Normal Lung Fibroblast Cells Research Articles

Development of water-dispersible gelatin stabilized hydroxyapatite nanoformulation for curcumin delivery

The therapeutic efficacy of hydrophobic curcumin (CUR) can be potentially enhanced by developing aqueous formulations of CUR. In the present study, we have prepared colloidally stable formulation of CUR by encapsulating it into the hydrophilic network of gelatin (Gel) and hydroxyapatite (HAp). The successful incorporation of CUR in the formulation was evident from spectroscopic analysis. The detailed structural characterization of CUR loaded formulation (CUR-Gel-HAp) was carried out using various techniques including PXRD, FTIR, TGA, FESEM, light scattering, and zeta-potential measurements. The formulation showed pH responsive sustained release of CUR with higher release rate under acidic environment. CUR-Gel-HAp showed enhanced cytotoxicity towards human lung cancer cells (A549) as compared to normal human lung fibroblast cells (WI-26 VA4). Moreover, CUR-Gel-HAp exhibited substantial cellular internalization and higher toxicity towards A549 cells as compared to free CUR. Further, the lyophilized CUR-Gel-HAp exhibited long-term stability and showed insignificant changes in the physicochemical properties and colloidal stability upon reconstituting in the aqueous medium.

Synthesis, Antiproliferative Activity, Apoptotic Profiling, and In‐silico ADME of New Thienylbenzamidine Derivatives

AbstractTwelve new thienylbenzamidines and their analogues 4 a–i, 7, and 12 a, b were synthesized and their anti‐proliferative activity was evaluated against 60 cancer cell lines. The tested compounds showed potent anticancer activity against most cancer cell lines with median growth inhibition (GI50)<2 μM. Leukemia and renal cancer cell lines were the most responsive. Compound 12 a was the most active exhibiting GI50, total growth inhibition (TGI), and median lethal concentration (LC50) at 1.65, 3.71, and 9.3 μM, respectively. The benzamidine derivatives exerted their anti‐proliferative activity without causing any toxicity in normal human lung fibroblast (WI‐38) cells. The selectivity index (SI) ranged from 5.6 to 59.0 fold. Compound 4 h was the most selective compound (SI=59), and it was the least cytotoxic to WI‐38 cells. The cationic compounds 4 c, 4 h, 4 i, 7, and 12 b with high SI were selected for further mechanistic studies. Compounds 4 c, 4 h, and 4 i exerted their antiproliferative activity by inducing the cell cycle arrest (elevated p53 and downregulated cyclin‐dependent kinase 1 (cdk1)) and inducing apoptosis (elevated caspase 3). Compounds 7 and 12 b exerted their activity by inhibiting the growth and proliferation of cancer cells through inhibiting both topoisomerase II (topoII) and thioredoxin reductase1 (txnrd1). Finally, in silico predictions of the physicochemical, pharmacokinetic and drug‐likeness profiles of these new derivatives proved the oral availability and the inability to cross the blood‐brain barrier.

Vitamin D3/phospholipid complex decorated caseinate nanomicelles for targeted delivery of synergistic combination therapy in breast cancer

Targeted delivery of cytotoxic drugs has shown great potential in cancer therapy. In this light, vitamin D3 (vit.D3)-coated micelles were fabricated to encapsulate the cytotoxic drug; etoposide (ETP). Sodium caseinate micelles were first utilized to encapsulate vit.D3 and ETP within their hydrophobic core, then drug-loaded micelles were further decorated with an envelope of vit.D3/ phospholipid complex to enhance the active targeting potency of fabricated micelles via exploiting vit.D3 receptors (VDRs) overexpressed on the outer surface of breast cancer cells. In vitro cytotoxicity studies showed that fabricated micelles exhibited improved anticancer effect on MDA MB-231 and MCF-7 human breast cancer cell lines in comparison to free vit.D3 + ETP without any significant toxicity on normal human lung fibroblast (Wi-38) cells. In vivo biodistribution and efficacy studies in Ehrlich ascites tumor animal model revealed that fabricated micelles manifested improved accumulation in tumor tissue due to active targeting potential of vit.D3 without any remarkable toxicity. More importantly, fabricated micelles resulted in enhanced tumor apoptosis, reduced angiogenesis, invasion and autophagy, besides a decline in the tumor expression levels of both miR-21 and miR-192. Therefore, vit.D3/ETP micelles could serve as a favorable actively targeted anticancer delivery system having a superior effect over the free combination.

