Redox Mediated Synthesis of Ag-CuO Hybrid Nanoparticles – DNA/BSA Binding Studies and in vitro Evaluation of Anti-cancer Activity on MCF-7 Cancer Cell Line

We herein report a nanoparticle-directed therapeutic approach to breast cancer using Ag-CuO hybrid nanoparticles. The nanoparticles were synthesized through redox-mediated process involving reduction of silver ion on the surface of Cu₂O nanostructures. Structural, microstructural and optical characterization were carried out and the hybrid nanoparticles were found to be phase pure with crystallite size between 100–200 nm and the absorption due to surface plasmon resonance from silver was observed around 460 nm. The binding affinities of the hybrid nanoparticles with the plasma protein BSA and calf thymus DNA were studied and the respective binding constants were found to be 5.1 × 10⁴ and 1.12 × 10⁵ M⁻¹ showing appreciable binding affinity of the substrate. The cytotoxicity of the as-synthesized hybrid nanoparticles induced in breast cancer cells was evaluated in vitro and the obtained results demonstrates the potential anti-cancer activity of the Ag-CuO hybrid nanoparticles against the MCF-7 breast cancer cell line.     

Synthesis and antitumor activity of new silver(I)-N-heterocyclic carbene complexes

Abstract

In this study, two novel benzimidazole-based N-heterocyclic carbene ligands (1a-b) and their silver(I) complexes (2a-b) were synthesized. All new compounds were characterized by FT-IR, LC-MS, ¹H NMR, and ¹³C NMR spectroscopies. The in vitro antitumor activities of NHC ligands (1a-b) and their silver(I) complexes (2a-b) against DU-145 human prostate cancer cells, MDA-MB-231 and MCF-7 human breast cancer cells and L-929 (normal cells adipose from mouse) were also determined using MTT analysis for 24?h, 48?h, and 72?h. The results showed that while NHC ligands did not have in vitro antitumor activity on MCF-7, MDA-MB-231 and DU-145 cells, Ag(I)-NHC complexes have in vitro antitumor activities. The in vitro antitumor activity of 2a was found to be lower than that of 2b. Ag(I)-NHC complexes were observed to have higher IC₅₀ values for non-cancerous cell lines than cancer cells.     

Development of a polymer system for the delivery of daunorubicin to tumor cells to overcome drug resistance

Method for the synthesis of polymeric nanoparticles (NP) with encapsulated daunorubicin (DNR) was developed on the basis of double emulsion solvent evaporation technique using biodegradable poly(lactide-co-glycolide) (PLGA), which is aimed at customization of pharmacokinetic properties of the preparation, enhanced accumulation of DNR in tumor cells and prolongation of its action. The obtained polymer nanoparticles (DNR-PLGA) had average size ranging around 138±36 nm, with zeta-potential of –25.3 mV and the polydispersity index (PDI) of 0.072. The release kinetics of DNR from polymer nanoparticles at pH 7.4 and 5.0 has been studied. In vitro studies showed similar specific activity of DNR- PLGA in K562 and MCF-7 cancer cell lines together with an increase in activity in K562 Adr and MCF-7 Adr cell lines, which are anthracycline resistant, by 1.6 and 3.4 times. The study demonstrated the efficacy of the developed PLGA-based DNR delivery system in the improvement of antitumor effect of DNR, overcoming multidrug resistance in cancer cells, and also in the decrease in nonspecific toxicity of the preparation.     

Revealing the Potential Application of EC-Synthetic Retinoid Analogues in Anticancer Therapy

(1) Background and Aim: All-trans retinoic acid (ATRA) induces differentiation and inhibits growth of many cancer cells. However, resistance develops rapidly prompting the urgent need for new synthetic and potent derivatives. EC19 and EC23 are two synthetic retinoids with potent stem cell neuro-differentiation activity. Here, these compounds were screened for their in vitro antiproliferative and cytotoxic activity using an array of different cancer cell lines. (2) Methods: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, AV/PI (annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI)), cell cycle analysis, immunocytochemistry, gene expression analysis, Western blotting, measurement of glutamate and total antioxidant concentrations were recruited. (3) Results: HepG2, Caco-2, and MCF-7 were the most sensitive cell lines; HepG2 (ATRA; 36.2, EC19; 42.2 and EC23; 0.74 µM), Caco-2 (ATRA; 58.0, EC19; 10.8 and EC23; 14.7 µM) and MCF-7 (ATRA; 99.0, EC19; 9.4 and EC23; 5.56 µM). Caco-2 cells were selected for further biochemical investigations. Isobologram analysis revealed the combined synergistic effects with 5-fluorouracil with substantial reduction in IC₅₀. All retinoids induced apoptosis but EC19 had higher potency, with significant cell cycle arrest at subG₀-G₁, -S and G₂/M phases, than ATRA and EC23. Moreover, EC19 reduced cellular metastasis in a transwell invasion assay due to overexpression of E-cadherin, retinoic acid-induced 2 (RAI2) and Werner (WRN) genes. (4) Conclusion: The present study suggests that EC-synthetic retinoids, particularly EC19, can be effective, alone or in combinations, for potential anticancer activity to colorectal cancer. Further in vivo studies are recommended to pave the way for clinical applications.     

