Considerable Cytotoxic Activity Research Articles

Regiospecific Synthesis of Thioether‐Linked 3‐Hydroxy Oxindoles From Spiroepoxy Oxindoles and Their Cytotoxicity Evaluation

AbstractA facile synthesis of thioether‐linked 3‐hydroxy oxindoles was achieved through regiospecific ring‐opening of spiroepoxy oxindoles with oxadiazole‐2‐thiols and benzimidazole‐2‐thiols as nucleophiles. The thiol heteronucleophile attacks from the less hindered position of spiroepoxides, yielding 3‐substituted‐3‐hydroxy oxindoles in high yields (up to 86%). The synthetic procedure offers an attractive route for diversely substituted 3‐hydroxy oxindoles that are prominent frameworks in many natural products. Further, the in vitro cytotoxicity evaluation shows that most of these molecules possessed considerable cytotoxic activity against a panel of human cancer cell lines by comparing 5‐fluorouracil (5‐FU) as control. The morphological studies like phase contrast, AO/EB, and DAPI of the most potent compound 5e highlight apoptotic features on skin melanoma cell lines (SKMEL‐29). Additionally, compound 5e was also studied for inhibition of tubulin polymerization, and the result was correlated with molecular docking studies.

Selective Metal‐Coordinated Nanodrugs Based on Thiazine Moiety for Anticancer Therapeutics: Spectroscopic, Theoretical, and Molecular Docking Studies

ABSTRACTThe current study involved production, comprehensive structural analysis, and physicochemical characterizing of two distinctive complexes namely, Cu(TBH) and Zn(TBH); TBH donor ligand: N′‐(1‐(3,6‐dihydro‐4‐hydroxy‐2,6‐dioxo‐2H‐1,3‐thiazin‐5‐yl)ethylidene)‐2‐hydroxybenzohydrazide) using a wide range of analytical methods, including elemental analysis, UV–Vis, FT‐IR, and 1HNMR spectrometry, molar conductivity and magnetic susceptibility measurements, and thermal analysis. According to the findings, chelation can occur through O, N, and O donor atoms of monoanionic chelator for generating mono‐nuclear chelates with tetrahedral geometry for Cu (II) and octahedral geometry for Zn (II). The anticarcinogenic ability of TBH chelator and its coordinated compounds against human liver cancer (HepG‐2) was investigated. The Cu(TBH) complex was found to have selective and promising anticancer activity against a liver cancer cell line, with lower IC50 (liver carcinoma cell line) and higher IC50 (normal human cell line) values than other produced compounds and standard drugs. Utilizing DFT computations, the molecular structures of the TBH and its complexes were verified, offering a detailed understanding of their quantum chemical characteristics. A quantitative structure–activity relationship (QSAR) model, which illustrates the association between DFT‐computed descriptors and biological activities pIC50, was also created using multiple linear regression (MLR) on the synthesized compounds as anticancer medicines. Additionally, there are no issues with the produced compounds' oral bioavailability according to (ROF) Lipinski's rule of five. Furthermore, docking studies of the synthesized TBH chelator and its chelates with CDK2 kinase have been performed to validate the biological findings. According to our findings, the novel Cu(TBH) nanodrug exhibits considerable cytotoxic activity, prompting further study into its pharmacological profile and exploring its potential in drug development.

