCL2, MMP1, CDK4, and VEGFR). Further studies proved cell cycle arrest of HCT116 cell lines at G2/M phase after treatment. In addition, our data revealed that our novel efficiently damage the genomic DNA of colorectal cells involving P53 dependent mechanism using DPA assay. Sever morphological and ultrastructural changes were detected in colorectal cells treated by compound 5 compared to control using both scanning electron microscopy (SEM) and transmission electron microscopy (TEM).

Novel 2-cyanoacrylamido-4,5,6,7-tetrahydrobenzo[b]thiophene derivatives as potent anticancer agents.

Ethyl 2-acrylamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate as well as its corresponding bis-derivatives, 5-10, with aliphatic linkers were synthesized, fully characterized, and tested as novel anticancer agents. The targeted compounds, 5-10, were obtained by the Knoevenagel condensation reactions of bis-o- or -p-aldehyde with a molar ratio of ethyl 2-(2-cyanoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate of 2 in the presence of piperidine in excellent yields (93-98%). The in vitro anticancer activities of the prepared compounds were evaluated against HepG2, MCF-7, HCT-116, and BJ1 cells. Compounds 7 and 9 emerged as the most promising compounds, with IC50 values of 13.5 and 32.2 µg/ml, respectively, against HepG2 cells, compared with the reference drug doxorubicin (IC50 : 21.6 µg/ml). Real-time reverse-transcription polymerase chain reaction was used to measure the changes in expression levels of the COL10A1 and COL11A1, ESR1, and ERBB2, or AXIN1 and CDKN2A genes within the treated cells, as genetic markers for colon, breast, or liver cancers, respectively. Treatment of the colon cancer cells with compounds 5, 9, and 10, or breast and liver cancers cells with compounds 7, 8, 9, and 10 downregulated the expression of the investigated tumor markers. The DNA damage values (depending on comet and DNA fragmentation assays) increased significantly upon treatment of colon cancer cells with compounds 5, 9, and 10, and breast and liver cells with compounds 8, 9, and 10. The structure-activity relationship suggested that the increase of the chain of the alkyl linker increases the anticancer activity and the compounds with bis-cyanoacrylamide moieties are more active than those with one cyanoacrylamide moiety.

Molecular docking simulation and anticancer assessment on human breast carcinoma cell line using novel bis(1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile) and bis(1,4-dihydropyrazolo[4',3':5,6]pyrano[2,3-b]pyridine-6-carbonitrile) derivatives.

An efficient route for the synthesis of novel bis(1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile) derivatives is reported. The synthetic pathway involves one pot, synthesis of bis-aldehydes, malononitrile, and pyrazolone in the presence of pyridine. The anticancer activity of the synthesized products against MCF7, HEPG2, and A549 cell lines was assessed. Docking studies were performed and indicated the best binding mode compared to the standard ligand sorafenib.

Apoptotic induction mediated p53 mechanism and Caspase-3 activity by novel promising cyanoacrylamide derivatives in breast carcinoma.

New cyanoacrylamide derivatives were theoretically examined for their binding abilities to a protein model of apoptosis inhibitor proteins x-IAP and c-IAP1 using molecular modeling. The two compounds 5a and 5b proved promising IAP antagonists, where they have good binding affinity toward the selected active domains. Anticancer activity of all derivatives was performed on different human cancer cell lines (HCT116, Caco2, and MCF7) as well as normal line (HBF4). Data revealed that breast carcinoma was more sensitive to the novel compounds than other lines especially compounds 5a and 5b, but all derivatives lost their cytotoxic effect in case of Caco2 cell line and they showed low cytotoxic effect toward HCT116 cells except compound 3. The flow cytometric analysis revealed that the two compounds 5a and 5b induced apoptosis to 46.5% and 54.8% respectively, relative to control 8.06%. In addition, PCR results indicated that the two compounds 5a and 5b induced the expression of p53 gene and decreased induction of BCL2 (anti-apoptotic gene), while the two compounds have no effect on the protein expression of Caspase-9. By monitoring the presence of Caspase-3 which was a mean to detect apoptotic death in breast carcinoma, the two compounds have stimulated the induction of apoptosis by increasing the production of Caspase-3 protein. Finally, it was concluded that the two compounds 5b and 5a have the most promising anti-cancer activity against human breast carcinoma (MCF7), and it is believed that the anticancer activities of these two compounds were due to being the most effective in the inhibition of a member of IAPs groups, leading to activation of p53 gene and the Caspase-3 dependent apoptosis.

