Fe(III)-salen and salphen complexes induce caspase activation and apoptosis in human cells

To explore the apoptotic and antitumor activities of metallo-salens, the authors have synthesized several Fe(III)-salen and salphen complexes and analyzed their effects on human cancer and noncancer cells. Their results demonstrated that Fe(III)-salen and salphen complexes affect cell viability and induce nuclear fragmentation and apoptosis in breast cancer (MCF7) cells. The IC(50) values for the active metallo-salen complexes ranged between 0.3 and 22 μM in MCF7 cells. Biochemically active Fe(III)-salen and salphen complexes induced caspase-3/7 activation and release of cytochrome c from the mitochondria to cytosol, suggesting the involvement of the mitochondrial pathway of apoptosis. Comparison of IC(50) values toward 3 different cell lines demonstrated that selected Fe(III)-salen complexes induce tumor cell-selective apoptosis in cultured cells. Overall, the studies demonstrated that Fe(III)-salen and salphen complexes induced efficient apoptosis in cultured human cells. The nature of the substituents and the bridging spacer between diamino groups play critical roles in determining the apoptotic activities of Fe(III)-salen and salphen complexes.     

The effect of sea anemone (H. magnifica) venom on two human breast cancer lines: death by apoptosis

Venom from the sea anemone, Heteractis magnifica, has multiple biological effects including, cytotoxic, cytolytic and hemolytic activities. In this study, cytotoxicity induced by H. magnifica venom was investigated using the crystal violet assay on human breast cancer T47D and MCF7 cell lines and normal human breast 184B5 cell line. Apoptosis was also assayed via Annexin V-flourescein isothiocyanate and propidium iodide (PI) staining followed by flow cytometric analysis. Cell cycle progression and mitochondria membrane potential were studied via flow cytometry following PI and JC-1 staining respectively. H. magnifica venom induced significant reductions in viable cell numbers and increases in apoptosis in T47D and MCF7 in dose-dependent manners. A significant apoptosis-related increase in the sub G1 peak of the cell cycle in both breast cancer cell lines was also observed. Moreover, treatment by venom cleaved caspase-8, caspase-9, and activated caspase-3. Overall, H. magnifica venom was highly cytotoxic to T47D and MCF7 human breast cancer cells, and the phenomenon could be the killing phenomenon via the death receptor-mediated and the mitochondria-mediated apoptotic pathways. Consequently, H. magnifica venom has potential for the development of a breast cancer therapeutic.     

Iron(III)-salen damages DNA and induces apoptosis in human cell via mitochondrial pathway

We synthesized a water soluble Fe(III)-salen complex and investigated its biochemical effects on DNA in vitro and on cultured human cells. We showed that Fe(III)-salen produces free radicals in the presence of reducing agent dithiothreitol (DTT) and induces DNA damage in vitro. Interestingly, upon treatment with Fe(III)-salen at concentration as low as 10microM, HEK293 human cells showed morphological changes, nuclear fragmentation, and nuclear condensation that are typical features of apoptotic cell death. The cytotoxicity measurement showed that IC(50) of Fe(III)-salen is 2.0microM for HEK293 cells. Furthermore, treatment with Fe(III)-salen resulted in translocation of cytochrome c from mitochondria to cytosol affecting mitochondrial membrane permeability. Our results demonstrated that Fe(III)-salen not only damages DNA in vitro, but also induces apoptosis in human cells via mitochondrial pathway.     