Colombian cyanobacteria with cytotoxic activity in cancer cell lines

In the last decade, cyanobacteria have emerged as significant reservoirs of bioactive molecule for the pharmaceutical, cosmetic, and alimentary industries, given the wide spectrum of new possibilities of different organic pigments, proteins, carbohydrates, lipids, and powerful antioxidant sources for specific and stronger cancer treatments, autoimmune syndromes, obesity, and inflammatory diseases. A bioactivity screening was executed for 12 strains of Colombian cyanobacteria (10 marine and 2 freshwater) representative of the orders present in the LAUN culture collection, performing methanol extracts per sample, which was fractionated by reverse phase HPLC protocol, obtaining 8 fractions for each crude extract. All these crude extracts were tested for antimicrobial activities through disk diffusion methodology, and fractions were tested for cytotoxic activity against cancer cell lines by cell viability detection with MTT. Cyanobacteria's extracts showed considerable cytotoxic activity for osteosarcoma (MG063) and colon cancer (HCT116) cell lines (61 and 66 % of reduced viability compared to untreated controls, respectively) and a surprising cell growth promotion for the control group fibroblast (3T3L1) and brain endothelial (HCMEC) cell lines (121 and 127 % growth, respectively), no bioactivity was observed in the antimicrobial tests. These findings underscore the expansive cytotoxic potential of Colombian cyanobacteria against cancer cell lines and, notably, their growth-promoting effects on healthy cell lines. This positions them as promising sources of bioactive compounds for future pharmaceutical developments.

Harnessing molecular hybridization approach to discover novel quinoline EGFR-TK inhibitors for cancer treatment.

Aim: Using molecular hybridization approach, novel 18 quinoline derivatives (6a-11) were designed and synthesized as EGFR-TK inhibitors. Materials & methods: The antiproliferative activity was assessed against breast (MCF-7), leukemia (HL-60) and lung (A549) cancer cell lines. Moreover, the most active quinoline derivatives (6d and 8b) were further investigated for their potential as EGFR-TK inhibitors. In addition, cell cycle analysis and apoptosis induction activity were conducted. Results: A considerable cytotoxic activity was attained with IC50 values spanning from 0.06 to 1.12μM. Besides, the quinoline derivatives 6d and 8b displayed potent inhibitory activity against EFGR with IC50 values of 0.18 and 0.08μM, respectively. Conclusion: Accordingly, the afforded quinoline derivatives can be used as promising lead anticancer candidates for future optimization.

Design and synthesis of novel 2-(2-(4-bromophenyl)quinolin-4-yl)-1,3,4-oxadiazole derivatives as anticancer and antimicrobial candidates: in vitro and in silico studies.

Cancer is the second leading cause of death globally, surpassed only by heart disease. Moreover, bacterial infections remain a significant global health burden, contributing substantially to morbidity and mortality, especially among hospitalized patients. EGFR has emerged as a prime therapeutic target due to its pivotal role in driving uncontrolled cell growth and survival across numerous cancer types. In addition, DNA gyrase represents a promising target for the development of novel antimicrobial agents. Therefore, we aimed to design and synthesize new multi-target quinoline hybrids (7-17e) capable of acting as anti-proliferative and antimicrobial agents by inhibiting EGFR and microbial DNA gyrase, respectively. The inhibitory potential of the synthesized compounds was determined using in vitro and in silico approaches. The antiproliferative activity of the synthesized quinoline-oxadiazole derivatives 7-17e was assessed against two cancer cell lines, namely, hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7). The assessed compounds 7-17e showed considerable cytotoxic activity activities against HepG2 and MCF-7 with IC50 values of 0.137-0.332 and 0.164-0.583 μg mL-1, respectively, in comparison to erlotinib as the positive control, which showed an IC50 value of 0.308 and 0.512 μg mL-1, respectively. Moreover, an EGFR tyrosine kinase inhibition assay was conducted on the most prominent candidates. The results showed good IC50 values of 0.14 and 0.18 μM for compounds 8c and 12d, respectively, compared to lapatinib (IC50 value of 0.12 μM). Furthermore, the minimum antimicrobial inhibitory concentration was evaluated for the most prominent candidates with S. aureus, E. coli, and C. albicans. Compounds 17b, 17d and 17e displayed the most potent inhibitory activity, exhibiting 4-, 16- and 8-fold more activity, respectively, than the reference neomycin. Hence, we can conclude that the afforded compounds can be used as lead dual anticancer and antimicrobial candidates for future optimization.

