Breast Adenocarcinoma Cell Line MCF-7 Research Articles

Effects of hydroxyl radicals produced by a zinc phthalocyanine photosensitizer on tumor DNA

Photodynamic therapy (PDT) is a new therapeutic approach for cancer treatment. Its mechanism relies on three elements: photosensitizer, light and oxygen. Under aerobic conditions, a suitable wavelength of light activates the photosensitizer that results in the formation of reactive oxygen species (ROS). We herein report that PDT with a zinc phthalocyanine (ZnPc) photosensitizer coupled with 2,4,6-tris (N, N-dimethylaminomethyl) phenoxy (TAP), termed as ZnPc(TAP)4, has the ability to photodegrade DNA in tumor cells via hydroxyl radicals produced under the red light irradiation, resulting in effective elimination of tumor cells. Furthermore, the high-efficient anti-tumor effect of ZnPc(TAP)4 was verified in a human breast adenocarcinoma cell line MCF-7 tumor-bearing animal model. To the best of our knowledge, this is the first time that destructive effects of hydroxyl radicals produced by PDT on DNA of tumor cells has been documented, which may open up new avenues of antitumor therapy on eliminating the DNA of tumor cells.

Primaquine homodimers as potential antiplasmodial and anticancer agents.

Primaquine homodimers, e.g. symmetric PQ-diamides of dicarboxylic acids containing 4 to 8 carbon atoms, were evaluated against Plasmodium berghei hepatic stages and P. falciparum blood stages, as well as against three cancer cell lines. Novel PQ-homodimers exerted much higher activity against hepatic stages, but less pronounced activity against blood stages in comparison to the parent drug. The submicromolar activity of succinic, fumaric and maleic derivatives against P. berghei was determined (IC50 values: 726.2, 198.1 and 358.4 nM, respectively). Our results indicated that the length and type of spacer between two PQ moieties highly modified the antiproliferative activities of PQ-homodimers. The general antiproliferative activity of the adipic and mesaconic derivatives against three cancer cell lines (MCF-7, HCT116, H 460) was observed (GI50 = 1.78-13.7 and 2.36-4.31 µM, respectively), but adipic derivative was less toxic to human embryonic kidney cells (HEK 293). High selectivity of fumaric and suberic derivatives against breast adenocarcinoma cell line MCF-7 was detected. These two compounds have shown no antiproliferative activity against other tumor cells and HEK 293.

The 5-hydrazino-3-methylisothiazole-4-carboxylic acid, its new 5-substituted derivatives and their antiproliferative activity

Currently, the basic method of treatment of colon cancer is surgery. The range of anticancer drugs used in the treatment of colorectal cancer is small and is based mainly on systemic combination chemotherapy. As a result of the designed syntheses, we received new isothiazole derivatives with anticancer activity. The synthesized 5-hydrazino-3-methylisothiazole-4-carboxylic acid has never been obtained before. It is also a substrate for the synthesis of its innovative derivatives, i.e. compounds that are Schiff bases. The identification of the structure of new compounds was carried out using mass spectrometry (MS), proton nuclear magnetic resonance spectroscopy (1H NMR), carbon nuclear magnetic resonance spectroscopy (13C NMR) and infrared spectroscopy (IR). Potential antitumor activity was confirmed in antiproliferative MTT and SRB tests. The selected, most biologically active substances were characterized by high selectivity towards leukemia and colon cancer cell lines. They caused high inhibition of proliferation of human biphenotypic B cell myelomonocytic leukemia MV4-11 (13 compounds), human colon adenocarcinoma cell lines sensitive LoVo (8 compounds) and resistant to doxorubicin LoVo/DX (12 compounds). However, in the conducted studies, their activity against breast adenocarcinoma MCF-7 and normal non-tumorigenic epithelial cell line derived from mammary gland MCF-10A was substantially lower. The result of this work is claimed Polish patent application.