Selective cytotoxicity and modulation of apoptotic signature of breast cancer cells by Pithecellobium dulce leaf extracts

We report the potent and selective cytotoxicity of the crude aqueous leaf extract from the medicinal plant, Pithecellobium dulce toward the human breast cancer cells (MCF‐7), but not the normal cells (MCF‐10A). The cytotoxicity was found to be dose and time dependent, as 300 µg/mL of the extract decreased the cell viability to 50% (IC₅₀) in 48 h. The induction of apoptosis in the breast cancer cells after treatment was confirmed by significant percentage (24.7%), of early apoptotic cells (AnnexinV ⁺Propidium Iodide^_) in treated cells as compared to control cells (3.5%). We observed a significant upregulation in the mRNA expression of various pro‐apoptotic gene such as Bax (21.1 folds), p21(14.4 folds), p53 (11.7 folds), TNF (10.2 folds) and fas (6.3 folds) after treatment as compared to untreated cells. On the other hand, the relative mRNA expression of anti‐apoptotic genes such as Bcl‐2, NF‐KB and Cdk was reduced. The selective upregulation of pro‐apoptotic gene and down regulation of specific anti‐apoptotic genes could be the inducing factor for apoptotic cell death in MCF‐7 cells after treatment with the herbal extract. We believe that our findings provide a foundation for further studies on this formulation as a potential therapeutic candidate for breast cancer. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:756–766, 2016     

A methylene chloride fraction of Saururus chinensis induces apoptosis through the activation of caspase-3 in prostate and breast cancer cells

The aerial parts of Saururus chinensis (SC) have been used for the treatment of edema, fever, jaundice, and inflammatory diseases in Korean folk medicine for centuries. However, the mechanism by which SC exerts these anti-tumorigenic activities in human prostate and breast cancer cells has not yet been fully understood. In this study, we report on the methylene chloride fraction from SC exerting cytotoxicity against prostate and breast cancer cells in a dose-dependent manner. Specifically, SC exerted the most potent cytotoxicity in LNCaP and MCF-7 cells. SC was shown to down-regulate various angiogenetic (VEGF), proliferative (Cyclin D₁), anti-apoptotic (Bcl-2) gene products in these cells. SC also increased the number of annexin V-positive apoptotic bodies and the sub-G1 DNA contents of the cell cycle undergoing apoptosis through caspase-3 activation in both LNCaP and MCF-7 cells. We further confirmed that caspase-3 plays an important role in SC-induced apoptosis in LNCaP and MCF-7 cells through the use of the caspase-3 inhibitor. Moreover, we observed that SC potentiated paclitaxel-induced apoptosis in MCF-7 cells and sauchinone is a major active constituent of SC, which could induce apoptosis in the cells. Taken together, our data provide the evidence that SC induces apoptosis depending on caspase-3 activation and overcomes the natural biological resistance to chemotherapy found in human prostate and breast cancer cells.     

Synthesis,characterization and cytotoxicity studies of 1,2,3-triazoles and 1,2,4-triazolo [1,5-a] pyrimidines in human breast cancer cells

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is essential for physiological functions of tissues and neovasculature. VEGFR signaling is associated with the progression of pathological angiogenesis in various types of malignancies, making it an attractive therapeutic target in cancer treatment. In the present work, we report the synthesis of 1,4-disubstituted 1,2,3-triazoles and 1,2,4-triazolo[1, 5-a]pyrimidine derivatives via copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and screened for their anticancer activity against MCF7 cells. We identified 1-(2′-ethoxy-4′-fluoro-[1,1′-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole (EFT) as lead cytotoxic agent against MCF7 cell lines with an IC₅₀ value of 1.69?µM. Further evaluation revealed that EFT induces cytotoxicity on Ishikawa, MDA-MB-231 and BT474 cells with IC₅₀ values of 1.97, 4.81 and 4.08?µM respectively. However, EFT did not induce cytotoxicity in normal lung epithelial (BEAS-2B) cells. Previous reports suggested that 1,2,3-triazoles are the inhibitors of VEGFR1 and therefore, we evaluated the effect of EFT on the expression of VEGFR1. The results demonstrated that EFT downregulates the expression of VEGFR1 in MCF7 cells. In summary, we identified a potent cytotoxic agent that imparts its antiproliferative activity by targeting VEGFR1 in breast cancer cells. The novel compound could serve as a lead structure in developing VEGFR1 inhibitors.     