Bismuth(III) halide complexes of aromatic thiosemicarbazones: Synthesis, structural characterization and biological evaluation

Four new bismuth(III) thiosemicarbazone complexes, {BiCl3(η1-S-Hacptsc)3} (1), {[BiBr3(η1-S-Hacptsc)3]·CH3OH} (2), {[BiI2(µ2-I](η1-S-Hacptsc)]2} (3) and {[BiCl2(µ2-Cl)(η1-S-Hbztsc)2]2} (4), were prepared with the ligands acetophenone thiosemicarbazone (Hacptsc) and benzaldehyde thiosemicarbazone (Hbztsc). The complexes were characterized by a series of spectroscopic techniques. The crystal structures of 1–4 were also determined by X-ray diffraction. To the best of our knowledge, complexes 1–4 are the first examples of bismuth(III) halide aromatic thiosemicarbazones. Hirshfeld surface analysis studies show that H…H and X…H/H…X interactions of complexes 1–4 play an important role in the formation of supramolecular aggregation. Complexes 1–4 have been tested for their in vitro cytotoxic activity against human breast adenocarcinoma (MCF-7) cells. The toxicity of 1–4 has been evaluated on normal human fetal lung fibroblast cells (MRC-5). Complexes 1–4 appeared to show low cytotoxic activity and low toxicity. The antibacterial activity of 1–4 and their ligands was evaluated against the Gram negative species Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli) and Gram positive ones Staphylococcus epidermidis (S. epidermidis) and Staphylococcus aureus (S. aureus) by the Inhibition Zone (IZ) method. The influence of 1–4 on the catalytic peroxidation of linoleic acid by the enzyme lipoxygenase (LOX) has been determined experimentally. The IC50 values reveal that the synthesized bismuth(III) aromatic thiosemicarbazone complexes have good potential to inhibit lipoxygenase, with values better than the free aromatic thiosemicarbazone ligands and cisplatin.

Abstract 1006: Combination therapy with MEK inhibitors and a novel anti-neoplastic drug, imipridone ONC212, demonstrates synergy in pancreatic ductal adenocarcinoma cell lines

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. Although KRAS is mutated or amplified in nearly 95% of PDAC, no effective KRAS directed therapy has entered clinical practice. There is emerging data suggesting that inhibition of downstream targets of KRAS, such as MEK or ERK, increases autophagic flux and dependence in KRAS-mutated tumors. Autophagy, a catabolic process used by many tumors to maintain viability, can be targeted with various agents such has hydroxychloroquine and chloroquine, and recent preclinical data has shown that the combination of these agents with inhibitors of MEK/ERK can synergistically induce cell death. Using viability assays, we established sensitivity of multiple KRAS-mutated and KRAS wild-type pancreatic cancer cell lines, BxPC3, PANC1, HPAF-II, AsPC-1 to ONC212, trametinib, chloroquine and combinations of these agents. Results were analyzed after 72 hours of incubation using Compusyn and Combenefit. We also performed Western Blotting on cell lysates after treatment for 48 hours with these agents. We found that trametinib exhibited strong synergy with both chloroquine and ONC212 in all cell lines. The synergistic potential appeared to be most profound in those cell lines treated with ONC212 and trametinib. We used MRC5, a normal lung fibroblast cell line, as a control and found that these combinations did not significantly induce cell death. Using Western Blotting, we assessed markers of autophagy, including Beclin-1 and LC3B, as well as key second messenger pathway activation/suppression with p-AKT/AKT and p-ERK/ERK. At increasing doses, trametinib increased conversion of LC3-I to LC3-II, more notably in KRAS mutant cell lines, suggesting increased autophagic flux. ONC212, however, reduced conversion of LC3-I to LC3-II and increased degradation of Beclin-1 suggesting inhibition of autophagy. The combination, did not appear to have as striking of an effect on this pathway. In addition, p-ERK, as expected, was downregulated with MEK inhibition. ONC212 also appeared to reduce p-ERK levels and, interestingly, increased p-AKT. This suggests possible PI3K pathway upregulation, however, this could be influenced by timing and dose of treatments. Western blot analysis also revealed increased cPARP/PARP with combination therapy across cell lines. In conclusion, the combination of trametinib and ONC212 produces a synergistic cytotoxic effect on tumor cells at doses that are non-toxic to normal cells. In KRAS-mutated pancreatic cancer cell lines, we hypothesize that this may, in part, be due to autophagy suppression by ON212. Similar synergistic effects were noted in a KRAS wild-type pancreatic cancer cell lines, suggesting an autophagy-independent mechanism. Thus, this combination may represent a potential therapeutic modality for PDAC. Citation Format: Alexander G. Raufi, Casssandra Parker, Lanlan Zhou, Varun V. Prabhu, Josh Allen, Wafik S. El-Deiry. Combination therapy with MEK inhibitors and a novel anti-neoplastic drug, imipridone ONC212, demonstrates synergy in pancreatic ductal adenocarcinoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1006.

