Human Liver Carcinoma Cell Research Articles

Screening of antioxidant and cytotoxic activities of several microalgal extracts with pharmaceutical potential

The bioactive molecules from microalgae have important properties such as antioxidant, anticancer, antiviral, antibacterial, antihypertensive, skin regenerative, neuroprotective, sunscreen, and, immunostimulatory effects. Bioactive molecules derived from microalgae is getting intense attention from pharmaceuticals, cosmetics and nutraceuticals industries because of these properties and numerous researches have been done to investigate the role of these bioactive molecules that can enlighten microalgal biotechnology to result in new nature derived pharmaceutical formulations. In this study we investigate antioxidant activities of crude extracts of G. Galdieria sulphuraria, Ettlia carotinosa, Neochloris texensis, Chlorella minutissima, Stichococcus bacillaris, Schizochytrium limacinum, Crypthecodinium cohnii, and Chlorella vulgaris with determining radical scavenging activity (RSA) by DPPH (2,2-diphenyl-1-picrylhydrazyl hydrate radical) method and total phenolic content by Folin-Ciocalteu method. Selected extracts according to their antioxidant activities cytotoxicity was evaluated after exposure to human hepatocellular liver carcinoma cells (HepG2) for 48 h. Antioxidant activities of these species ranged from 89 to 95% RSA (radical scavenging activity) while their phenolic contents were also very high, varied from 41 to 312 mg GAE (gallic acid equivalents)/mg extract. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay also showed microalgae has a potential to be used as a novel therapeutic compound.

Effects of strobilanthes crispus extract on the apoptotic pathway of human liver carcinoma cell lines

Previous study has been shown the potential anticarcinogenic effect of Strobilanthes crispus, a plant native to countries from Madagascar to Indonesia, on human liver cancer (HepG-2) cell lines. The objective of the present study was to investigate the mechanism of anticarcinogenic effectof S.crispus extract through apoptotic pathway. Exposure of HepG-2 cells to S.crispus extract resulted in induction of apoptosis in a dose-dependent manner as measured by Fluoresence Microscopy and Confocal Laser Scanning Microscopy analysis. These findings provide important new insight into the possible molecular mechanisms of the anticancer activity of S.crispus.

Amino Acid-functionalized hollow mesoporous silica nanospheres as efficient biocompatible drug carriers for anticancer applications.

Herein, a series of new amino acid-functionalized hollow mesoporous silica nanospheres (HMSNs) by post-grafting methods were prepared. These new materials were characterized by different techniques and were studied as matrices for the antineoplastic drug (cisplatin) transport and delivery. The results demonstrate that the surface functionalization of the carriers has a remarkable positive influence on the loading efficiency and release rate of cisplatin. The highest drug entrapment efficiency and the most optimal release properties were observed when the (2-(butylamino) ethyl) glycine groups are grafted on the HMSNs surface (AFS-2-HMSNs sample). Moreover, the in vitro cytotoxic effect of both empty and cisplatin-loaded AFS-2-HMSNs sample (CDDP@AFS-2-HMSNs) on MCF-7 cells (human breast adenocarcinoma cell line) and HepG2 cells (human liver carcinoma cell line) were evaluated by MTT assay. The most important outcome is that the empty carrier revealed no cytotoxicity to cancer cells. However, CDDP@AFS-2-HMSNs caused a notable inhibition of cell viability which was affected from the dose and time. Our results demonstrate that the synthesized materials could be used as carriers for drug delivery with controlled release applications.

The Cytotoxicity and Insecticidal Activity of Extracts from Delphinium formosum Boiss. & Huet