Investigation of acetylcholinesterase and mammalian DNA topoisomerases,carbonic anhydrase inhibition profiles,and cytotoxic activity of novel bis(α‐aminoalkyl)phosphinic acid derivatives against human breast cancer

The aim of this study was to evaluate biologically active novel molecules having potentials to be drugs by their antitumor properties and by activities of apoptotic caspase and topoisomerase. Following syntheses of novel eight bis(α‐aminoalkyl)phosphinic acid derivatives ( 4a–h ) as a result of array of reactions, compounds were evaluated by cytotoxic effects in vitro on human breast cancer (MCF‐7) and normal endothelial (HUVEC) cell lines. All phosphinic acid derivatives were effective for cytotoxicity on both MCF‐7 and HUVEC lines, while 4c , 4e , and 4f compounds were found significantly more effective. For the evaluation of antitumor properties of compounds in a highly sensitive method, their effects on inhibiting topoisomerases I and II were investigated. Also, some of the bis(α‐aminoalkyl)phosphinic acid derivatives ( 4a, 4e–h ) showed nice inhibitory action against acetylcholinesterase and human carbonic anhydrase isoforms I and II.     

Targeting abnormal DNA repair in therapy-resistant breast cancers

Although hereditary breast cancers have defects in the DNA damage response that result in genomic instability, DNA repair abnormalities in sporadic breast cancers have not been extensively characterized. Recently, we showed that, relative to nontumorigenic breast epithelial MCF10A cells, estrogen receptor-positive (ER+) MCF7 breast cancer cells and progesterone receptor-positive (PR+) MCF7 breast cancer cells have reduced steady-state levels of DNA ligase IV, a component of the major DNA-protein kinase (PK)-dependent nonhomologous end joining (NHEJ) pathway, whereas the steady-state level of DNA ligase IIIα, a component of the highly error-prone alternative NHEJ (ALT NHEJ) pathway, is increased. Here, we show that tamoxifen- and aromatase-resistant derivatives of MCF7 cells and ER(-)/PR(-) cells have even higher steady-state levels of DNA ligase IIIα and increased levels of PARP1, another ALT NHEJ component. This results in increased dependence upon microhomology-mediated ALT NHEJ to repair DNA double-strand breaks (DSB) and the accumulation of chromosomal deletions. Notably, therapy-resistant derivatives of MCF7 cells and ER(-)/PR(-) cells exhibited significantly increased sensitivity to a combination of PARP and DNA ligase III inhibitors that increased the number of DSBs. Biopsies from ER(-)/PR(-) tumors had elevated levels of ALT NHEJ and reduced levels of DNA-PK-dependent NHEJ factors. Thus, our results show that ALT NHEJ is a novel therapeutic target in breast cancers that are resistant to frontline therapies and suggest that changes in NHEJ protein levels may serve as biomarkers to identify tumors that are candidates for this therapeutic approach.     

Synthesis and Cytotoxicity Evaluation of Panaxadiol Derivatives

In this study, 13 panaxadiol (PD) derivatives were synthesized via reactions with aromatic compounds and amino acids. Following this, the cytotoxicity of these compounds was evaluated against four cancer cell lines (human hepatoma cells HepG‐2, human lung cancer cells A549, human breast cancer cells MCF‐7, and human colon cancer cells HCT‐116) and one normal cell lines (human gastric epithelial cells GES‐1). The results showed that the panaxadiol derivatives 3 , 12 , and 13 showed significant inhibition of cellular proliferation against cancer cells compared with PD, and the panaxadiol derivative 12 had the lowest IC₅₀ value for A549 (IC₅₀=18.91±1.03 μm ). For MCF‐7 cells, most compounds exhibited good inhibition of cellular proliferation, and the panaxadiol derivative 13 showed the strongest inhibitory effect (IC₅₀=8.62±0.23 μm ), which significantly increased the cytotoxicity of PD and was stronger than the positive control (mitomycin). For normal cells, all compounds exhibited low or no toxic effects; thus, these derivatives can be used to develop novel antiproliferative agents.     