Cytotoxic, Antibacterial, Antioxidant, Anthelmintic, and Anticoagulant Potential of Phytochemicals from Simarouba glauca Leaf Extract

This study’s primary objectives were to evaluate phytochemical screening and identify therapeutic uses for the herb Simarouba glauca. By employing a Soxhlet apparatus, the leaves were extracted using ethyl acetate. Standard techniques were used for preliminary phytochemical analysis to screen the presence of secondary metabolites. The agar plate method was used to test for antimicrobial activity against Escherichia coli and Bacillus subtilis. The antidiabetic activity aimed to identify the alpha-amylase enzyme inhibition that is most effective at regulating blood glucose levels. The DPPH assay was used to screen the antioxidant activity. The extract’s bioactive components were purified using column and thin-layer chromatography. Simarouba glauca extract was tested for its cytotoxic property on the lung cancer cell line (A549) using the MTT assay. To find the phytocompounds present in the extract, GC-MS analysis was carried out. Anticoagulation activity was carried out to assess the prothrombin time of blood and therapeutic applications such as anthelminthic activity were determined by determining the time of death of parasites like earthworms. The tested extract showed considerable cytotoxic, antibacterial, antioxidant, anthelmintic, and anticoagulant activity.

Ten undescribed eremophilane and guaiane sesquiterpenes from Penicillium roqueforti

Nine undescribed eremophilane sesquiterpenes, one undescribed guaiane sesquiterpene, along with ten known analogues were isolated and identified from fungus Penicillium roqueforti, which was separated from the root soil of Hypericum beanii N. Robson collected from the Shennongjia Forestry District, Hubei Province. Their structures were elucidated on the basis of various spectroscopic analyses, mainly including NMR and HRESIMS data, 13C NMR calculations with DP4+ probability analyses, ECD calculations, and single-crystal X-ray diffraction experiments. Furthermore, all twenty compounds were evaluated for the in vitro cytotoxic activities against seven human tumor cell lines, and the result suggested that 14-hydroxymethylene-1(10)-ene-epi-guaidiol A exhibited considerable cytotoxic activity against the Farage (IC50 < 10 μM, 48 h), SU-DHL-2, and HL-60 cells. Further mechanism study demonstrated that 14-hydroxymethylene-1(10)-ene-epi-guaidiol A could significantly promote apoptosis by inhibiting tumor cell respiration and decreasing intracellular ROS levels, thereby inducing S-phase blockade in tumor cells.

Cytotoxic Effects of Aminotriles with Bioactive Potential: An Integrative Review

Aminonitriles are pharmacological-interest bioactive due to their promising antimicrobial and antitumor activity. Since cytotoxicity tests are inherent to the new drug development process, this work aimed to verify reports in the scientific literature on the cytotoxic effects of aminonitriles. The method adopted was an integrative review of works published in the last 10 years in the PubMed, Embase, Web of Science, and Virtual Health Library (VHL) databases. Three articles that matched the selection and eligibility criteria were included in this review. A total of 33 aminonitriles were used in the cytotoxicity experiments, and of the nine molecules based on pyridine, two exerted moderate cytotoxic activity, of the twelve synthesized from benzimidazole, none showed cytotoxic activity, and of the twelve derived from renieramycins, all showed considerable cytotoxic activities. The studies used in this research evaluated the cytotoxic effects of aminonitriles with evident anticancer and antimicrobial activity. The importance of evaluating the cytotoxicity of aminonitriles is emphasized, as well as the need for investigative research that explores other evaluation methods in pre-clinical tests that may corroborate the existing findings, with a view to the development of therapies against emerging health problems.

The anticancer effect of Salvia pisidica essential oil through promotion intrinsic and extrinsic apoptosis pathways in human cancer cell lines