Biodegradation of Nonylphenol Ethoxylate in waste water by Penicillium chrysogenum

Current research aims to isolate fungal isolates capable of biodegrading Nonylphenol Ethoxylate (NPEOs) from secondary activated sludge. Samples were collected from Zenin wastewater treatment plant, El-Giza, Egypt. Physical and chemical analysis were performed. Screening of microbial isolates capable of degrading Nonylphenol Ethoxylate was performed on basal salts medium with Nonylephenol Ethoxylate as the only carbon source. Quantification of the residual amount of the (NPEOs) was determined by using a liquid chromatography technique. Morphological identification of the most promising fungal isolates degrading NPEOs was performed based on current universal keys, Penicillium database management system and molecular technique 18S rDNA using ITS1 (forward) and ITS4 (reverse) primers. Cytotoxicity test for microbes was performed by using different concentrations of NPEOs. Results revealed that eight microbes were isolated, which achieved the highest percentage of NPEOs biodegradation ( 70 - 80 %) .One novel species named Penicillium chrysogenum was able to biodegrade (NPEOs) (80%). In case of the Penicillium chrysogenum cytotoxic activity against mammalian cells from African green monkey kidney cells was detected under these experimental conditions (CC50) was 46.5 ± 4.8 µg/ml and the inhibitory cytotoxic activity against normal human lung fibroblast cells was detected under these experimental conditions with CC50 was 74.1 ± 6.1 µg/ml.

Antiproliferative labdane diterpenes from the rhizomes of Hedychium flavescens Carey ex Roscoe

Antiproliferative activity was confirmed in the various extracts of rhizomes of Hedychium flavescens (Zingiberaceae). The phytochemical investigation of the rhizomes of Hedychium flavescens led to the isolation of four labdane diterpenes. Their structures were established as coronarin E (1), C-14 epimers of isocoronarin D (2), C-15 epimers of coronarin D methyl ether (3) and isocoronarin D (4). The structure of the compounds was identified based on spectroscopic analysis and on comparison with literature reports. All these compounds were assessed for their in vitro cytotoxicity against human lung adenocarcinoma (A549) cell line and showed significant cytotoxicity as reflected in IC50 value, that is, 0.52, 0.59, 0.68 and 1.22μM compared with the control doxorubicin (IC50 0.92μM). Moreover, all the compounds were nontoxic towards the normal lung fibroblast (WI-38) cells. The chemo-profiling and cytotoxicity study of Hedychium flavescens is reported for the first time.

Oridonin improves the therapeutic effect of lentinan on lung cancer

Oridonin, a compound from Rabdosia rubescens, has been shown to exhibit a potent ability to improve the antitumor effects of lentinan (LNT). In the present study, the effects of oridonin, LNT, and the combination of these treatments were assessed on the normal human fetal lung fibroblast cell line MRC-5, as well as the non-small cell lung cancer cell line A549. Next, their effects on metastasis and survival in vivo were assessed in a mouse model of lung cancer. The effects of the treatments on the mRNA and protein expression levels of several regulatory factors in A549 cells and lung tissues were determined using reverse transcription-quantitative PCR and western blotting. The results showed that the viability of MRC-5 and A549 cells were not affected by 0-20 µg/ml oridonin; 0-300 µg/ml LNT did not affect the viability of MRC-5 cells, but 50-400 µg/ml LNT reduced the viability of A549 cells. Thus, 20 µg/ml oridonin and 100 or 300 µg/ml LNT were used in the subsequent experiments. Treatment with oridonin and LNT, alone or combined, had no effect on MRC-5 cell viability. Oridonin treatment had no effect on A549 cell viability; however, LNT suppressed A549 cell viability, and oridonin promoted the suppressive effects of LNT on A549 cells. In vivo analysis showed that oridonin alone had no effect on metastasis and survival, but LNT decreased metastasis and survival in mice. Oridonin augmented the effects of LNT against metastasis and further improved the survival rates of mice. In both A549 cells and lung tissues, LNT increased the mRNA and protein expression levels of caspase-3, caspase-8, caspase-9, Bax, p53, p21 and inhibitor of nuclear factor-κB (NF-κB)-α, and reduced the mRNA and protein expression levels of Bcl-2 and NF-κB. Oridonin augmented all the effects of LNT on expression of these proteins in the cells. Together, the results showed that oridonin enhanced the antitumor effects of LNT, and may thus serve as an adjuvant alongside LNT as a novel anticancer regimen for treatment of lung cancer.