DOI : 10.26650/IstanbulJPharm.2019.19034 Delphinium species are well-known toxic plants with their diterpenoid alkaloid contents. There has been no previous investigation on the cytotoxicity of Delphinium formosum Boiss. & Huet. The extracts of the different parts of D. formosum, an endemic species in Turkey, were investigated for their cytotoxic activity against the human liver carcinoma cell line (HepG2) and primary human umbilical vein endothelial cells (HUVEC). The cytotoxic effects of twelve extracts and subfractions were determined against HepG2 cells using MTT assay. The only active extract was applied to the HUVEC as a model for healthy cells. Only one of the alkaloid-containing extracts from the aerial parts was toxic (IC50 = 244,9 μg/mL against HepG2 and 144,4 μg/mL against HUVEC), while the root extracts were inactive. The results were improbable although it’s predicted secondary metabolites, such as diterpene alkaloids (methyllycaconitine, browniine, lycoctonine, avardharidine, antranoyllycoctonine, delsemine A/B and lycoctonine). Based on previous studies in literature, the cytotoxic plants were also expected to exhibit insecticidal activity. Therefore, the cytotoxic extract of D. formosum was examined for its adulticidal and larvicidal activity against the yellow fever, dengue fevers and Zika virus vector Aedes aegypti L. You may cite this article as : Sen-Utsukarci B, Tabanca N, Estep AS, Akbal-Dagistan O, Kessler SM, Ozturk Z, Becnel J, Kiemer AK, Mat A (2019). The Cytotoxicity and Insecticidal Activity of Extracts from Delphinium formosum Boiss. & Huet. Istanbul J Pharm 10.26650/IstanbulJPharm.2019.19034.

Cytotoxic Xanthones from Hypericum stellatum, an Ethnomedicine in Southwest China.

Hypericum stellatum, a species endemic to China, is used to treat hepatitis by several ethnic groups in Guizhou Province. This research was inspired by the traditional medicinal usage of H. stellatum, and aims to explore the phytochemistry and bioactivity of H. stellatum to explain why local people in Guizhou widely apply H. stellatum for liver protection. In this study, two new prenylated xanthones, hypxanthones A (8) and B (9), together with seven known compounds, were isolated from the aerial parts of the plant. Spectroscopic data as well as experimental and calculated ECD spectra were used to establish the structures of these compounds. Six xanthones isolated in this study, together with four xanthones previously isolated from H. stellatum, were evaluated for their growth-inhibitory activities against five human liver carcinoma cell lines to analyze the bioactivity and structure-activity relationship of xanthones from H. stellatum. Isojacareubin (6) showed significant cytotoxicity against five human liver carcinoma cell lines, with an IC50 value ranging from 1.41 to 11.83 μM, which was stronger than the positive control cisplatin (IC50 = 4.47–20.62 μM). Hypxanthone B (9) showed moderate cytotoxicity to three of the five cell lines. Finally, structure-activity analysis revealed that the prenyl and pyrano substituent groups of these xanthones contributed to their cytotoxicity.

Angiopoietin-like protein 8 (betatrophin) may inhibit hepatocellular carcinoma through suppressing of the Wnt signaling pathway.

Objective(s):Hepatocellular carcinoma (HCC) is one of the leading fatal neoplasms and the most common primary liver malignancy worldwide. Peptide hormone ANGPTL8 (betatrophin) may act as an important regulator in HCC development through the Wnt/β-catenin pathway. We aimed to evaluate the effects of recombinant ANGPTL8 on Wnt/β-catenin signaling in human liver carcinoma cells (HepG2) and their viability. Materials and Methods:The expression of ANGPTL8 was conducted in the pET-21b-E. coli Bl21 (DE3) system and the produced peptide was purified. HepG2 cells were treated with different concentrations of ANGPTL8 (25, 50, 100, 150, 200, and 250 ng/ml) for 24, 48, and 72 hr. MTT assay was performed to detect the viability of treated cells, and apoptotic induction by ANGPTL8 was measured by flow cytometry assay. Finally, using qRT-PCR the mRNA levels of Wnt signaling modulators WIF-1 and β-catenin were evaluated in treated cells. Results:MTT assay showed that ANGPTL8 inhibits proliferation of HepG2 cells moderately in a time-independent manner. The highest concentration of the ANGPTL8, 250 ng/ml, reduced cell proliferation after 24, 48, and 72 hr similarly about 30%. In the same concentration of ANGPTL8, after 24 hr of treatment flow cytometry assay revealed a mild increase in early and late apoptosis up to 7.7 and 14.3%, respectively. The qRT-PCR showed that in a concentration-dependent and time-independent fashion, the expression of WIF-1 and β-catenin genes respectively increased and decreased significantly (P<0.05). Conclusion:Our findings suggest that ANGPTL8 may act as a moderate suppressor against HCC cell proliferation possibly via affecting Wnt signaling modulators.