Alpha mangostin loaded crosslinked silk fibroin-based nanoparticles for cancer chemotherapy

Silk fibroin has been utilized extensively for biomedical purposes, especially the drug delivery systems. This study introduced and characterized three novel α-mangostin loaded crosslinked fibroin nanoparticles (FNPs), using EDC or PEI as a crosslinker, for cancer treatment. All three formulas were spherical particles with a mean size of approximately 300 nm. By varying the type and/or amount of the crosslinkers, particle surface charge was controllable from −15 to +30 mV. Crosslinked FNPs exhibited higher drug entrapment efficiency (70%) and drug loading (7%) than non-crosslinked FNP. FT-IR, XRD, and DSC analytical methods confirmed that α-mangostin was entrapped in FNPs in molecular dispersion form. Compared to the free α-mangostin, the crosslinked FNPs increased the drug’s solubility up to threefold. They also showed sustained release characteristics of more than 3 days, and reduced free α-mangostin hematotoxicity by 90%. The α-mangostin loaded FNPs were physicochemically stable for up to 24 h when dispersed in intravenous diluent and for at least 6 months when preserved as lyophilized powder at 4 °C. In terms of anticancer efficacy, on both Caco-2 colorectal and MCF-7 breast adenocarcinoma cell lines, all formulas maintain α-mangostin’s apoptotic effect while exhibit greater cytotoxicity than the free drug. In conclusion, α-mangostin loaded crosslinked FNPs show high potential for cancer chemotherapy.

Cytotoxic Activity and Memory T Cell Subset Distribution of in vitro-Stimulated CD8+ T Cells Specific for HER2/neu Epitopes.

Minimal residual disease remaining after resection of primary tumors can lead to tumor recurrence and metastasis, increasing mortality and morbidity rates among cancer patients. Thus, there is a need for new technologies for recognition and elimination of single cancer cells remaining in a patient's body after radiation therapy, chemotherapy, or surgical resection. Effector CD8+ T cells, also commonly known as cytotoxic T lymphocytes (CTLs), play a key role in antitumor cellular immunity and, when properly activated, are able to effectively destroy tumor cells. The aims of this study were to obtain CD8+ CTLs specific for the HER2/neu epitopes E75 and E88 and to assess the cytotoxic activity and composition of these cells in terms of the distribution of memory T-cell subsets. We obtained HER2-specific CD8+ T cells and assessed T cell subset distribution among them including naive T cells (TN), central memory T cells (TCM), effector memory T cells (TEM), stem cell-like memory T cells (TSCM) and terminally-differentiated T cells (TEMRA) via eight-color flow cytometry. HER2-specific CTLs were largely (~40–50%) represented by TSCM cells, a population capable of mounting pronounced antitumor immune responses due to a combination of effector function and self-maintenance. In comparison with activated peripheral blood mononuclear cells (PBMCs) and bulk CD8+ T cells, HER2-specific CTLs exhibited greater cytotoxicity against the HER2-expressing human breast adenocarcinoma cell line MCF-7 and produced higher levels of IFN-γ in response to tumor cells. We also showed the presence of HER2-specific CTLs in healthy individuals and increase in them in HER2-positive breast cancer patients. Collectively, our results suggest that HER2-specific CD8+ T cells isolated using this approach could be used for adoptive T-cell transfer to eliminate tumor cells and prevent metastasis and relapse in patients with HER2-overexpressing cancers.

Synthesis and Evaluation of Antioxidant, Antimicrobial and Anticancer Properties of 2-(Prop-2-yn-1-yloxy)benzaldehyde Derivatives

5-bromo-2-(prop-2-yn-1-yloxy)benzaldehyde (compound 3) and 3,5-di-tert-butyl-2-(prop-2- yn-1-yloxy)benzaldehyde (compound 5) were synthesized via nucleophilic substitution reactions. Compound 5 showed higher antioxidant capacity with respect to compound 3 in all the four different antioxidant activity methods used. Moreover, in phosphomolybdenum assay, compound 5, with 1.1 proportion value, showed almost the same total antioxidant capacity compared to universal trolox standard. Furthermore, Broth microdilution method and agar disc diffusion tests demonstrated that the same compound also exhibited good antibacterial activity towards the bacteria Bacillus subtilis. Finally, both of the benzaldehyde compounds showed high antifungal activity against Aspergillus niger. In this study, compound 5 (IC50: 54.3 µg/ml) showed significant cytotoxic activity against breast adenocarcinoma cell line MCF-7 with respect to compound 3 (IC50: 173.4 µg/ml).