Lectin of Abelmoschus esculentus (okra) promotes selective antitumor effects in human breast cancer cells

The anti-tumor effects of a newly-discovered lectin, isolated from okra, Abelmoschus esculentus (AEL), were investigated in human breast cancer (MCF7) and skin fibroblast (CCD-1059 sk) cells. AEL induced significant cell growth inhibition (63 %) in MCF7 cells. The expression of pro-apoptotic caspase-3, caspase-9, and p21 genes was increased in MCF7 cells treated with AEL, compared to those treated with controls. In addition, AEL treatment increased the Bax/Bcl-2 ratio in MCF7 cells. Flow cytometry also indicated that cell death (72 %) predominantly occurred through apoptosis. Thus, AEL in its native form promotes selective antitumor effects in human breast cancer cells and may represent a potential therapeutic to combat human breast cancer.     

Cytotoxic,tubulin-interfering and proapoptotic activities of 4′-methylthio-<Emphasis Type="Italic">trans</Emphasis>-stilbene derivatives,analogues of <Emphasis Type="Italic">trans</Emphasis>-resveratrol

The aim of this study was to evaluate the cytotoxicity of a series of seven 4′-methylthio-trans-stilbene derivatives against cancer cells: MCF7 and A431 in comparison with non-tumorigenic MCF12A and HaCaT cells. The mechanism of anti-proliferative activity of the most cytotoxic trans-resveratrol analogs: 3,4,5-trimethoxy-4′-methylthio-trans-stilbene (3,4,5-MTS) and 2,4,5-trimethoxy-4′-methylthio-trans-stilbene (2,4,5-MTS) was analyzed and compared with the effect of trans-resveratrol. All the compounds that were studied exerted a stronger cytotoxic effect than trans-resveratrol did. MCF7 cells were the most sensitive to the cytotoxic effect of trans-resveratrol analogs with IC₅₀ in the range of 2.1–6.0 µM. Comparing the cytotoxicity of 3,4,5-MTS and 2,4,5-MTS, a significantly higher cytotoxic activity of these compounds against MCF7 versus MCF12A was observed, whereas no significant difference was observed in cytotoxicity against A431 and HaCaT. In the series of 4′-methylthio-trans-stilbenes, 3,4,5-MTS and 2,4,5-MTS were the most promising compounds for further mechanistic studies. The proapoptotic activity of 3,4,5-MTS and 2,4,5-MTS, estimated with the use of annexin-V/propidium iodide assay, was comparable to that of trans-resveratrol. An analysis of cell cycle distribution showed a significant increase in the percentage of apoptotic cells and G2/M phase arrest in MCF7 and A431 as a result of treatment with 3,4,5-MTS, whereas trans-resveratrol tended to increase the percentage of cells in S phase, particularly in epithelial breast cells MCF12A and MCF7. Both trans-stilbene derivatives enhanced potently tubulin polymerization in a dose-dependent manner with sulfur atom participating in the interactions with critical residues of the paclitaxel binding site of β-tubulin.     

Evaluation of antioxidant and antiproliferative activities of 1,2‐bis (p‐amino‐phenoxy) ethane derivative Schiff bases and metal complexes

In this study, the effects of the two Schiff base derivatives and their metal complexes were tested for MDA concentration, which is an indicator of lipid peroxidation, antioxidant vitamin A, vitamin E, and vitamin C levels in cell culture. A comparison was performed among the groups and it was observed that MDA, vitamin A, vitamin E, and vitamin C concentrations were statistically changed. According to the results, all compounds caused a significant oxidative stress without Zn complexes. Moreover, Mn(II), Cu(II), Zn(II), and Ni(II) complexes of Schiff bases derived from a condensation of 1,2‐bis (p‐aminophenoxy) ethane with naphthaldehydes and 4‐methoxy benzaldehyde were examined in terms of antitumor activity against MCF‐7 human breast cancer and L1210 murine leukemia cells. Furthermore, the derivatives were tested for antioxidative and prooxidative effects on MCF‐7 breast cancer cells. The compounds which were tested revealed that there was an antitumor activity for MCF‐7 and L 1210 cancer cells. Also, some of the compounds induced oxidative harmful.     