Nano-fibre Integrated Microcapsules: A Nano-in-Micro Platform for 3D Cell Culture

Nano-in-micro (NIM) system is a promising approach to enhance the performance of devices for a wide range of applications in disease treatment and tissue regeneration. In this study, polymeric nanofibre-integrated alginate (PNA) hydrogel microcapsules were designed using NIM technology. Various ratios of cryo-ground poly (lactide-co-glycolide) (PLGA) nanofibres (CPN) were incorporated into PNA hydrogel microcapsule. Electrostatic encapsulation method was used to incorporate living cells into the PNA microcapsules (~500 µm diameter). Human liver carcinoma cells, HepG2, were encapsulated into the microcapsules and their physio-chemical properties were studied. Morphology, stability, and chemical composition of the PNA microcapsules were analysed by light microscopy, fluorescent microscopy, scanning electron microscopy (SEM), Fourier-Transform Infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). The incorporation of CPN caused no significant changes in the morphology, size, and chemical structure of PNA microcapsules in cell culture media. Among four PNA microcapsule products (PNA-0, PNA-10, PNA-30, and PNA-50 with size 489 ± 31 µm, 480 ± 40 µm, 473 ± 51 µm and 464 ± 35 µm, respectively), PNA-10 showed overall suitability for HepG2 growth with high cellular metabolic activity, indicating that the 3D PNA-10 microcapsule could be suitable to maintain better vitality and liver-specific metabolic functions. Overall, this novel design of PNA microcapsule and the one-step method of cell encapsulation can be a versatile 3D NIM system for spontaneous generation of organoids with in vivo like tissue architectures, and the system can be useful for numerous biomedical applications, especially for liver tissue engineering, cell preservation, and drug toxicity study.

Design, efficient synthesis and molecular docking of some novel thiazolyl-pyrazole derivatives as anticancer agents

Pyrazoles, thiazoles and fused thiazoles have been reported to possess many biological activities. 3-Methyl-5-oxo-4-(2-arylhydrazono)-4,5-dihydro-1H-pyrazole-1-carbothioamides 3a,b (obtained from the reaction of ethyl 3-oxo-2-(2-arylhydrazono)butanoates 1a,b with thiosemicarbazide) could be transformed into a variety of thiazolyl-pyrazole derivatives 6a–h, 10a–c, 15a–c, 17, 19 and 21 via their reaction with a diversity hydrazonoyl chlorides as well as bromoacetyl derivatives. Moreover, the computational studies were carried out for all new compounds. The results indicated that five compounds showed promising binding affinities (10a: − 3.4 kcal/mol, 6d: − 3.0 kcal/mol, 15a: − 2.2 kcal/mol, 3a: − 1.6 kcal/mol, and 21: − 1.3 kcal/mol) against the active site of the epidermal growth factor receptor kinase (EGFR). The cytotoxicity of the potent products 3a, 6d, 10a, 15a, and 21 was examined against human liver carcinoma cell line (HepG-2) and revealed activities close to Doxorubicin standard drug. There was an understanding between the benefits of restricting affinities and the data obtained from the practical anticancer screening of the tested compounds.

Electrochemical and Cell Response of Surface Modified Ti6Al4V for Biomedical Applications

Ti6Al4V titanium alloy was used as a metallic permanent implant for the internal fixation during surgery of orthopedic and dental implants. But due to poor bioactivity like release of aluminum and vanadium, ions cause allergic problems and weak osseointegration with host environment. Surface modifications of those implants are required to make it biocompatible. The aim of the present research is to modify the surface of Ti6Al4V implant by electrodeposition of cathodic bioactive Calcium Phosphate (CaP) coating. The morphology of the modified surface was characterized by Scanning Electron Microscopy and Atomic Force Microscopy while electrochemical response was measured in simulated body fluid (SBF) at 37 °C by Open Circuit Potential, Cyclic polarization, and Electrochemical Impedance Spectroscopy techniques. In vitro biocompatibility of modified Ti6Al4V surfaces was further evaluated by coculturing them with a human liver carcinoma cell line, HEPG2. The bond strength of the CaP coating is 65 MPa in anodized Ti6Al4V surface. The CaP coating was dominated by hydroxyapatite with flake-like appearance which eventually decreases the Ti6Al4V dissolution rate to 0.206 mpy in SBF and the cell viability analysis further highlighted highest level of biocompatibility of coated titanium alloy which boosted cell growth by 78% competed to other surfaces.