IntroductionSpecies of the Salvia genus are aromatic herbs and traditionally used for many medicinal purposes in Anatolia. The genus has produced an extraordinarily large number of beneficial secondary metabolites belonging to numerous chemical groups. Salvia pisidica is an endemic plant of southwest Anatolia, the dried parts of which are used as herbal tea and local materia medica. MethodsThe composition of endemic S. pisidica essential oil was determined through GC-MS studies. In vitro cytotoxicity activity and apoptosis analysis were investigated by MTT assay, q-PCR and Annexin V staining experiments. ResultsOur results showed that 1,8 cineole (19.15 %) camphor (18.12 %) and γ-gurjunene (8.58 %) were the major constituents of the essential oil. It showed cytotoxic effects on the human breast cancer MCF-7, colon carcinoma Caco-2, hepatocyte carcinoma HepG2, and prostate carcinoma LnCap. The results of q-PCR and image-cytometer analysis showed that the essential oil caused induction of apoptosis by intrinsic and extrinsic pathways in all cancer cell lines. ConclusionS. pisidica essential oil demonstrates considerable cytotoxic activity due to an apoptosis-related mechanism, suggesting that their bioactive components could be used as natural anticancer substances.

Cytotoxic Activity of the Ethyl Acetate Extract of Iraqi Carica papaya Leaves in Breast and Lung Cancer Cell Lines.

The ethyl acetate extract of Iraqi C. papaya leaves was prepared and tested for its phytochemical constitution. The 3-(4,5-dimethylthiazoline-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed in breast (MCF-7) and lung (A549) cells lines that were treated with different concentrations of ethyl acetate extract (3.125,6.25,12.5, 25, 50, and 100μg/ml). After 72 hrs of treatment, cell viability was evaluated. The ethyl acetate extract of C. papaya showed considerable cytotoxic activity in the MCF-7 and A549 cell lines. The activity was dose-dependent; The half-maximum inhibitory concentration (IC50) values were 22.74μg/ml and 8.674 μg/ml in the MCF-7 and A549 cell lines, respectively. The ethyl acetate fraction of Iraqi C. papaya leaves has potential anticancer activity in lung and breast cancer.

Understanding the Antilymphoma Activity of Annona macroprophyllata Donn and Its Acyclic Terpenoids: In Vivo, In Vitro, and In Silico Studies.

Annona macroprophyllata Donn (A. macroprophyllata) is used in traditional Mexican medicine for the treatment of cancer, diabetes, inflammation, and pain. In this work, we evaluated the antitumor activity of three acyclic terpenoids obtained from A. macroprophyllata to assess their potential as antilymphoma agents. We identified the terpenoids farnesyl acetate (FA), phytol (PT) and geranylgeraniol (Gg) using gas chromatography–mass spectroscopy (GC-MS) and spectroscopic (1H, and 13C NMR) methods applied to petroleum ether extract of leaves from A. macroprophyllata (PEAm). We investigated antitumor potential in Balb/c mice inoculated with U-937 cells by assessing brine shrimp lethality (BSL), and cytotoxic activity in these cells. In addition, to assess the potential toxicity of PEAm, FA, PT and Gg in humans, we tested their acute oral toxicity in mice. Our results showed that the three terpenoids exhibited considerable antilymphoma and cytotoxic activity. In terms of lethality, we determined a median lethal dose (LD50) for thirteen isolated products of PEAm. Gg, PT and AF all exhibited a higher lethality with values of 1.41 ± 0.42, 3.03 ± 0.33 and 5.82 ± 0.58 µg mL−1, respectively. To assess cytotoxic activity against U-937 cells, we calculated the mean cytotoxic concentration (CC50) and found that FA and PT were closer in respect to the control drug methotrexate (MTX, 0.243 ± 0.007 µM). In terms of antilymphoma activity, we found that FA, PT and Gg considerably inhibited lymph node growth, with median effective doses (ED50) of 5.89 ± 0.39, 6.71 ± 0.31 and 7.22 ± 0.51 mg kg−1 in females and 5.09 ± 0.66, 5.83 ± 0.50 and 6.98 ± 0.57mg kg −1 in males, respectively. Regarding acute oral toxicity, we classified all three terpenoids as category IV, indicating a high safety margin for human administration. Finally, in a molecular docking study of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, we found binding of terpenoids to some amino acids of the catalytic site, suggesting an effect upon activity with a resulting decrease in the synthesis of intermediates involved in the prenylation of proteins involved in cancer progression. Our findings suggest that the acyclic terpenoids FA, PT, and Gg may serve as scaffolds for the development of new treatments for non-Hodgkin’s lymphoma.