A Novel Copper Oxide Nanoparticle Conjugated by Thiosemicarbazone Promote Apoptosis in Human Breast Cancer Cell Line

The current study highlights the apoptotic activity of copper oxide (CuO) nanoparticles functionalized by Glutamic acid and conjugated by thiosemicarbazone (TSC) toward human breast cancer (MCF-7) and normal (HEK293) cell lines. To this aim, the co-precipitation method was used for preparation the CuO nanoparticles. Afterward, the CuO nanoparticles functionalized by glutamic acid. After that the functionalized copper oxide nanoparticles (CuO@Glu) conjugated to thiosemicarbazone. In next step, the final nanoparticle product (CuO@Glu/TSC) was characterized by physico-chemical techniques including Fourier transform infrared (FT-IR) spectroscopy, Scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Energy dispersive X-ray analysis (EDX), zeta potential analysis and dynamic light scattering (DLS). The effects of in vitro cell viability in CuO@Glu/TSC nanoparticles showed the anti-proliferative properties with a dose-dependent manner (IC₅₀?=?133.97 µg/ml). The IC₅₀ of CuO@Glu/TSC on normal cell line was 230.2 µg/ml. This IC₅₀ deference shows high cytotoxicity of CuO@Glu/TSC nanoparticles on tumor cells and low cytotoxicity on non-tumorigenic cells (HEK293) and is considered as an important aspect for this nanoparticles. Also, CuO@Glu/TSC nanoparticles had efficient effects in inhibiting the growth of breast cancer cell line (MCF-7). In addition, the CuO@Glu/TSC nanoparticle induced apoptosis symptoms which were assessed by Caspase-3 activation assay, Annexin V/ propidium iodide flow cytometry, and Hoechst 33258 staining. Further, Bax and Bcl-2 genes expression was estimated by real time PCR. The expression of Bax increased 1.69 fold, while the expression of Bcl-2 decreased 0.6 fold. The results of the current study propose that CuO@Glu/TSC nanoparticles reveal effective anti-cancer activity against breast cancer cell line.

     

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design,Synthesis, In Vitro,and In Silico Study

Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC₅₀ of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC₅₀ = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC₅₀ = 0.093 µM) compared to Sorafenib (IC₅₀ = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds.     

含1,2,3-三氮唑基团的新型四氧杂杯[2]芳烃[2]嘧啶衍生物的合成与抗肿瘤活性研究

以4-氯-2-甲硫基-6-丙炔氧基嘧啶为原料,依次经Williamson醚合成、氧化和聚合反应制得新型四氧杂杯[2]芳烃[2]嘧啶母体(4),并通过点击化学反应合成了4个结构新颖的含1,2,3-三氮唑基团的四氧杂杯[2]芳烃[2]嘧啶衍生物(5a^5d),其结构经1H MNR,13C MNR和HR-MS(ESI)表征。采用MTT法研究了5a^5d对人宫颈癌细胞(Hela),人乳腺癌细胞(MCF-7),人肝癌细胞(HepG2)和人肺癌细胞(A549)的体外抗肿瘤活性。结果表明:化合物5a对MCF-7具有明显的抑制活性,在50μM浓度下抑制率可达82%,优于阳性对照药5-氟尿嘧啶。     

Green-synthesized Zinc oxide nanoparticle,an efficient safe anticancer compound for human breast MCF7 cancer cells