Transition Metal Complexes of (E)‐2((2‐hydroxybenzylidene) amino‐3‐mercaptopropanoic acid: XRD, Anticancer, Molecular modeling and Molecular Docking Studies

AbstractThe anticancer studies of a Schiff base; (E)‐2((2‐hydroxybenzylidene)amino‐3‐mercaptopropanoic acid (H2L) (obtained from 2‐hydroxybenzaldehyde and L‐cysteine) and its transition metal complexes have been reported. The evaluation of the growth inhibitory action was studied for the compounds against human colon carcinoma (HCT‐116), human hepatocellular liver carcinoma (HEPG‐2), normal melanocytes (HFB‐4) and human breast carcinoma (MCF‐7) cell lines. The obtained results revealed that the Schiff base and its chelates are active against human hepatocellular liver carcinoma (HEPG‐2) cell lines. The powder X‐ray diffraction analysis for the compounds was carried out through Phillips X′Pert High score software. The density functional theory computation for ligand and Co(II), Ni(II) and Cu(II) metal complexes were made to understand the mode of bonding by GAUSSIAN 03 rev. A.01 programme. The quantitative structure‐activity relationship investigation was performed by using HyperChem Professional 8.0.3 software to understand the biological potency of the ligands. Moreover, a docking analysis using iGEMDOCKv2.1 software was carried out against the kinase enzyme PDB ID:1fvv.

Anticancer Action of Psilostachyin-A in 5-Fluorouracil-Resistant Human Liver Carcinoma are Mediated Through Autophagy Induction, G2/M Phase Cell Cycle Arrest and Inhibiting Extracellular-Signal-Regulated Kinase/Mitogen Activated Protein Kinase (ERK/MAPK) Signaling Pathway.

BackgroundLiver cancer is one of the most common malignancies around the world and one of the major causes of cancer related mortality. The objective of this study was to evaluate the anticancer effect of the natural compound psilostachyin-A on 5-fluorouracil-resistant human liver carcinoma cells and its effects on autophagy, cell cycle, caspase activation, and the ERK/MAPK signaling pathway.Material/MethodsCell Counting Kit 8 (CCK-8) assay was used to evaluate the effects on HepG2 cell viability at different doses of psilostachyin-A. Cell cycle analysis was performed using flow cytometry, and Transwell assay was used to check effects on cell invasion. Transmission electron microscopic studies were done to evaluate autophagy induced by psilostachyin-A, and the western blot method was carried out to evaluate the effects on autophagy and the ERK/MAPK signaling pathway.ResultsCCK-8 assay revealed that the psilostachyin-A reduced the cell viability of HepG2 cancer cells in a dose dependent manner. Psilostachyin-A also reduced the colony forming potential of HepG2 cells, concentration dependently. The IC50 of psilostachyin was found to be 25 μM. The anticancer effects of psilostachyin-A were due to the induction of autophagy which was accompanied by enhancement of LC3B II expression. Psilostachyin also caused cell cycle arrest by enhancing the accumulation of HepG2 cells in the G2/M phase. Transwell assay showed that psilostachyin-A suppressed the invasion of HepG2 cells. The results also showed that psilostachyin-A could block the ERK/MAPK pathway, indicative of the cytotoxic effects of psilostachyin-A on liver cancer.ConclusionsThese preliminary observations suggested that psilostachyin-A might prove beneficial in the treatment of liver cancer.

Development of Promising Thiopyrimidine-Based Anti-cancer and Antimicrobial Agents: Synthesis and QSAR Analysis.

Objective & Methodology: New hybrids of thiopyrimidine-five/six heterocyclic rings were synthesized and in vitro evaluated for their antiproliferative activity against three human cancer cell lines, namely HCT116 (human colorectal carcinoma), PC-3 (human prostate adenocarcinoma) and HepG2 (human liver carcinoma) cell lines. The most potency was elicited by the target candidates against the viability of HCT116 cell lines. It was higher than that obtained by the positive control 5-Fluorouracil (IC50 range; 0.11-0.49 μM, IC50, 5-FU; 1.10 μM). Results: Cell cycle analysis and apoptosis activation revealed that compound 20 induced G2/M phase arrest and apoptosis in HCT116 cells. In addition, compound 20 activates the caspases-9 and -3, a process which might mediate the apoptosis of HCT116 cells. Quantitative structure activity relationship study was done and revealed a high predictive power R2 suggesting goodness of the models. Conclusion: Furthermore, there is a good agreement between the observed pIC50 and the predicted pIC50 values, in addition, the low RMSD and standard error values indicate the accuracy of the model. Antimicrobial evaluation revealed that some of these compounds exhibited significant activities against the tested pathogenic bacteria and fungi, wherein compounds 7a, 14, 15a, 21a, produced the most potent and broad spectrum antibacterial and antifungal potency that was equivalent to that revealed by Vibramycin and Ketoconazole (MIC; 125 μg/mL). Moreover, compounds 15a, 21c, investigated dual potent antimicrobial and anticancer activity.