Activation of Autophagy and Nrf2 Signaling in Human Breast Adenocarcinoma MCF-7 Cells by Novel Monophenolic Antioxidants

The effect of novel water-soluble structurally related monophenolic compounds on the activity of two most important mechanisms of maintaining intracellular homeostasis, autophagy and the redox-sensitive signal system Keap1/Nrf2/ARE, has been studied in human breast adenocarcinoma cell line MCF-7 using confocal microscopy. Autophagy processes were analyzed on the basis of the amount of intracellular vesicles that were positive for the autophagy marker (LC3B). The activation of the Keap1/Nrf2/ARE system was determined by the translocation of the transcription factor Nrf2 into the nucleus. It was found that the effect of the tested compounds depended on their structure and concentration. When the inhibitor of autophagosome–lysosome fusion chloroquine was added to the culture medium (20 μM), the asymmetrically hindered by the tert-butyl group phenols with thiosulfonate (TS-13) and sulfonate group in the para-propyl substituent increased the rate of autophagosome elimination in MCF-7 cells. Shortening of the para-alkyl substituent by one methylene unit abolished the effect. The addition of the second ortho-tert-butyl substituent had the reverse result. Both tested compounds enhanced the translocation of the transcription factor Nrf2 into the nucleus of MCF-7 cells (which is a critical step in Keap1/Nrf2/ARE activation). It was observed after incubation with asymmetrically hindered by the tert-butyl group phenol with selenosulfonate group in para-propyl substituent (5−100 μM) for 4 h and with TS-13 (5−100 μM) for 24 h. Taking into account our previous findings on the toxicity of this group of compounds for MCF-7 cells we can conclude that these compounds exert different effect on autophagy and activation of the antioxidant response element signaling system Keap1/Nrf2/ARE.

EVALUATION OF PHYTOCHEMICAL COMPOUNDS IN Moringa oliefera Lam. EXTRACTS ON CYTOTOXICITY OF MCF-7 CELL LINE

Moringa olifera Lam. which called Miracle tree was an enormous usage of medical, nutritional and economic benefits so its leaves and roots extracts were vitro examined for phytochemicals contents, antioxidant, and cytotoxicity against MCF-7 cell line. Leaves and roots both extracts were estimate using 2,2-di phenyl-1-picryl hydrazyl (DPPH) radical scavenging assay and high performance liquid chromatography (HPLC) to determine phenolic and flavonoids compounds. The leaves aqueous and ethyl acetate extracts contained a significantly (p<0.05) more phenolic compounds than root extracts, while roots ethyl acetate extracts were significantly more active in DPPH assay comparing with aqueous extracts . However, the leaves aqueous extract and roots ethyl extracts were contained high values flavonoids compound but in case of phenolic compounds the aqueous roots ex tract recorded the greatest highest number followed by the leaves ethyl acetate extract. The ethyl acetate extractions for leaves and roots have a high inhibition percentage against breast adenocarcinoma MCF-7 cell line comparing with aqueous extracts.

Effect of Chemotherapeutics and Tocopherols on MCF-7 Breast Adenocarcinoma and KGN Ovarian Carcinoma Cell Lines In Vitro.

The combination of doxorubicin and cyclophosphamide commonly used to treat breast cancer can cause premature ovarian failure and infertility. α-Tocopherol is a potent antioxidant whereas γ-tocopherol causes apoptosis in a variety of cancer models in vitro including breast cancer. We hypothesised that the combination of doxorubicin (Dox) and 4-hydroperoxycyclophosphamide (4-Cyc) would be more cytotoxic in vitro than each agent alone, and that α-tocopherol would reduce and γ-tocopherol would augment the cytotoxicity of the combined chemotherapeutics. Human MCF-7 breast cancer and KGN ovarian cells were exposed to Dox, 4-Cyc, combined Dox and 4-Cyc, α-tocopherol, γ-tocopherol, or a combination of Dox and 4-Cyc with α-tocopherol or γ–tocopherol. Cell viability was assessed using a crystal violet assay according to four schedules: 24h exposure, 24h exposure + 24h culture in medium, 24h exposure + 48h culture in medium, or 72h continuous exposure. Supernatants from each separate KGN culture experiment (n=3) were examined using an estradiol ELISA. Dox was cytotoxic to both MCF-7 and KGN cells, but 4-Cyc only killed MCF-7 cells. γ-Tocopherol significantly decreased MCF-7 but not KGN cell viability. The combined chemotherapeutics and γ-tocopherol were more cytotoxic to MCF-7 than KGN cells, and α-tocopherol reduced the cytotoxicity of the combined chemotherapeutics towards KGN ovarian cells, but not MCF-7 cells. The addition of both γ-tocopherol and α-tocopherol to the chemotherapeutic combination of Dox and cyclophosphamide has the potential to increase in vitro chemotherapeutic efficacy against breast cancer cells whilst decreasing cytotoxicity towards ovarian granulosa cells.