10H‐3,6‐Diazaphenothiazines triggered the mitochondrial‐dependent and cell death receptor‐dependent apoptosis pathways and further increased the chemosensitivity of MCF‐7 breast cancer cells via inhibition of AKT1 pathways

Breast cancer is one of the leading causes of death in cancer categories, followed by lung, colorectal, and ovarian among the female gender across the world. 10H‐3,6‐diazaphenothiazine (PTZ) is a thiazine derivative compound that exhibits many pharmacological activities. Herein, we proceed to investigate the pharmacological activities of PTZ toward breast cancer MCF‐7 cells as a representative in vitro breast cancer cell model. The PTZ exhibited a proliferation inhibition (IC₅₀ = 0.895 µM) toward MCF‐7 cells. Further, cell cycle analysis illustrated that the S‐phase checkpoint was activated to achieve proliferation inhibition. In vitro cytotoxicity test on three normal cell lines (HEK293 normal kidney cells, MCF‐10A normal breast cells, and H9C2 normal heart cells) demonstrated that PTZ was more potent toward cancer cells. Increase in the levels of reactive oxygen species results in polarization of mitochondrial membrane potential (ΔΨm), together with suppression of mitochondrial thioredoxin reductase enzymatic activity suggested that PTZ induced oxidative damages toward mitochondria and contributed to improved drug efficacy toward treatment. The RT² PCR Profiler Array (human apoptosis pathways) proved that PTZ induced cell death via mitochondria‐dependent and cell death receptor‐dependent pathways, through a series of modulation of caspases, and the respective morphology of apoptosis was observed. Mechanistic studies of apoptosis suggested that PTZ inhibited AKT1 pathways resulting in enhanced drug efficacy despite it preventing invasion of cancer cells. These results showed the effectiveness of PTZ in initiation of apoptosis, programmed cell death, toward highly chemoresistant MCF‐7 cells, thus suggesting its potential as a chemotherapeutic drug.     

Hybrid pharmacophore design and synthesis of isatin–benzothiazole analogs for their anti-breast cancer activity

A hybrid pharmacophore approach was used to design and synthesize isatin–benzothiazole analogs to examine their anti-breast cancer activity. The cytotoxicity of these compounds were determined using three different human breast tumor cell lines, MDA-MB231, MDA-MB468, MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Although all compounds examined were quite effective on all the cancer cell lines examined, the compounds 4-bromo-1-diethylaminomethyl-1H-indole-2,3-dione (2l) and 4-chloro-1-dimethylaminomethyl-3-(6-methyl-benzothiazol-2-ylimino)-1,3-dihydro-indol-2-one (5e) emerged as the most active compounds of this series. Importantly, the cytotoxic effect of 2l was 10–15-fold higher on cancer than non-cancer cells, suggesting that this compound can be very effective for the control of breast cancer with low side effects. Since 2l showed effective cytotoxicity on MCF7 cells and arrested the cells at G2/M at a similar concentration, these two phenomena may be closely correlated. We conclude that the isatin-linked benzothiazole analog can serve as a prototype molecule for further development of a new class of anti-breast cancer agents.     