Cytotoxic and antimicrobial evaluations of novel apoptotic and anti-angiogenic spiro cyclic 2-oxindole derivatives of 2-amino-tetrahydroquinolin-5-one.

A novel series of cyclic 2-oxindole derivatives incorporating 2-amino-tetrahydroquinolin-5-one were prepared. The structures of the prepared compounds were elucidated using different spectral tools. The regio-orientation of the reaction products was elucidated through NOE difference experiments and through using substituents on the ortho position to affect further cyclization. Antitumor and antimicrobial evaluations were performed on the prepared compounds. Most of these compounds exhibited high to moderate antimicrobial activity. With respect to the antitumor activity, the compounds showed more potent cytotoxic effect only toward the human breast cancer cell line MCF-7. Also, we found that derivatives containing an ester group (8c, 11b, 14b, and 15b) are more active than those containing a cyanide group (8a, 11a, 14a, and 15a). Moreover, compounds 15b and 8b are the most active derivatives in this group. These two compounds showed apoptotic inhibition of the proliferation of human breast adenocarcinoma MCF-7 cells through DNA fragmentation, induction of the tumor suppressor protein p53, induction of caspase-9, and finally the inhibition of angiogenesis by decreasing vascular endothelial growth factor expression and secretion.

Novel cyanochalcones as potential anticancer agents: apoptosis, cell cycle arrest, DNA binding, and molecular docking studies.

In the light of anticancer drug discovery and development, a new series of cyanochalcones incorporating indole moiety (5a-g) were efficiently synthesized and characterized by different spectral analysis. MTT assay was used to evaluate the antiproliferative activity of the synthesized compounds towards different cancer cells (Hela, MDA-MB-231, A375, and A549) in parallel with normal cells (HSF). Trimethoxy and diethoxy-containing derivatives (5d and 5e) displayed the most selective cytotoxic activities against cervical Hela cells with IC50 values of 8.29 and 11.82 µM, respectively, with great safety pattern toward normal HSF cells (Selectivity index: 21.3 and 13.9, respectively). Therefore, 5d and 5e were chosen to study their effects on apoptosis, cell cycle arrest, and migration of Hela cells using flow cytometric analysis and wound healing assay. They induced apoptosis and cell cycle arrest at the S phase and impaired migration of HeLa cells. Regarding their effects on the expression profile of crucial genes related to the potential anticancer activities, 5d and 5e remarkably upregulated caspase 3 and Beclin1 and downregulated cyclin A1, CDK2, CDH2, MMP9, and HIF1A using qRT-PCR and ELISA techniques. UV-Vis spectral measurement demonstrated the ability of 5d and 5e to bind CT-DNA efficiently with Kb values of 3.7 × 105 and 1 × 105 M-1, respectively. Moreover, in silico molecular docking was performed to assess the binding affinities of the compounds toward the active sites of Bcl2, CDK2, and DNA. Therefore, cyanochalcones 5d and 5e might be promising anticancer agents and could offer a scientific basis for intensive research into cancer chemotherapy.Communicated by Ramaswamy H. Sarma.

A novel series of cyanochalcones incorporating indole moiety (5a­g) were designed and synthesized.Cytotoxic activities of the designed compounds were evaluated in vitro against different human cancer cell lines (Hela, MDA-MB-231, A375, and A549) in parallel with human normal cells (HSF).5d and 5e stimulated apoptosis (through deregulating Bcl2 and upregulating Cas3), cell cycle arrest at the S phase (by suppressing cyclin A and CDK2), and inhibited migration (through downregulating CDH2 and MMP9) of Hela cells.5d and 5e demonstrated good DNA binding affinities.Molecular docking was carried out to confirm the binding abilities of 5d and 5e toward Bcl2, CDK2, and DNA.