Evaluation of nonlinear dynamics of the cell structure damage as a promising method for personalized cancer diagnostics

Background:Modulation interference microscopy is one of the promising technologies for early personalized cancer diagnostics, while it gives the possibility to obtain real-time images of living functioning cells at a nanometer resolution, as well as to assess spatio-temporal changes of their intracellular structures.Aim:To identify the markers of malignant transformation of cells based on a multiple scale spatio-temporal of the data obtained by lase interferometry duringin situregistration of changes in intracellular structures.Materials and methods:The study was performed with the breast adenocarcinoma MCF-7 cell line and human kidney epithelial cells HEK 293 provided by the N.N. Blokhin National Medical Research Centre of Oncology (Moscow, Russia). Changes in fluctuation of the living cell phase thickness were measured with a laser modulation interference microscope MIM-340 (PA UOMZ, Russia). The multifractal detrended fluctuation analysis (MF-DFA) was used to assess the results obtained.Results:By comparison of the scaling exponential spectra and corresponding spectra of the singular fluctuations in the minimal and maximal diameters of the phase pictures of HEK 293 cells and MCF-7 cells, it was shown that the cancer cell dynamics has definite monofractal properties: a linear dependency of the scaling exponentsτfrom the actualqparameter and “dotted” singularity spectrum (the spectral width does not exceed 0.1). The dynamics of healthy cell demonstrated multifractal properties, such as a non-linear dependencyτ(q)and a bell shaped singularity spectrum (the spectral width over 0.1).Conclusion:We have proposed a new approach to assess the intracellular structural damage during oncogenesis. The signs of monofractality are objective criteria of malignization. The results obtained seems promising as early diagnostic markers of cancer transformation (damage) of cells and determination of tumor cell sensitivity / resistance to anti-tumor agents in an individual patient.

The investigation of in vitro dark cytotoxicity and photodynamic therapy effect of a 2,6-dibromo-3,5-distyryl BODIPY dye encapsulated in Pluronic® F-127 micelles

A 2,6-dibrominated 3,5-distyryl boron-dipyrromethene (BODIPY) dye with a moderately high singlet oxygen quantum yield was encapsulated in Pluronic® F-127 micelles, and its dark cytotoxicity and photodynamic activity were investigated on the human breast adenocarcinoma MCF-7 cell line. The BODIPY dye exhibited very low dark toxicity and a significant PDT effect when added in drug formulations consisting of 5.0% (v/v) DMSO in supplemented Dulbecco’s modified Eagle’s medium (DMEM) and as Pluronic® F-127 micelle encapsulation complexes in supplemented DMEM alone. An IC50 value of 4 ± 2 μM was obtained when the BODIPY dye was encapsulated in Pluronic® F-127 micelles during in vitro photodynamic activity studies in MCF-7 cancer cells with a 660 nm light emitting diode.

QSAR and docking studies of α,β-unsaturated carbonyl compounds against human breast adenocarcinoma cell line MCF-7

A quantitative structure-activity relationships (QSAR) studies were carried out by correlating activity against human breast adenocarcinoma cell line MCF-7 of series of α,β-unsaturated carbonyl compounds with their physicochemical descriptors using multiple linear regression method. The predictability of the QSAR model was estimated using internal and external predictivity methods. The best QSAR model was selected, having the squared correlation coefficient r2 = 0.84684, correlation coefficient r = 0.9202, standard deviation s = 0.38484, and cross-validated squared correlation coefficient Q2 = 0.7621. Model obtained was used to predicted the activity against breast cancer for a set of designed α,β-unsaturated carbonyl compounds (A1-A16). Docking studies was performed for A1-A16 compounds to evaluated their inhibition on c-Met kinase, which has been overexpressed in a number of cancers.