Cytotoxic effect of <Emphasis Type="Italic">Semialarium mexicanum</Emphasis> (Miers) Mennega root bark extracts and fractions against breast cancer cells

The root bark of Semialarium mexicanum (Miers) Mennega (cancerina) is traditionally used in Mexico to treat cancer. However, there are no studies supporting its use. We evaluated whether S. mexicanum root bark induces cytotoxicity in breast cancer cells to determine if it has potential applications in the treatment of this disease. Extracts of S. mexicanum root bark in petroleum ether, ethanol, and water were obtained by ultrasound-assisted extraction. MTT and WST-1 assays were used to evaluate the cytotoxicity of the extracts toward breast cancer cells (MDA-MB-231 and MCF7), non-tumorigenic breast-derived cells (MCF 10A), and peripheral blood mononuclear cells (PBMCs). For the extract with greatest cytotoxicity, induction of apoptosis and oxidative stress were determined using flow cytometry. The extract was fractionated, and the cytotoxicity of its fractions was evaluated with the four cell types. The fractions were also analyzed by HPLC. Only the petroleum ether extract was cytotoxic for all cell types (MDA-MB-231?>?MCF 10A/MCF7?>?PBMCs). Cell death occurred by apoptosis, which could be associated with the induction of oxidative stress. Two fractions that were highly cytotoxic for breast cancer cells were obtained from this extract (IC₅₀?≤?4.15 µg/mL for the most active fraction at 72 h). The MCF 10A cells were less affected, while PBMCs were not affected after 72 h of treatment. Pristimerin was identified in both fractions and may be partially responsible for the cytotoxic effect. These results suggest that S. mexicanum root bark has a potential application in breast cancer treatment.     

Design and synthesis of anti-breast cancer agents from 4-piperazinylquinoline: A hybrid pharmacophore approach

A novel class of 4-piperazinylquinoline derivatives based on the isatin scaffold were designed by molecular hybridization approach and synthesized for biological evaluation. Subsequently, the compounds were examined for their cytotoxic effects on two human breast tumor cell lines, MDA-MB468 and MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Although all compounds examined were quite effective on the breast cancer cell lines examined, the compound 4-bromo-1-[4-(7-chloro-quinolin-4-yl)-piperazin-1-ylmethyl]-1H-indole-2,3-dione (5b) and N¹-[4-(7-trifluoromethyl-quinolin-4-yl)]-piperazin-1-ylmethyl-4-chloro-1H-indole-2,3-dione-3-thiosemicarbazone (8a) emerged as the most active among this series. It appeared that both 5b and 8a caused apoptosis to MCF7 cancer cells, but not MCF10A non-cancer cells. Thus, 4-piperazinylquinoline linked isatin analog can serve as the prototype molecule for further development of a new class of anti-breast cancer agents.     

Synthesis,Characterization and In Vitro Study of Biocompatible Cinnamaldehyde Functionalized Magnetite Nanoparticles (CPGF Nps) For Hyperthermia and Drug Delivery Applications in Breast Cancer

Cinnamaldehyde, the bioactive component of the spice cinnamon, and its derivatives have been shown to possess anti-cancer activity against various cancer cell lines. However, its hydrophobic nature invites attention for efficient drug delivery systems that would enhance the bioavailability of cinnamaldehyde without affecting its bioactivity. Here, we report the synthesis of stable aqueous suspension of cinnamaldehyde tagged Fe₃O₄ nanoparticles capped with glycine and pluronic polymer (CPGF NPs) for their potential application in drug delivery and hyperthermia in breast cancer. The monodispersed superparamagnetic NPs had an average particulate size of ∼20 nm. TGA data revealed the drug payload of ∼18%. Compared to the free cinnamaldehyde, CPGF NPs reduced the viability of breast cancer cell lines, MCF7 and MDAMB231, at lower doses of cinnamaldehyde suggesting its increased bioavailability and in turn its therapeutic efficacy in the cells. Interestingly, the NPs were non-toxic to the non-cancerous HEK293 and MCF10A cell lines compared to the free cinnamaldehyde. The novelty of CPGF nanoparticulate system was that it could induce cytotoxicity in both ER/PR positive/Her2 negative (MCF7) and ER/PR negative/Her2 negative (MDAMB231) breast cancer cells, the latter being insensitive to most of the chemotherapeutic drugs. The NPs decreased the growth of the breast cancer cells in a dose-dependent manner and altered their migration through reduction in MMP-2 expression. CPGF NPs also decreased the expression of VEGF, an important oncomarker of tumor angiogenesis. They induced apoptosis in breast cancer cells through loss of mitochondrial membrane potential and activation of caspase-3. Interestingly, upon exposure to the radiofrequency waves, the NPs heated up to 41.6°C within 1 min, suggesting their promise as a magnetic hyperthermia agent. All these findings indicate that CPGF NPs prove to be potential nano-chemotherapeutic agents in breast cancer.     