Anticancer behaviour of 2,2'-(pyridin-2-ylmethylene)bis(5,5-dimethylcyclohexane-1,3-dione)-based palladium(II) complex and its DNA, BSA binding propensity and DFT study.

Herein, we report the synthesis and biological evaluation of [Pd(L)(OH2)Cl] complex (where L = 2,2'-(pyridin-2-ylmethylene)bis(5,5-dimethylcyclohexane-1,3-dione) as a novel promising anticancer candidate. The complex was characterized by single-crystal X-ray diffraction and other various spectroscopic techniques. Besides, the optimized structure was determined through DFT calculations revealing that the coordination geometry of [Pd(L)(OH2)Cl] complex is square planar. The binding propensity of [Pd(L)(OH2)Cl] complex with DNA and BSA was assessed by the spectrophotometric method. The antimicrobial profile of the ligand and its [Pd(L)(OH2)Cl] complex was screened against clinically important bacterial strains. [Pd(L)(OH2)Cl] complex showed promising activity against these microorganisms. Pd(L)(OH2)Cl] complex exhibited a potent antiproliferative potential compared to its ligand against different human cancer cells (A549, HCT116, MDA-MB-231, and HepG2) with less toxic effect against normal cells (WI-38). Additionally, [Pd(L)(OH2)Cl] complex exerted its anticancer effects against the most responsive cells (HCT116 cells; IC50 = 11 ± 1 µM) through suppressing their colony-forming capabilities and triggering apoptosis and cell cycle arrest at S phase. Quantitative PCR analysis revealed a remarkable upregulation of the mRNA expression level of p53 and caspase-3 by 4.8- and 5.9-fold, respectively, relative to control. Remarkable binding properties and non-covalent interactions between L and its [Pd(L)(OH2)Cl] complex with the binding sites of different receptors including CDK2, MurE ligase, DNA, and BSA were established using molecular docking. Based on our results, [Pd(L)(OH2)Cl] complex is an intriguing candidate for future investigations as a potential anticancer drug for the treatment of colon cancer.

Utility of 2-Chloro-N-arylacetamide and 1,1'-(Piperazine-1,4-diyl)bis(2-chloroethanone) as Versatile Precursors for Novel Mono- and Bis[thienopyridines].

A series of novel thieno[2,3-b]pyridines linked to N-aryl carboxamides or (carbonylphenoxy)-N-(aryl)acetamides, as well as bis(thieno[2,3-b]pyridines) linked to piperazine core via methanone or carbonylphenoxyethanone units, were synthesized by treating the appropriate chloroacetyl- or bis-bromoacetyl derivatives with 2-mercaptonicotinonitrile derivatives in ethanolic sodium ethoxide at reflux. The spectral data were used to determine the compositions of novel compounds.

Synthesis of novel chitosan-Schiff bases nanoparticles for high efficiency Helicobacter pylori inhibition.

Two chitosan Schiff bases were synthesized by condensation of chitosan with 2-(4-formylphenoxy)-N-phenylacetamide and N-(4-bromophenyl)-2-(4-formylphenoxy) acetamide denoted as Cs-SBA and Cs-SBBr, respectively. The molecular structures of the resulting chitosan derivatives were characterized using FTIR and 1HNMR and their thermal properties were investigated by TGA. These derivatives were treated with sodium tripolyphosphate (TPP) to produce Cs Schiff base nanoparticles. The nanoparticles physicochemical properties were determined by FTIR, XRD, TEM, and zeta potential analysis. The antimicrobial action against Helicobacter pylori (H. pylori) was evaluated and the results indicated that the anti-H. pylori activity had minimal inhibitory concentration MIC values of 15.62 ± 0.05 and 3.9 ± 0.03 µg/mL for Cs-SBA and Cs-SBBr nanoparticles (Cs-SBA NPs and Cs-SBBr NPs), respectively. The better biologically active nanoparticles, Cs-SBBr NPs, were tested for their cyclooxygenases (COX-1 and COX-2) inhibitory potential. Cs-SBBr NPs demonstrated COX enzyme inhibition activity against COX-2 (IC50 4.5 ± 0.165 µg/mL) higher than the conventional Indomethacin (IC50 0.08 ± 0.003 µg/mL), and Celecoxib (IC50 0.79 ± 0.029 µg/mL). Additionally, the cytotoxicity test of Cs-SBBr NPs showed cytotoxic effect on Vero cells (CCL-81) with IC50 = 17.95 ± 0.12 µg/mL which is regarded as a safe compound. Therefore, Cs-SBBr NPs may become an alternative to cure H. pylori and prevent gastric cancer.