Assessment of anti-hemolytic, cytotoxicity, antioxidant activities and molecular docking study based on thienopyrazole scaffold as pharmacophore

Thienopyrazole compound was used as a key synthon for a one- two- and three- pot component synthesis of new fused heterocyclic moieties which are known to have different biological activities. The investigated compounds were previously synthesized by environmentally benign techniques besides the conventional heating. The current study focused on biological evaluation of cytotoxicity, anti-hemolytic and antioxidant activities of some thienopyrazole compounds. The results showed the strongest anti-hemolytic and antioxidant activities are compounds 3a and 14c, respectively. All compounds were examined against normal human lung fibroblast cell line (WI-38) and four human cancer cell lines as human prostate cancer (PC-3), Hepatocellular carcinoma (HEPG-2), Colorectal carcinoma (HCT-116) and Epitheliod carcinoma (Hela). Molecular docking was performed inside the active site of P53 for compounds 1, 2, 11b and 14c. Moreover, quantum chemical calculations were performed on the selected compounds. Both techniques suggested that compound 1 displays high binding affinity in the P53 active site with respect to compound 2 while compound 14c owns a lower affinity with respect to 11b thereby suggesting that compound 11b may possibly act as P53 inhibitor and thus may participate in anticancer activity.

Ru(II) Polypyridine Complex-Functionalized Mesoporous Silica Nanoparticles as Photosensitizers for Cancer Targeted Photodynamic Therapy

Cancer is the leading cause of death in the developed world. In the last few decades, photodynamic therapy (PDT) has augmented the number of medical techniques to treat this disease in the clinics. As the pharmacological active species to kill cancer cells are only generated upon light irradiation, PDT is associated with an intrinsic first level of selectivity. However, since PDT agents also accumulate in the surrounding, healthy tissue and since it is practically very challenging to only expose the tumor site to light, some side effects can be observed. Consequently, there is a need for a selective drug delivery system, which would give a second level of selectivity. In this work, a dual tumor targeting approach is presented based on mesoporous silica nanoparticles, which act by the enhanced permeability and retention effect, and the conjugation to folic acid, which acts as a targeting moiety for folate receptor-overexpressed cancer cells. The conjugates were found to be nontoxic in noncancerous human normal lung fibroblast cells while showing a phototoxic effect upon irradiation at 480 or 540 nm in the low nanomolar range in folate receptor overexpressing cancerous human ovarian carcinoma cells, demonstrating their potential for cancer targeted treatment.

Synthesis of (4R)‐2‐(3‐hydroxyphenyl)thiazolidine‐4‐carboxylic acid substituted phthalocyanines: Anticancer activity on different cancer cell lines and molecular docking studies

In this study, firstly, (4R)‐2‐(3‐hydroxyphenyl)thiazolidine‐4‐carboxylic acid (1) and (4R)‐2‐(3‐(3,4‐dicyanophenoxy)phenyl)thiazolidine‐4‐carboxylic acid (2) were prepared. Then, the novel type metallophthalocyanines (ZnPc (3), CuPc (4), and CoPc (5)) bearing thiazolidine groups in peripheral positions were synthesized using by compound (2). The synthesized new compounds (1–5) were characterized by the combination of standard spectroscopic methods such as FT‐IR, 1H NMR, 13C NMR, UV–Vis spectral data, and MALDI‐TOF. Aggregation behaviors of peripheral tetra‐substituted metallophthalocyanines were investigated in dimethyl sulfoxide (DMSO) media. Fluorescence properties and fluorescence quantum yield of the new type zinc phthalocyanine (3) were performed in DMSO at room temperature. The anticancer activity of novel type metallophthalocyanines bearing thiazolidine groups in peripheral positions were investigated on rat glioma cancer (C6), human prostate carcinoma (DU‐145), and normal human lung fibroblast (WI‐38) cell lines. Finally, the biological and chemical activities of (4R)‐2‐(3‐(3,4‐dicyanophenoxy)phenyl)thiazolidine‐4‐carboxylic acid (2) and its novel type metallophthalocyanines (ZnPc (3), CuPc (4), and CoPc (5)) have been compared with many parameters obtained using theoretical methods that are the Gaussian software and molecular docking.