Novel series of nanosized mono- and homobi-nuclear metal complexes of sulfathiazole azo dye ligand: Synthesis, characterization, DNA-binding affinity, and anticancer activity

Novel five nanosized mono- and homobi-nuclear complexes of 4-(2,4-dihydroxy-5-formylphen-1-ylazo)-N-thiazol-2-yl-benzenesulfonamide (H2L) ligand were synthesized for developing new anticancer agents. H2L was prepared by coupling the diazonium salt of 2-(p-aminobenzenesulfonamido)thiazole with 2,4-dihydroxybenzaldehyde in order to integrate the bio-effectiveness of both azo group and sulfonamide part in the synthesized metal chelates which strongly increase their bio-activities. H2L and synthesized Cu, Co, Ni, Mn and Zn complexes were characterized applying different analytical and spectral methods. The obtained results revealed that H2L coordinated with divalent metal ions of copper, cobalt and nickel in a monobasic bidentate mode through the azo group nitrogen, and deprotonated phenolic oxygen whereas H2L coordinates with Mn(II), and Zn(II) in dibasic tetradentate mode via the azo group nitrogen, deprotonated phenolic oxygen, sulfonamide oxygen, and N-atom of thiazole ring. All metal complexes had a tetrahedral geometry around the metal centers. XRD patterns denoted the ligand crystalline and the complexes amorphous natures. TEM images proved the nanosized range of all complex's particles. UV–Vis spectra and viscosity techniques revealed that H2L and complexes exhibited groove binding mode interactions with DNA. Anticancer efficiency of the ligand and complexes were examined against breast carcinoma cells (MCF-7) and human liver carcinoma cells (HepG-2). Co(II) and Zn(II) complexes displayed the greatest anticancer activity and are very promising candidates for future applications in cancer therapy.

Synthesis and Anticancer Activity of New ((Furan-2-yl)-1,3,4-thiadiazolyl)-1,3,4-oxadiazole Acyclic Sugar Derivatives.

New sugar hydrazones incorporating furan and/or 1,3,4-thiadiazole ring systems were synthesized by reaction of the corresponding hydrazide with different aldose sugars. Heterocyclization of the formed hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the heterocyclization process. The anticancer activity of the synthesized compounds was studied against human liver carcinoma cell (HepG-2) and at human normal retina pigmented epithelium cells (RPE-1). High activities were revealed by compounds 3, 12 and 14 with IC50 values near to that of the reference drug doxorubicin.

Development of a Novel Series of Anticancer and Antidiabetic: Spirothiazolidines Analogs.

4-(4-Aminophenyl)-1-thia-4-azaspiro[4.5]decan-3-one 1 was prepared and allowed to react with nitrogen nucleophiles to give the corresponding hydrazones 2–4. Further, compound 1 underwent diazotization and afforded the parallel hydrazono derivative 5; moreover, compound 1 refluxed with active methylene derivatives yielded the corresponding aminospirothiazolo pyridine–carbonitrile derivative 6 and spirothiazolopyridinone–carbonitrile derivative 7. Condensation of spirothiazolidine 1 with 4-chlorobenzaldehyde gave the corresponding spiro arylidiene derivative 8, which was utilized as a component of Micheal addition to react with excess of nitrogen nucleophiles to yield novel ring frameworks 4-(3′-(4-chlorophenyl)–spiro [cyclohexane-1,5′-pyrazolo[3,4-d]thiazol]-6′(1′H)-yl)aniline (9) and 4-(3′-(4-chlorophenyl)-6′H- spiro[cyclohexane-1,5′-thiazolo[5,4-d]isoxazol]-6′-yl)aniline (10). Finally, when spirothiazolo pyridinone–carbonitrile derivative 7 sodium salt generated in situ was reacted with different alkyl halides, it produced the corresponding N-derivatives 12–16. Three compounds, 6, 14, and 16, showed high significantly anticancer activities compared with Doxorubicin® (positive control) against human breast carcinoma (MCF-7) and human liver carcinoma (HepG-2) cell lines. On the other hand, compounds 6 and 9 showed higher therapeutic indices for both of alpha-amylase inhibitor and alpha-glucosidase inhibitor than the other tested compounds compared with the antidiabetic Acarbose (positive control).