Synthesis, cytotoxicity, anti-inflammatory, anti-metastatic and anti-oxidant activities of novel chalcones incorporating 2-phenoxy-N-arylacetamide and thiophene moieties: induction of apoptosis in MCF7 and HEP2 cells.

Eight Novel chalcones were synthesized and their structures were confirmed by different spectral tools. All the prepared compounds were subjected to SRB cytotoxic screening against several cancer cell lines. Compound 5c exerted the most promising effect against MCF7 and HEP2 cells with IC50 values of 9.5 and 12 µg/mL, respectively. Real-time PCR demonstrated the inhibitory effect of compound 5c on the expression level of Antigen kiel 67 (KI-67), Survivin, Interleukin-1beta (IL-1B), Interleukin-6 (IL-6), Cyclooxygenase-2 (COX-2) and Protein kinase B (AKT1) genes. Flow-cytometric analysis of the cell cycle indicated that compound 5c stopped the cell cycle at the G0/G1 and G2/M phases in MCF7 and HEP2 treated cells, respectively. ELISA assay showed that Caspase 8, Caspase 9, P53, BAX, and Glutathione (GSH) were extremely activated and Matrix metalloproteinase 2 (MMP2), Matrix metalloproteinase 9 (MMP9), BCL2, Malondialdehyde (MDA), and IL-6 were deactivated in 5c treated MCF7 and HEP2 cells. Wound healing revealed that chalcone 5c reduced the ability to close the scrape wound and decreased the number of migrating MCF7 and HEP2 cells compared to the untreated cells after 48 h. Theoretical molecular modeling against P53 cancer mutant Y220C and Bcl2 showed binding energies of -22.8 and -24.2 Kcal/mole, respectively, which confirmed our ELISA results.

Synthesis, anticancer evaluation of novel hybrid pyrazole-based chalcones, molecular docking, DNA fragmentation, and gene expression: in vitro studies.

A unique series of pyrazolyl-chalcone derivatives was synthesized via the method of Claisen-Schmidt condensation. The desired chalcone derivatives 7a-d and 9a-f were obtained in good yields by reacting the 4-acetyl-5-thiophene-pyrazole with the appropriate heteroaryl aldehyde derivatives. The novel chalcones have undergone complete elemental analysis, 1H-NMR, 13C-NMR, mass spectrometry, and IR characterization. The three human cancer cell lines MCF7 (human Caucasian breast adenocarcinoma), PC3 (prostatic cancer) and PACA2 (pancreatic carcinoma) as well as the normal cell line BJ1 (normal skin fibroblasts) were tested in vitro for the anti-cancer properties of the newly synthesized chalcone derivatives. When compared to the reference medicine doxorubicin (IC50 = 52.1 µM), compound 9e showed the most promise derivative (IC50 = 27.6 µM) against PACA2 cells, while compound 7d demonstrated anticancer efficacy (IC50 = 42.6 µM against MCF7 cells compared to the reference drug doxorubicin (IC50 = 48 µM). Using breast and pancreatic cell lines, the gene expression, DNA damage, and DNA fragmentation percentages for compounds 7d and 9e were evaluated. Moreover, the molecular docking study of compounds 7d and 9e was assessed. The binding affinities of compound 9e toward P53 mutant Y220C was -22 kcal per mole, while those of compound 7d towards Bcl2 and CDK4 were -27.81 and -26.9 kcal per mole, respectively, compared to the standard values (-15.82, -33.96 and -29.9 kcal per mole).