The Antimicrobial, Antioxidant, and Anticancer Activity of Greenly Synthesized Selenium and Zinc Composite Nanoparticles Using Ephedra aphylla Extract.

The current work aimed to synthesize selenium and zinc nanoparticles using the aqueous extract of Ephedra aphylla as a valuable medicinal plant. The prepared nanoparticles were characterized by TEM, zeta potential, and changes in the phytochemical constituents. Hence, the phenolic, flavonoid, and tannin contents were reduced in the case of the prepared samples of nanoparticles than the original values in the aqueous extract. The prepared extract of Ephedra aphylla and its selenium and zinc nanoparticles showed high potency as antioxidant agents as a result of the DPPH• assay. The samples were assessed as anticancer agents against six tumor cells and a normal lung fibroblast (WI-38) cell line. The selenium nanoparticles of Ephedra aphylla extract revealed very strong cytotoxicity against HePG-2 cells (inhibitory concentration (IC50) = 7.56 ± 0.6 µg/mL), HCT-116 cells (IC50 = 10.02 ± 0.9 µg/mL), and HeLa cells (IC50 = 9.23 ± 0.8 µg/mL). The samples were evaluated as antimicrobial agents against bacterial and fungal strains. Thus, selenium nanoparticles showed potent activities against Gram-negative strains (Salmonella typhimurium, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli), Gram-positive strains (Bacillus cereus, Listeria monocytogenes, Staphylococcus aureus, and Staphylococcus epidermidis), and the fungal strain Candida albicans. In conclusion, the preparation of nanoparticles of either selenium or zinc is crucial for improved biological characteristics.

Oxidative stress cytotoxicity induced by platinum-doped magnesia nanoparticles in cancer cells

The aim of this study was to prepare, characterize, and determine the in vitro anticancer effects of platinum-doped magnesia (Pt/MgO) nanoparticles. The chemical compositions, functional groups, and size of nanoparticles were determined using X-ray diffraction, Fourier transform infrared spectroscopy, energy dispersive X-ray spectroscopy, transmission electron microscopy, and scanning electron microscopy. Pt/MgO nanoparticles were cuboid and in the nanosize range of 30–50 nm. The cytotoxicity of Pt/MgO nanoparticles was determined via the 3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyltetrazolium bromide assay on the human lung and colonic cancer cells (A549 and HT29 respectively) and normal human lung and colonic fibroblasts cells (MRC-5 and CCD-18Co repectively). The Pt/MgO nanoparticles were relatively innocuous to normal cells. Pt/MgO nanoparticles downregulated Bcl-2 and upregulated Bax and p53 tumor suppressor proteins in the cancer cells. Pt/MgO nanoparticles also induced production of reactive oxygen species, decreased cellular glutathione level, and increased lipid peroxidation. Thus, the anticancer effects of Pt/MgO nanoparticles were attributed to the induction of oxidative stress and apoptosis. The study showed the potential of Pt/MgO nanoparticles as an anti-cancer compound.

3D bioprinting of cell-laden carbopol bioinks

Traditional in vitro culture models are unable to fully reflect the organ microenvironment, due to differences in terms of cell morphology, protein expression, cell-cell and cell-matrix interactions, and drug response. In contrast, the flexibility of bioprinting modes allows for the deposition of cell-containing biomaterials in any free-form-inspired 3D structures on chip. The main purpose of this study was to design and optimize commercially available Carbopol-based 3D printing formulations, because of their many advantages, such as low-cost, the ability to produce clear and stable gels, and the water thickening. For this purpose, three different Carbopol gels (EDT 2020 NF, Ultrez 10 NF and NF-980) were tested in terms of printability and biocompatibility, with lung cancer epithelial (A549) and normal lung fibroblast (MRC-5) cells. This study demonstrates that Carbopol is a promising candidate for the 3D printing of cell-laden constructs, both in terms of rheology and printing performance.