There are many types of researches investigating anticancer therapeutics for breast cancer therapy. Zinc oxide nanoparticles (ZnONPs) as an efficient drug delivery system, has been widely being used in various biomedical applications. In the current study, we synthesized ZnONP applying Rheum rhaponticum Waste (RRW) as a novel bio-platform to investigate its anticancer impacts on MCF7 breast cancer cells compared with normal Human HFF and HDF cells. In this regard, RRW was triggered to synthesize the ZnONPs. Then, they were characterized by XRD, FTIR, TEM, and SEM analysis. Next, the MCF-7, HFF, and HDF cell lines were cultured and treated as the following plane: Incubation of all cell lines for 72, 48, and 24 hours at the presence of different ZnONPs doses. Finally, the cell morphology, BCL2- BAX genes expression profile and AO/PI-fluorescent cell staining on the 48-hour incubated cells were analyzed to check the ZnONP apoptotic activity. Moreover, the ZnONP antioxidant activity was analyzed by a DPPH antioxidant test. We produced the 30 nm ZnONPs which significantly increased the BAX and decreased the BCL-2 gene expression. According to the results including the Sub G1 enhancement peaks, apoptotic hallmarks, MTT assay, and the AO/PI-fluorescent stained cells, ZnONPs can specifically induce apoptotic death in MCF7 breast cancer cells compared with normal HFF and HDF cells. The IC₅₀ values of MCF-7 in 72, 48, and 24 hr were measured at 8, 11, and 12 μg/ml in 72, 48, and 24 hr, respectively. This is while the mentioned values in the normal cells (HFF, HDF) were estimated at higher treatment doses. In conclusion, we suggest that the ZnONPs have the potential to be applied as a safe cell-specific apoptosis inducer in breast cancer treatment. However, there are many challenges that need to be clarified for applying them as an efficient anticancer agent.     

Induction of Apoptosis and Regulation of MicroRNA Expression by (2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) Treatment on MCF-7 Breast Cancer Cells

(2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) is a synthetic curcumin analogue, which has been reported to possess anti-tumor, anti-metastatic, and anti-invasion properties on estrogen receptor (ER) negative breast cancer cells in vitro and in vivo. However, the cytotoxic effects of BHMC on ER positive breast cancer cells were not widely reported. This study was aimed to investigate the cytotoxic potential of BHMC on MCF-7 cells using cell viability, cell cycle, and apoptotic assays. Besides, microarray and quantitative polymerase chain reaction (qPCR) were performed to identify the list of miRNAs and genes, which could be dysregulated following BHMC treatment. The current study discovered that BHMC exhibits selective cytotoxic effects on ER positive MCF-7 cells as compared to ER negative MDA-MB-231 cells and normal breast cells, MCF-10A. BHMC was shown to promote G2/M cell cycle arrest and apoptosis in MCF-7 cells. Microarray and qPCR analysis demonstrated that BHMC treatment would upregulate several miRNAs like miR-3195 and miR-30a-3p and downregulate miRNAs such as miR-6813-5p and miR-6132 in MCF-7 cells. Besides, BHMC administration was also found to downregulate few tumor-promoting genes like VEGF and SNAIL in MCF-7. In conclusion, BHMC induced apoptosis in the MCF-7 cells by altering the expressions of apoptotic-regulating miRNAs and associated genes.     

The Anti-Breast Cancer Activity of Dihydroartemisinin-5-methylisatin Hybrids Tethered via Different Carbon Spacers

Sixteen dihydroartemisinin-5-methylisatin hybrids 6a–c and 7a–m tethered via different carbon spacers were assessed for their antiproliferative activity against MCF-7, MDA-MB-231, MCF-7/ADR and MDA-MB-231/ADR breast cancer cell lines as well as cytotoxicity towards MCF-10A cells to investigate the influence of the length of carbon spacers on the activity. The preliminary results illustrated that the length of the carbon spacer was the main parameter which affected the activity, and hybrids tethered via the two-carbon linker showed the highest activity. Amongst the synthesized hybrids, the representative hybrid 7a (IC₅₀: 15.3–20.1 µM) not only demonstrated profound activity against both drug-sensitive and drug-resistant breast cancer cell lines, but also possessed excellent safety and selectivity profile. Collectivity, hybrid 7a was a promising candidate for the treatment of both drug-sensitive and drug-resistant breast cancers and worthy of further preclinical evaluations.     

Synthesis,cytotoxicity and apoptosis-inducing activity of novel 1H-benzo[d]imidazole derivatives of dehydroabietic acid

With the expectation of finding new and effective antitumor drugs, a series of novel N-(1H-benzo[d]imidazole-2-yl)-benzamide/benzenesulfonamide derivatives of dehydroabietic acid were synthesized and evaluated for cytotoxic activity against three human cancer cell lines (MCF-7, HeLa, and HepG2 cells) and one human normal hepatocyte cell line (LO2). As a result, a number of derivatives showed moderate to good antitumor activities. Among them, compound 8h exhibited the most potent activities against three cancer cell lines with IC₅₀ values of 0.87 ± 0.18, 9.39 ± 0.72, and 8.31 ± 0.64 μM, respectively, and was less active to normal hepatocyte LO2 cells. Further mechanism studies revealed that compound 8h could arrest the cell cycle of MCF-7 cells at S phase and induce the apoptosis of MCF-7 cells in ROS-mediated mitochondrial pathway.     