Thais savignyi tissue extract: bioactivity, chemical composition, and molecular docking

Context Thais savignyi Deshayes (Muricidae) is widely distributed in the Red Sea. Its abundance and the history of Muricidae in traditional medicine make it a tempting target for investigation. Objective To investigate the chemical profile and biological activities of T. savignyi tissue extracts. Materials and methods Methanol, ethanol, acetone, and ethyl acetate extracts from T. savignyi tissue were compared in their antioxidant by total antioxidant capacity, DPPH free radical scavenging, and total phenolic content. In addition, the antimicrobial, and antibiofilm properties (at 250 µg/mL) of the extracts were tested against Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella pneumoniae, Staphylococcus aureus, and Candida albicans. The antioxidant extract with greatest activity was assessed for cytotoxicity (range 0.4–100 µg/mL) against 3 human cancer cell lines (UO-31, A549 and A431), and its chemical composition was investigated using GC-MS. Moreover, docking simulation was performed to predict its constituents’ binding modes/scores to the active sites of thymidylate kinase. Results The ethyl acetate extract (Ts-EtOAc) showed the highest total antioxidant capacity (551.33 mg AAE/g dry weight), total phenolics (254.46 mg GAE/g dry weight), and DPPH scavenging (IC50= 24.0 µg/mL). Ts-EtOAc exhibited strong antibacterial (MIC: 3.9 µg/mL against K. pneumoniae), antibiofilm (MIC: 7.81 µg/mL against S. aureus), and antifungal (MIC: 3.9 µg/mL against C. albicans) activities and considerable cytotoxicity against cancer cells (UO-31: IC50= 19.96 ± 0.93, A549: IC50= 25.04 ± 1.15 μg/mL). GC-MS identified multiple bioactive metabolites in Ts-EtOAc extract belonging to miscellaneous chemical classes. Molecular docking studies revealed that the constituents of Ts-EtOAc have antibacterial potential. Discussion and conclusions T. savignyi extract has considerable antimicrobial and cytotoxic activities. Further studies are needed to isolate the active constituents of this snail for comprehensive drug discovery tests.

Investigation of Potential In Vitro Anticancer and Antimicrobial Activities of Balanites aegyptiaca (L.) Delile Fruit Extract and Its Phytochemical Components.

The therapeutic importance of Balanites aegyptiaca in folk medicine for the treatment of several common human diseases has led researchers to conduct phytochemical and pharmacological studies on extracts from various parts of the plant. In the current study, the phytochemical composition of the B. aegyptiaca methanolic fruit extract was characterized, and its antimicrobial activity was evaluated together with the cytotoxic activity against MCF-7, PC-3, and Caco-2, compared with normal Vero cells. Further, its effects on cell cycle arrest, apoptosis induction and expression of apoptosis-related genes were assessed. The phytochemical screening revealed the presence of fatty acids and their esters in addition to phytosterols, steroid derivatives, and bioflavonoid glycosides with oleic and palmitic acids being the prevalent components (24.12 and 21.56%, respectively). The results showed considerable cytotoxic activity of the extract against the three cancer cell lines (MCF-7, PC-3, and Caco-2) with a selectivity index ranging from 5.07 to 6.52. This effect was further confirmed with the accompanied increased total apoptosis of treated PC-3 cells (19.22% of the total number of cells) compared to the control cells (0.64% of the total number of cells) with cell cycle arrest at G1 phase and the increased transcription of pro-apoptotic genes including P53 (3.69) and BAX (3.33) expressed as fold change (2^ ΔΔCT). The calculated minimum inhibitory concentration (MIC) was similar (62.5 µg/mL) against the three tested bacterial strains (Acinetobacter johnsonii, Serratia marcescens and Agrobacterium tumefaciens), while it was higher than 1000 µg/mL for the fungal species (Rhizoctonia solani, Penicillium italicum, and Fusarium oxysporium). Our findings suggest a promising anticancer activity for B. aegyptiaca, which paves the way for more detailed future studies.

Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments.

Inflammation is the main cause of several autoimmune diseases, including type I diabetes, rheumatoid arthritis, bullous pemphigoid, paraneoplastic pemphigoid, and multiple sclerosis. Currently, there is an urgent demand for the discovery of novel anti-inflammatory drugs with potent activity but also safe for long-term application. Toward this aim, the present study reported the design, synthesis, and characterization of a set of novel 1,3-disubstituted-2-thiohydantoins derivatives. The anti-inflammatory activity of synthesized compounds was assessed against murine leukemia cell line (RAW264.7) by evaluating the cytotoxicity activity and their potency to prevent nitric oxide (NO) production. The results revealed that the synthesized compounds possess a considerable cytotoxic activity together with the ability to reduce the NO production in murine leukemia cell line (RAW264.7). Among synthesized compounds, compound 7 exhibited the most potent cytotoxic activity with IC50 of 197.68 μg/mL, compared to celecoxib drug (IC50 value 251.2 μg/mL), and demonstrated a significant ability to diminish the NO production (six-fold reduction). Exploring the mode of action responsible for the anti-inflammatory activity revealed that compound 7 displays a significant and dose-dependent inhibitory effect on the expression of pro-inflammatory cytokines IL-1β. Furthermore, compound 7 demonstrated the ability to significantly reduce the expression of the inflammatory cytokines IL-6 and TNF-α at 50 μg/mL, as compared to Celecoxib. Finally, detailed molecular modelling studies indicated that compound 7 exhibits a substantial binding affinity toward the binding pocket of the cyclooxygenase 2 enzyme. Taken together, our study reveals that 1,3-disubstituted-2-thiohydantoin could be considered as a promising scaffold for the development of potent anti-inflammatory agents.

Design, synthesis, anti-infective and anti-cancer potential of thiazole based Pyrazoles bearing benzothiazole moiety

A new series of (E)-6-methyl-N-((3-phenyl-1-(4-phenylthiazol-2-yl)-1H-pyrazol-4-yl)methylene)benzo[d]thiazol-2-amine derivatives was developed. Structural investigation of the synthesized derivatives was carried out by several instrumental method of analysis like IR, and 1H-NMR spectroscopy. The titled analogues were examined for in-vitro anticancer and antiinfective activities. The biological findings specified that analogues 5a, 5b, 5d, 5e, 5f and 5g showed most potent antibacterial activity (MIC 62.5-250μg/mL) and 5a, 5e, 5f and 5g displayed most potent antifungal action (MIC 62.5-500 μg/mL) than standard drugs. Compounds 5a and 5e were reported to be most active antimalarial analogue having IC50 value of 0.24-0.49μg/mL. Compounds 5a, 5e and 5f showed shortest mean paralysis time of (25.6±4.56 min, 26.4±4.97 min and 26.8±4.76 min) and mean death time (47.6±8.01min, 45.6±3.04min and 46.6±7.40min), respectively. Compound 5e showed moderate cytotoxicity with IC50 value of 65.4 against MCF-7. The results proved that 1,3-thiazolyl-pyrazole clubbed benzothiazole derivatives showed considerable antiinfective and cytotoxic activity. Keywords: Anti-infective activity, Cytotoxic activity, Spectroscopic methods, Thiazole, Pyrazole, Benzothiazole.