Structural characterization and biological evaluation of antimony(III) and bismuth(III) complexes with imidazolidine-2-thione

There is an emerging interest in the synthesis of antimony(III) and bismuth(III) complexes with sulfur containing ligands, this has been attributed to their wide structural diversity and their interesting application as biological agents. In the present work, four new antimony(III) and bismuth(III) complexes {[SbCl(IMT)3(μ-Cl)SbCl3(μ-Cl)]n} (1), {[SbBr2(IMT)2(μ-Br)]n} (2), {[BiBr2(IMT)2(μ-Br)]n} (3), and {mer-[BiI3(IMT)3]} (4) with imidazolidine-2-thione (IMT) have been prepared and characterized structurally, spectroscopically, and thermogravimetrically. The crystal structures of 1-4 have been determined by single-crystal X-ray diffraction. Complex 1 is the first structural example of polymeric antimony(III) chloride thioamide complex containing two different metallic centers. Complexes 2 and 3 are isostructural and the central atoms are six-coordinate in a distorted octahedral geometry with the zigzag chains formed by corner-sharing octahedra. Complex 4 is an example of neutral mononuclear bismuth(III) iodide complex with octahedral geometry. Complexes 1-4 have been evaluated for in vitro cytotoxic activity against human breast adenocarcinoma (MCF-7) cells. Complexes 1-4 appeared to show low cytotoxic activity against MCF-7 cells. The toxicity of 1-4 has been evaluated on normal human fetal lung fibroblast cells (MRC-5). The toxicity of antimony compounds 1-2 was greater than that of bismuth compounds 3-4. The influence of 1-4, on the catalytic peroxidation of the linoleic acid by the enzyme lipoxygenase (LOX) has been determined experimentally.

Cytotoxic Physalins from Aeroponically Grown Physalis acutifolia.

Aeroponically grown Physalis acutifolia afforded five new and six known withanolides including 10 physalins. The structures of the new withanolides, acutifolactone (1), 5β,6β-epoxyphysalin C (2), 5α-chloro-6β-hydroxyphysalin C (3), and an inseparable mixture of 5β,6β-epoxy-2,3-dihydrophysalin F-3β-O-sulfate (4) and 5β,6β-epoxy-2,3-dihydrophysalin C-3β-O-sulfate (5), were elucidated by analysis of their spectroscopic data and chemical interconversions. The known withanolides were identified as physalins B (6), D (7), F (8), H (9), I (10), and U (11) by comparison of their spectroscopic data with those reported. Evaluation of 1-11 and the derivatives, 13 and 13a, obtained from 4 and 5 against a panel of four human cancer cell lines [NCI-H460 (non-small-cell lung), SF-268 (CNS glioma), PC-3 (prostate adenocarcinoma), and MCF-7 (breast adenocarcinoma)] and normal human lung fibroblast (WI-38) cells revealed that physalins 2, 3, 8, and 9 exhibited selective cytotoxic activity to at least one of the cancer cell lines tested compared to the normal cells and that 7, 10, and 11 were inactive up to a concentration of 10.0 μM. These data provided some preliminary structure-activity relationships and suggested that the mechanism of cytotoxic activity of physalins may differ from other classes of withanolides.

Design, synthesis and molecular modeling of new quinazolin-4(3H)-one based VEGFR-2 kinase inhibitors for potential anticancer evaluation

Globally cancer is the second leading cause of death. So that this work is an attempt to develop new effective anti-cancer agents. In line with pharmacophoric features of VEGFR-2 kinase inhibitors, new nineteen quinazolin-4-one derivatives were designed, synthesized and biologically evaluated for their potential anticancer activity. All target compounds were evaluated in vitro for VEGFR-2 tyrosine kinase inhibition. Then, nine compounds of best results were further investigated by in vitro assay against three human cancer cell lines, namely HepG2, PC3 and MCF. N’-{2-](3-Ethyl-6-nitro-4-oxo-3,4-dihydroquinazoline-2-yl)thio[acetyl}benzohydrazide (36) was found to be the most potent candidate as it showed IC50 = 4.6 ± 0.06 µM against VEGFR-2 kinase. It also exhibited IC50 = 17.23 ± 1.5, 26.10 ± 2.2 and 30.85 ± 2.3 µg/mL against HepG2, PC3 and MCF, respectively. At the same time it showed IC50 = 145.93 ± 1.1 µg/mL against the normal human lung fibroblasts cell line (WI-38), indicating good selectivity index. Further investigation into HepG2 cell cycle showed the ability of compound 36 to induce apoptosis and arrest cell growth at G2/M phase. Moreover, docking studies demonstrated the ability of compound 36 to bind VEGFR-2 in a correct manner making three essential hydrogen bonds with the key residues Glu885, Asp1046 and Cys919. In sum, this work suggests that compound 36 can serve as a lead for development of effective anticancer agents targeting VEGFR-2.