Synthesis and in vitro antitumor activity of 1,3,4-thiadiazole derivatives based on benzisoselenazolone

A series of novel 1,3,4-thiadiazole derivatives based on benzisoselenazolone were synthesized and evaluated for their cytotoxicity in vitro against human liver cancer cell SSMC-7721,human breast cancer cell MCF-7 and human lung cancer cell A549 by CCK-8 assay.The results showed mat compounds 7e,7f,7h,7k,71 and 7m displayed good cytotoxicity against MCF-7 cell lines.Compound 71 exhibited the most potent antitumor activities among the tested compounds.     

Novel synthesis of hydrazide-hydrazone derivatives and their utilization in the synthesis of coumarin, pyridine, thiazole and thiophene derivatives with antitumor activity

The reaction of cyanoacetyl hydrazine (1) with 3-acetylpyridine (2) gave the hydrazide-hydrazone derivative 3. The latter compound undergoes a series of heterocyclization reactions to give new heterocyclic compounds. The antitumor evaluation of the newly synthesized products against three cancer cell lines, namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) was performed. Most of the synthesized compounds showed high inhibitory effects.     

Pyrrolizine/Indolizine-NSAID Hybrids: Design,Synthesis, Biological Evaluation,and Molecular Docking Studies

In the current study, eight new hybrids of the NSAIDs, ibuprofen and ketoprofen with five pyrrolizine/indolizine derivatives were designed and synthesized. The chemical structures of these hybrids were confirmed by spectral and elemental analyses. The antiproliferative activities of these hybrids (5 μM) was investigated against MCF-7, A549, and HT-29 cancer cell lines using the cell viability assay, MTT assay. The results revealed 4–71% inhibition of the growth of the three cancer cell lines, where 8a,e,f were the most active. In addition, an investigation of the antiproliferative activity of 8a,e,f against MCF-7 cells revealed IC₅₀ values of 7.61, 1.07, and 3.16 μM, respectively. Cell cycle analysis of MCF-7 cells treated with the three hybrids at 5 μM revealed a pro-apoptotic increase in cells at preG1 and cell cycle arrest at the G1 and S phases. In addition, the three hybrids induced early apoptotic events in MCF-7 cells. The results of the molecular docking of the three hybrids into COX-1/2 revealed higher binding free energies than their parent compounds 5a,c and the co-crystallized ligands, ibuprofen and SC-558. The results also indicated higher binding free energies toward COX-2 over COX-1. Moreover, analysis of the binding modes of 8a,e,f into COX-2 revealed partial superposition with the co-crystallized ligand, SC-558 with the formation of essential hydrogen bonds, electrostatic, or hydrophobic interactions with the key amino acid His90 and Arg513. The new hybrids also showed drug-likeness scores in the range of 1.06–2.03 compared to ibuprofen (0.65) and ketoprofen (0.57). These results above indicated that compounds 8a,e,f deserve additional investigation as potential anticancer candidates.     

Diethylstilbestrol glucuronide (DESG): synthesis, labeling with radioiodine and in vivo/in vitro evaluations

Diethylstilbestrol (DES) is a synthetic non-steroidal estrogen, pharmacologic effects of which resemble natural estrons; today it is being used to treat some types of postmenopausal breast cancer and advanced prostate cancer. The aim of current study is conjugation of glucuronic acid (G) to DES and to evaluate radiopharmaceutical potential of this estrogen glucuronide derivative (DESG) which is specific to β glucuronidase enzyme consisting tumor cells. Taking into consideration the compatibility to the chemical structures of the synthesized product, ¹³¹I and ¹²⁵I were chosen as the appropriate radionuclides and DESG was labeled with these radionuclides utilizing iodogen method. The radiochemical yields of ^125/131I-DESG were over 90 % according to thin layer radio chromatography method. The biodistribution of ¹³¹I-DESG in healthy female Wistar Albino rats has been investigated and the range of the breast/blood and breast/muscle ratios were approximately 2 and 13 in 240 min for ER unsaturated studies. Effects of the radioiodinated DES and DESG on the cells were examined using MCF-7, A-549, Caco-2 cell lines. ¹²⁵I-DESG has higher incorporation percentages than ¹²⁵I-DES on MCF-7 cells. The radioiodinated DESG has the desired radiopharmaceutical properties which could be candidate radiopharmaceuticals for diagnosis and especially radionuclide therapy of breast tumors.     