Synthesis, screening as potential antitumor of new poly heterocyclic compounds based on pyrimidine-2-thiones

BackgroundContinuing our interest in preparing of new heterocyclic compounds and examining their various biological activities, this work was designed to prepare new condensed and non-condensed heterocyclic compounds 9a-c, 10a-c, 11a-c, 13a-c and 14a-c were synthesized starting with pyrimidine-2-thiones 4a-c.ResultsThiazolo[3,2-a]pyrimidines 9a-c were synthesized by S-alkylation of pyrimidine-2-thiones,4a-c, internal cyclization in alkaline medium with ammonia, condensation with benzaldehyde and finally reaction with hydroxylamine hydrochloride.[1,2,4]thiadiazolo[4,5-a]pyrimidines 11a-c were formed by heating of the 4a-c with benzoylcholride to afford 10a-c followed by reaction with sodium hypochlorite, ammonia and sodium hydroxide. Cyclocondensation of 4a-c with ethyl acetoacetate or formic acid yielded pyrazol-3-ones 13a-c or [1,2,4] triazolo[4,3-a]pyrimidines 14a-c, respectively Elements analysis, IR, 1H-NMR, 13C-NMR and mass spectra were used to validate the structures of newly synthesized heterocycles. Screening of the selected compounds 4a, 6a, 7a, 9a, 10a, 13a and 14a against colon carcinoma cell lines (HCT-116) and hepatocellular carcinoma cell lines (HepG-2).ConclusionsElements analysis, IR, 1H-NMR, 13C-NMR and mass spectra were used to validate the structures of newly synthesized heterocycles. Screening of the selected compounds 4a, 6a, 7a, 9a, 10a, 13a and 14a against colon carcinoma cell lines (HCT-116) and hepatocellular carcinoma cell lines (HepG-2) showed that compound 10a exhibited the most cytotoxic, while compounds 4a, 6a and 14a exhibited considerable cytotoxic activity.

Experimental Study of the In Vitro and In Vivo Functional Activity of NKG2D Chimeric Antigen Receptor

Aim. To study antitumor cytotoxic effect of CAR-T NKG2D and CAR-T anti-CD19 in vitro and in vivo in order to compare antitumor activity of chimeric antigen receptors (CAR) with different structural and functional properties. Materials &amp; Methods. CAR constructions were produced by molecular cloning. CAR-T cell populations were obtained by transduction of healthy donor T-lymphocytes with recombinant lentiviral particles coding CAR NKG2D or CD19 target antigen CAR sequences. CAR-T cell proportion was assessed by FusionRed fluorescence and EGFR membrane receptor imaging. Specific in vitro cytotoxic activity of CAR-T effector cells was analyzed by Real-Time Cytotoxicity Assay (RTCA) during co-cultivation with HeLa_CD19 target cell line using xCELLigence. Interferon-Y (IFN-y) synthesis in vitro and in vivo along with the degree of cytotoxic effect were analyzed by immunoassay of culture medium of co-cultivated effector cells and target cells as well as isolated auto-plasma from the peripheral blood of mice. To assess the in vivo functional activity, CAR-T cell populations were infused into immunodeficient NSG-SGM3 mice (10 000 000 cells/mouse) 12 days after HeLa_CD19 cell injection and confirmation of engraftment and tumor growth. Upon euthanasia, tumors were removed and fixed in paraffin to prepare histological sections. CAR-T cell tumor infiltration was assessed by CD3 antigen immunohistochemical staining. Results. The highest ligand (molecules MICA, ULBP1/2/3/4/5/6) expression levels were detected in HeLa cell line. The obtained NKG2D CAR-T cells showed a considerable cytotoxic activity against HeLa_CD19 target line (cell index [CI] = 1.27), which was, however, twice as low as that of CAR-T anti-CD19 (CI = 0.60) (p = 0.0038). IFN-y level during co-cultivation of CAR-T anti-CD19 with HeLa_CD19 at the ratio of Е/Т = 1:1 was 64,852 pcg/mL, which was 3.5 times higher than IFN-y level during co-cultivation of CAR-T NKG2D with HeLa_CD19 (18,635 pcg/mL) (p = 0.0360). The degree of tumor infiltration by CAR-T anti-CD19 cells was higher than that by CAR-T NKG2D. The absence of NKG2D proliferating CAR-T cells in mice peripheral blood confirms their low persistence. IFN-y concentration in mice auto-plasma was 11.89 pcg/mL after CAR-T anti-CD19 infusion and 0.57 pcg/mL after CAR-T NKG2D infusion (p = 0.0079). The mean weight of tumor xenografts in experimental groups 10 days after CAR-T anti-CD19 injection was 0.72 g (p = 0.0142), after Т-lymphocyte and NKG2D CAR-T cell infusions it was 2.12 g and 1.2 g, respectively. Conclusion. CAR-T anti-CD19 cells are characterized by more pronounced cytotoxic effect under both in vitro and in vivo experimental conditions compared with CAR-T NKG2D cells. The degree of CAR-T anti-CD19 proliferation and their infiltration in mice xenograft models is considerably higher than the levels reached with NKG2D CAR-T cell injections. A single CAR-T NKG2D injection results only in short-term tumor reduction.