(E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides as tubulin polymerization inhibitors: Structure-based bioisosterism design, synthesis, biological evaluation, molecular docking and in silico ADME prediction

A series of (E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides have been synthesized and evaluated for their anticancer activity in human hepatocellular liver carcinoma HepG2 and breast adenocarcinoma MCF-7 cell lines. Among all the tested compounds, compound 3a, 3e and 3n displayed more activity than lead compound with IC50 value of 0.26–0.61 μM. Meanwhile, these compounds (3a, 3e and 3n) showed potent antiproliferative activity against a panel of cancer cells and the HCT-8/T multidrug resistant cell line with IC50 values in the range of 0.077– 7.44 μM. Flow cytometric analyses revealed that compound 3n induced cell cycle arrest in G2/M phases in a dose dependent manner. The compound 3n also displayed potent tubulin polymerization inhibition with an IC50 value of 0.9 µM, with ten folds more active than colchicine (IC50 = 9 μM). Molecular docking studies revealed that compound 3n efficiently interacted with the colchicine binding site of tubulin through hydrophobic, cation-π and hydrogen bond interaction. Furthermore, in silico pharmacokinetic prediction shown that these compounds have a good ADME-related physicochemical parameters. These results demonstrate that 3n exhibits potent cytotoxicity in cancer cells by targeting the colchicine binding site of tubulin and potentially acts as a therapeutic lead compound for the development of anticancer drugs.

Synthesis of 4,6-disubstituted pyrazolo[3,4-d]pyrimidine analogues: Cyclin-dependent kinase 2 (CDK2) inhibition, molecular docking and anticancer evaluation

The cyclin-dependent kinases (CDKs) play a crucial role in cell cycle progression and are validated targets of cancer therapy. Pyrazolopyrimidines are versatile scaffolds, which have been exploited for developing potential anticancer agents. We herein report the synthesis and in vitro CDK2/cyclin E kinase inhibitory activity of 34 novel 4,6-disubstituted pyrazolo [3,4-d]pyrimidines (9a-9s, 13a-13h, 14a-14d, 15a-15c). The structure-activity relationship (SAR) studies revealed that compounds with thiopentane/thiophenethyl group at C-6 and heteroatom-containing bicyclic moiety (benzofuran) at C-4 exhibited good CDK2 inhibitory activity. Further, the binding energies obtained for the active compounds from in silico molecular docking studies with CDK2 were found to be in consonance with the observed SAR and experimental results. In addition, some of the synthesized compounds showed anti-proliferative activity against K-562 (chronic myelogenous leukaemia) and MCF-7 (breast adenocarcinoma) cell lines in micromolar ranges. Further, the cytotoxicity studies on CHO cell line revealed that all the compounds are non-toxic to normal cells and are safe. Thus, the research findings revealed the anticancer potential of 4,6-disubstituted pyrazolo [3,4-d]pyrimidine derivatives which could be further considered for lead optimization.

Half-Sandwich Ir(III) Complex of N1-Pyridyl-7-azaindole Exceeds Cytotoxicity of Cisplatin at Various Human Cancer Cells and 3D Multicellular Tumor Spheroids

The half-sandwich iridium(III) complexes [Ir(η5-Cpx)(phaza–)Cl] (1, 2), [Ir(η5-Cpx)(thaza–)Cl] (3, 4), and [Ir(η5-Cpx)(pyaza)Cl]PF6 (5, 6) containing deprotonated 1-phenyl-7-azaindole (phaza–) and 1-(thiophen-2-yl)-7-azaindole (thaza–) and electroneutral 1-(pyridin-2-yl)-7-azaindole (pyaza), were prepared; Cpx = pentamethylcyclopentadienyl (Cp*; for 1, 3, and 5) or 1,2,3,4-tetramethyl-5-phenylcyclopentadienyl (Cpph; for 2, 4, and 6). The complexes were thoroughly characterized, including a single-crystal X-ray analysis of complexes 1, 5, and 6. All of the complexes were screened for their in vitro cytotoxicity at the A2780 human ovarian carcinoma cell line and its A2780R cisplatin-resistant variant (2D culture cells). The best-performing complex 6 was further studied against the human DU-145 prostatic carcinoma, A549 lung carcinoma, HCT116 colon carcinoma, HeLa cervix adenocarcinoma, and MCF7 breast adenocarcinoma cell lines (2D culture cells). Complex 6 showed a cytotoxic profile different from that of c...