Chitosan-Linseed mucilage polyelectrolyte complex nanoparticles of Methotrexate: In vitro cytotoxic efficacy and toxicological studies

The goal of this research was to develop, fabricate and analyze polymeric nanoparticles for the administration of methotrexate (MTX). Linseed mucilage and chitosan nanoparticles (NPs) were prepared using a slightly modified polyelectrolyte complex (PEC) method. The size, shape, and encapsulation effectiveness of the resultant nanoparticles were measured. MTX release profiles at gastrointestinal pH (1.2 and 7.4) and tumor pH (5.5) were examined to determine the targeted potential of NPs as pH-responsive nanocarriers. Zeta analysis showed that nanoparticles prepared by PEC have a size range of 192.1 nm to 246 nm, and PDI was 0.3 of the optimized formulation, which showed homogenous nature of prepared nanoparticles formulation. The findings demonstrated that NPs have a low polydispersity index and a positive zeta potential (PDI). The in-vitro release of the drug indicated a pH-dependent, sustained drug release up to 24 h. Blank LSMCSNPs had almost no in-vivo cytotoxicity for 14 days, while optimum MTX loaded NPs had strong antitumor effects on HepG2 and MCF-7 cells as measured by the MTT assay. Cell apoptosis induction was also checked and MCF-7 cells treated with MTX-LSMCSNPs had a significantly greater rate of apoptosis (21.2 %) than those treated with MTX alone (14.14 %). The findings show that LSMCSNPs could be a potential delivery mechanism for methotrexate to cancer cells in a secure, steady, and ideally controlled manner to improve therapeutic outcomes.     

Utility of thiophene-2-carbonyl isothiocyanate as a precursor for the synthesis of 1,2,4-triazole, 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives with evaluation of their antitumor and antimicrobial activities

Abstract

The reaction of thiophene-2-carbonyl isothiocyanate with phenylhydrazine gave 1-phenyl-5-(thien-2-yl)-1,2,4-triazole-3-thiol which was transformed by follow-up reactions into derivatives substituted in the 3-position by 1,2,4-oxadiazole and 1,2,4-thiadiazole moieties via thioethers linkages. The antitumor activity of the products against two human tumor cell lines, namely hepatocellular carcinoma HePG-2 and mammary gland breast cancer MCF-7 as well as the antimicrobial activity of some of these compounds was evaluated.     

Antioxidant and cytotoxic properties of some new dipeptide-indole conjugates

In this study, 10 new indole-dipeptide conjugates were synthesized, and their anticancer activity was determined against on A2780 (ovarian cancer cell line) and MCF-7 (breast cancer cell line) cells. Among compounds, 5 and 10 showed better activity against A2780 cell lines than the standard drug docatexel at 0.1 and 1 μM concentrations, while only compound 5 showed better activity than docatexel, the MCF-7 cell line at 0.1 and 1 μM concentrations. The antioxidant potencies of the compounds were low in both the DPPH and iron reducing power methods tested when compared to standard antioxidants used in this work.     

Novel Spiro-pyrrolizidine-Oxindole and Spiropyrrolidine-Oxindoles: Green synthesis under Classical,Ultrasonic, and microwave conditions and Molecular docking simulation for antitumor and type 2 diabetes

Novel spiropyrrolizine / pyrrolidineoxindole moieties were synthesized chemo-, and regio-selectively in high yields from knoevenagel reaction of bis[arylmethylidene]piperidin-4-ones, isatin and L-proline or sarcosine under classical, ultrasonic, and microwave conditions. Seven derivatives of the synthesized dispiro-pyrrolizidine-oxindole and spiropyrrolidine were screened for their antitumor activity against two cell lines MCF-7 (breast cancer) and HEPG2 (liver cancer). The results of biological activity indicated that the tested derivatives showed potent activity against breast cancer cell MCF-7. Molecular docking simulation screening studies of the synthesized products with each of the receptors of (3hb5) for breast cancer and (4k9g) for liver cancer and their interaction with 1H5U of glycogen phosphorylase B, type 2 diabetes drug were examined. The docking study of dispiro-pyrrolizidine-oxindole and spiropyrrolidine showed promising results with several derivatives.