Synthesis of bioactive quinoline acting as anticancer agents and their mode of action using in silico analysis towards Aurora kinase A inhibitors

In the present investigation, novel quinolines have been synthesized and analyzed for their invitro cytotoxic activity against human colon cancer and lung cancer cells. Among the newly synthesized quinoline derivatives, 2-(3-chlorophenyl)-6,7-dimethoxyquinoline ( Q6 ) showed considerable cytotoxic activity against human colon cancer (HCT116) and lung cancer (A549) cell lines with IC 50 values of 25.5 ± 2.7 and 32 ± 4.7 μM respectively. Since these quinolines interacted with an Aurora kinase A, we carried out the molecular docking investigation and observed that this quinoline displayed inhibitory potentials. Overall, the compound Q6 was well suited to develop a newer quinolines-based anticancer medication, especially to block cell cycle arrest through Aurora kinase A inhibitors in human cancer.

Biotransformation of the Phenolic Constituents from Licorice and Cytotoxicity Evaluation of Their Metabolites.

Biotransformation of four bioactive phenolic constituents from licorice, namely licoisoflavanone (1), glycyrrhisoflavone (2), echinatin (3), and isobavachalcone (4), was performed by the selected fungal strain Aspergillus niger KCCM 60332, leading to the isolation of seventeen metabolites (5–21). Structures of the isolated compounds were determined on the basis of extensive spectroscopic methods, twelve of which (5–7, 10–17 and 19) have been previously undescribed. A series of reactions including hydroxylation, hydrogenation, epoxidation, hydrolysis, reduction, cyclization, and alkylation was observed in the biotransformation process. All compounds were tested for their cytotoxic activities against three different human cancer cell lines including A375P, MCF-7, and HT-29. Compounds 1 and 12 exhibited most considerable cytotoxic activities against all the cell lines investigated, while compounds 2 and 4 were moderately cytotoxic. These findings will contribute to expanding the chemical diversity of phenolic compounds, and compounds 1 and 12 may serve as leads for the development of potential cancer chemopreventive agents.

Sildenafil (VIAGRATM): A Promising Anticancer Drug Against Certain Human Cancer Cell Lines

Sildenafil has been identified as the first agent for treating male erectile dysfunction and is a selective inhibitor of phosphodiesterase 5 (PDE5). Its chemical structure consists of three moieties named; 1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one, 5-(2-ethoxy-1-ylsulfonyl)phenyl and 4-methylpiperazine. Many articles are reported the cytotoxic activity of each moiety individually. The combination into a single molecule (sildenafil) of these three structural features could have promising anti-cancer and cytotoxic effects. The study evaluated sildenafil cytototoxic activity in vitro against mammalian cell lines: MCF-7, HCT-116, HeLa cells and A-549 cells with their IC50 values. Sildenafil showed considerable cytotoxic activity (IC50 = 28.2 ± 0.92, 45.2 ± 1.5, 30.5 ± 0.87 and 60.5 ± 3.2 μg/mL) against HCT-116, MCF-7, A-549 and HeLa cells, respectively. HCT-116 was the most sensitive cell line towards sildenafil followed by A-549, A375, MCF-7 and HeLa cells. These findings shed light on the antitumor activity of sildenafil and its possible impact on potentiating of cytokines, antitumor and anti-inflammatory markers in tumour cells. These effects might be related to the structure feature of sildenafil.