Synthesis, docking and anticancer activity of azo-linked hybrids of 1,3,4-thia-/oxadiazoles with cyclic imides.

A series of novel analogues based on a diazole-imide pharmacophore were synthesized by diazotizing substituted 1,3,4-thia-/oxadiazol-2-amines and subsequently coupling the resulting diazonium salts with N-substituted cyclic imides. The resulting compounds C1 to C28 were characterized by various spectral methods, viz. IR, NMR and mass spectroscopy. All the synthesized compounds were tested against two human cancer cell lines: human breast adenocarcinoma cell line MCF-7 and colorectal adenocarcinoma cell line HT-29. Among the synthesized compounds, C14 (2-(4-chloro-3-((5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)diazenyl)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione) emerged as a potential candidate against both MCF-7 and HT-29 with [Formula: see text] values of 0.09 ± 0.02 [Formula: see text]M and 0.11 ± 0.03 [Formula: see text]M, respectively. Similarly, compound C16 displayed highest anticancer activity against MCF-7 cell line with [Formula: see text] = 0.07 ± 0.02 [Formula: see text]M. Target fishing (inverse docking) using ChemMapper server identified EGFR tyrosine and CDK2 kinases as high priority targets for this pharmacophore. Computational docking (AutoDock 4.2) was used to analyse the interactions between the target proteins and active compounds.

PO-411 Novel HIF1α inhibitors suppress cancer cell growth and circumvent multidrug resistance

Introduction Hypoxia is one of the causes of the resistance of tumours to various chemotherapeutic agents. Most solid tumours contain hypoxic regions and adapt to low levels of oxygen by producing hypoxia-activated molecules, among which HIF-1α (Hypoxia-Inducible Factor 1-alpha) is key. HIF-1α is upregulated in many types of solid cancers and contributes to tumour progression by stimulation of VEGF-A expression and subsequent neoangiogenesis. The goal of the study was to synthesise a series of novel hypoxic cytotoxins and to evaluate their anticancer potencies. Material and methods A series of 3-aryl/heteroarylquinoxaline-2-carbonitrile 1,4-dioxides was synthesised by Beirut reaction. Cancer cell lines were purchased from ATCC. The cytotoxic activity of quinoxaline 1,4-dioxides was evaluated in normoxia (21%O2) and hypoxia (1%O2). The cytotoxicity was assessed by MTT test (72 hour growth with compounds). HIF-1α and p53 activation was assessed by reporter analysis. The presence of ROS in MDA-MB-231 breast cancer cells was detected using the fluorescent probe 2′,7′-dichlorofluorescin diacetate. Results and discussions Lead compounds in series new quinoxaline 1,4-dioxides demonstrated better cytotoxicity and comparable hypoxia selectivity for human breast adenocarcinoma cell lines MCF-7 and MDA-MB-231 than the reference agent tirapazamine. In contrast to reference antibiotic doxorubicin, quinoxaline 1,4-dioxides inhibited hypoxia-mediated HIF-1α activation and showed potent cytotoxicity against multidrug resistant human chronic myeloid leukaemia K562/4 cells with overexpression P-glycoprotein (Pgp). Selected compound LCTA-2809 (6,7-dichloro-3-phenylquinoxaline-2-carbonitrile 1,4-dioxide) inhibited of cancer cell growth through p53-independent mechanisms. Compound LCTA-2809 showed no effects on p53-dependant luciferase activity, when doxorubicin revealed high potency to activate p53-dependant reporter in MCF-7 cells. Our results revealed that compound LCTA-2809 sensitised MCF-7 cells to biguanide metformin in hypoxia. Short-term treatment with LCTA-2809 resulted in the fast increase of ROS accumulation in cancer cells. Conclusion HIF-1α inhibitor LCTA-2809 can be considered as the lead compound for further anticancer drug design, evaluation, and development of new potent antitumor agents. The biology experiments of the research were supported by RSF 14-15-00362.

Structure-Activity Relationships of Nitro-Substituted Aroylhydrazone Iron Chelators with Antioxidant and Antiproliferative Activities.