Bisindole‐oxadiazole hybrids,T3P®‐mediated synthesis,and appraisal of their apoptotic,antimetastatic, and computational Bcl‐2 binding potential

In the pursuit of novel anticancer leads, new bisindole‐oxadiazoles were synthesized using propyl phosphonic anhydride as a mild and efficient reagent. The molecule, 3‐[5‐(1H‐indol‐3‐ylmethyl)‐1,3,4‐oxadiazol‐2‐yl]‐1H‐indole ( 3a ) exhibited selective cytotoxicity to MCF‐7 cells with a cell cycle arrest in the G1 phase. The mechanism of cytotoxicity of 3a involved caspase‐2‐dependent apoptotic pathway with characteristic apoptotic morphological alterations as observed in acridine orange/ethidium bromide and Hoechst staining. The wound healing migratory assay exhibited an intense impairment in the motility of MCF‐7 cells on incubation with 3a . Docking simulations with anti‐apoptotic protein Bcl‐2, which is also involved in cancer metastasis displayed good affinity and high binding energy of 3a into the well characterized BH3 binding site. The positive correlation between the Bcl‐2 binding studies and the results of in vitro investigations exemplifies compound 3a as a lead molecule exhibiting MCF‐7 differential cytotoxicity via apoptotic mode of cell death in addition to its anti‐metastatic activity.     

Synthesis of novel 6-substituted amino-9-(β-d-ribofuranosyl)purine analogs and their bioactivities on human epithelial cancer cells

New nucleoside derivatives with nitrogen substitution at the C-6 position were prepared and screened initially for their in vitro anticancer bioactivity against human epithelial cancer cells (liver Huh7, colon HCT116, breast MCF7) by the NCI-sulforhodamine B assay. N⁶-(4-trifluoromethylphenyl)piperazine analog (27) exhibited promising cytotoxic activity. The compound 27 was more cytotoxic (IC₅₀?=?1–4?μM) than 5-FU, fludarabine on Huh7, HCT116 and MCF7 cell lines. The most potent nucleosides (11, 13, 16, 18, 19, 21, 27, 28) were further screened for their cytotoxicity in hepatocellular cancer cell lines. The compound 27 demonstrated the highest cytotoxic activity against Huh7, Mahlavu and FOCUS cells (IC₅₀?=?1, 3 and 1?μM respectively). Physicochemical properties, drug-likeness, and drug score profiles of the molecules showed that they are estimated to be orally bioavailable. The results pointed that the novel derivatives would be potential drug candidates.     

Mn(II) complex of a vitamin B6 Schiff base as an exclusive apoptosis inducer in human MCF7 and HepG2 cancer cells: Synthesis,characterization, and biological studies

Herein, a Mn(II) complex of the N,N′-dipyridoxyl(1,4-butanediamine) (═H₂L) Schiff base has been newly synthesized. The synthesized complex was characterized by several experimental methods. In addition, the density functional theory approaches were used for theoretical identification of the complex. A good agreement between the computed and experimental infrared frequencies demonstrates validity of the optimized geometry for the synthesized complex. In a N₂O₂ manner, two azomethine nitrogens and two phenolate oxygens of the L²⁻ ligand are coordinated to the Mn²⁺ metal ion. The biological studies indicate an efficient apoptotic and antioxidant activities of the synthesized [MnL(CH₃OH)₂] complex on both of the HepG2 and MCF7 cancer cells. Since it has been suggested that the complex is an exclusive potent antitumor for treatment of the human breast and liver cancers.