Selina-1,3,7(11)-trien-8-one and Oxidoselina-1,3,7(11)-trien-8-one from Eugenia uniflora Leaf Essential Oil and Their Cytotoxic Effects on Human Cell Lines.

The sesquiterpenes selina-1,3,7(11)-trien-8-one and oxidoselina-1,3,7(11)-trien-8-one were isolated from the essential oil of Eugenia uniflora L. leaves. The structures were elucidated using spectrometric methods (UV, GC–MS, NMR, and specific optical rotation). The relationship between antioxidant activity, as determined by DPPH assay, and the cytotoxic effect was evaluated using tumor cells, namely lung adenocarcinoma epithelial cells (A549) and human hepatoma carcinoma cells (HepG2), as well as a model of normal human lung fibroblast cells (IMR90). Both compounds did not show prominent free-radical scavenging activity according to DPPH assay, and did not inhibit lipid peroxidation in Wistar rat brain homogenate. The isolated compounds showed pro-oxidative effects and cytotoxicity in relation to the IMR90 cell line.

Design and Synthesis of 4-O-Podophyllotoxin Sulfamate Derivatives as Potential Cytotoxic Agents.

4-O-Podophyllotoxin sulfamate derivatives were prepared using the natural lignan podophyllotoxin. The prepared compounds were afforded by reacting O-sulfonyl chloride podophyllotoxin with ammonia or aminoaryl/heteroaryl motif. Biological evaluation was performed in human breast cancer (MCF7), ovarian cancer (A2780), colon adenocarcinoma (HT29), and normal lung fibroblast (MRC5) cell lines. Compound 3 exhibited potent inhibitory activity and good selectivity margin. Compounds 2, 3, and 7 exerted apoptotic effect in MCF7 cells in a dose-dependent manner. The cytotoxicity of the verified compounds was inferior to that of podophyllotoxin.

Organotin derivatives of cholic acid induce apoptosis into breast cancer cells and interfere with mitochondrion; Synthesis, characterization and biological evaluation

Organotin(IV) derivatives of cholic acid (CAH) with the formulae R3Sn(CA) (R = Ph- (1), n-Bu- (2)) and R2Sn(CA)2 (R = Ph- (3), n-Bu- (4) and Me- (5)) were synthesized. The compounds were characterized in solid state by melting point, FT-IR, 119Sn Mössbauer, X-ray fluorescence (XRF) spectroscopy and in solution by 1H NMR, UV–Vis spectral data and by Electrospray Ionisation Mass spectrometry (ESI-MS), High Resolution Mass spectrometry (HRMS), and atomic absorption analysis.The in vitro bioactivity of 1–5 against human breast adenocarcinoma cancer cells MCF-7 (positive to hormone receptors) and MDA-MB-231 (negative to hormone receptors) reveal that triorganotin derivatives 1–2 exhibit significantly stronger activity than the corresponding diorganotin ones. Compound 5 is inactive against both cell lines at the concentrations tested. Triorganotins 1–2 inhibit selectively MCF-7 than MDA-MB-231 cells, suggesting hormone mimetic behavior of them. Organotins 1–4 inhibit both cancerous cell lines, stronger than cisplatin which rise up to 55-fold against MCF-7 and 170-fold against MDA-MB-231. The in vitro toxicity of 1–4 was evaluated on normal human fetal lung fibroblast cells (MRC-5), while their genotoxicity in vitro by micronucleus assay (MN). Moreover, the in vivo toxicity of 1–4 was tested by Artemia salina assay and their in vivo genotoxicity with Allium cepa test. The mechanism of action of 1–4 against MCF-7 was clarified in vitro by the means of cell morphology studies, cell cycle arrest, Acridine Orange/Ethidium Bromide (AO/EB) Staining, mitochondrial membrane permeabilization test and by their binding affinity toward the calf thymus (CT) DNA.