Aroylhydrazone iron chelators such as salicylaldehyde isonicotinoyl hydrazone (SIH) protect various cells against oxidative injury and display antineoplastic activities. Previous studies have shown that a nitro-substituted hydrazone, namely, NHAPI, displayed markedly improved plasma stability, selective antitumor activity, and moderate antioxidant properties. In this study, we prepared four series of novel NHAPI derivatives and explored their iron chelation activities, anti- or pro-oxidant effects, protection against model oxidative injury in the H9c2 cell line derived from rat embryonic cardiac myoblasts, cytotoxicities to the corresponding noncancerous H9c2 cells, and antiproliferative activities against the MCF-7 human breast adenocarcinoma and HL-60 human promyelocytic leukemia cell lines. Nitro substitution had both negative and positive effects on the examined properties, and we identified new structure-activity relationships. Naphthyl and biphenyl derivatives showed selective antiproliferative action, particularly in the breast adenocarcinoma MCF-7 cell line, where they exceeded the selectivity of the parent compound NHAPI. Of particular interest is a compound prepared from 2-hydroxy-5-methyl-3-nitroacetophenone and biphenyl-4-carbohydrazide, which protected cardiomyoblasts against oxidative injury at 1.8 ± 1.2 μM with 24-fold higher selectivity than SIH. These compounds will serve as leads for further structural optimization and mechanistic studies.

Synthesis, anticancer evaluation, and molecular docking studies of some novel 4,6-disubstituted pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 (CDK2) inhibitors

A novel series of 4,6-disubstituted pyrazolo[3,4-d]pyrimidines (7–43) bearing various anilines at C-4 position and thiophenethyl or thiopentane moieties at C-6 position have been designed and synthesized by molecular hybridization approach. All the synthesized compounds were evaluated for in vitro CDK2/cyclin E and Abl kinase inhibitory activity as well as anti-proliferative activity against K-562 (chronic myelogeneous leukemia), and MCF-7 (breast adenocarcinoma) cell lines. The structure–activity relationship (SAR) studies revealed that compounds with thiophenethyl group at C-6 with mono-substituted anilines at C-4 exhibited better CDK2 inhibitory activity compared to alkyl group (thiopentane) at C-6 and di-substituted anilines at C-4 of the scaffold. In particular, compounds having 2-chloro, 3-nitro and 4-methylthio aniline groups at C-4 displayed significant enzymatic inhibitory activity against CDK2 with single digit micromolar IC50 values. The in silico molecular docking studies suggested possible binding orientation and the binding energies were in agreement with the observed SAR as well as experimental results. In addition, some of the synthesized compounds showed anti-proliferative effects against K-562 and MCF-7 cancer cell lines with IC50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization.

Antitumor and antioxidant activity of the freshwater macroalga Cladophora surera

Macroalgae are currently being explored as novel and sustainable sources of bioactive compounds for both pharmaceutical and nutraceutical applications arising from their antioxidant, anticancer, and antimicrobial activity. In the present study, the antitumoral and antioxidant activities of crude methanolic extracts of the freshwater macroalga Cladophora surera Parodi & Caceres, harvested from Naposta Creek (Argentina), were investigated in vitro. The antioxidant activity was assessed by DPPH method and polyphenol content using Folin-Ciocalteu phenol reagent. Antitumoral activity was evaluated on the human breast adenocarcinoma cell line MCF-7 by measuring proliferation, migration, and cell adhesion. The algal extract (AE) showed a total phenol content of 1.62 ± 0.17 μg GAE mg−1 dry alga and DPPH scavenging activity of 25.03 ± 1.99% (10 mg)−1 dry alga. The trypan blue assay after 48 h of treatment indicated that the AE significantly inhibits proliferation in a dose-dependent manner (1–100 μg mL−1), being more effective the highest dose employed, with a concomitant increment in dead cells. However, the colorimetric MTS assay only showed a significant decrease in cell viability at 100 μg mL−1 AE. Using the wound healing assay, we demonstrated that AE inhibits cell migration. Through a cell adhesion assay, we found that AE affects considerably the cell adhesion capacity at all doses probed. Analysis of cell spreading indicated that cell morphology was also affected by AE treatment. These results indicate that C. surera could be a source of valuable bioactive compounds usable as antitumoral preventive therapy for their effects on the regulation of processes involved in metastasis in cells derived from human mammary cancer.