In vitro cytotoxic efficacy of PEG encapsulated manganese-doped zinc oxide nanoparticles on hepatocellular carcinoma cells

ABSTRACTThe present study investigates the in vitro cytotoxic efficacy of polymer encapsulated bare and Mn-doped ZnO nanoparticles against human liver carcinoma Huh7 cell lines. PEG capped bare and Mn (2.0, 2.5 and 3.0 wt%) doped ZnO nanoparticles were synthesised through chemical precipitation method. The structural and morphological interpretations of the prepared nanoparticles were carried out using X-Ray Diffraction (XRD), Transmission Electron Microscopy (TEM) techniques. Optical absorption, emission properties and functional group analysis were carried out using UV-Vis, PL and FTIR techniques. The XRD results confirmed the hexagonal wurtzite crystal structure of nanoparticles with an average particle size of 17.19 nm. The anticancer ability of the prepared samples against the human liver carcinoma cell line Huh7 was investigated by studying the cell penetration, cell viability and ROS generation mechanisms.

Screening DNA-targeted anticancer drug in vitro based on cancer cells DNA-templated silver nanoclusters

A reliable and sensitive cancer cells DNA-templated silver nanoclusters probe has been proposed for screening DNA-targeted anticancer drugs in vitro. In this paper, the DNA-templated silver nanoclusters was used to investigate the binding between anthracycline antibiotics and DNA. The template of DNA-templated silver nanoclusters was extracted from human liver carcinoma cells directly, which can express the drug activities against cancer cells more direct than the normal cells DNA. The anti-tumor activities of the four drugs were validated by MTT and apoptotic assay as Mitoxantrone > Epirubicin > Daunorubicin > Adriamycin.

Evaluating the role of dithiolane rich fraction of Ferula asafoetida (apiaceae) for its antiproliferative and apoptotic properties: in vitro studies.

In vitro study of the anticancer potential of microwave-extracted essential oil (EO) of Ferula asafoetida. The phytochemical investigation and in vitro cytotoxicity assessment was carried out in two human liver cancer cell lines. The expression of NFKB1, TGFB1, TNF, CASP3 was analyzed by reverse transcription polymerase chain reaction. Ferula asafoetida EO contains high concentrations of dithiolane, which possess antiproliferative activity in human liver carcinoma cell lines (HepG2 and SK-Hep1) in a dose-dependent manner. The bioactive compounds in F.asafoetida are capable of induction of apoptosis and altered NF-kB and TGF-β signalling with increase in caspase-3 and TNF-α expression. Further elucidation of bioactive molecules and underlying mechanisms could lead to potential intervention in liver cancer in animal models. The safety and efficacy as well as the mode of EO action in animal models would be highly crucial.

Potentiation of β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations against MDR and XDR Pseudomonas aeruginosa using non-ribosomal tobramycin-cyclam conjugates.

To develop a multifunctional adjuvant molecule that can rescue β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations from resistance in carbapenem-resistant Pseudomonas aeruginosa clinical isolates. Preparation of adjuvant was guided by structure-activity relationships, following standard protocols. Susceptibility and chequerboard studies were assessed using serial 2-fold dilution assays. Toxicity was evaluated against porcine erythrocytes, human embryonic kidney (HEK293) cells and liver carcinoma (HepG2) cells via MTS assay. Preliminary in vivo efficacy was evaluated using a Galleria mellonella infection model. Conjugation of tobramycin and cyclam abrogates the ribosomal effects of tobramycin but confers a potent adjuvant property that restores full antibiotic activity of meropenem and aztreonam against carbapenem-resistant P. aeruginosa. Therapeutic levels of susceptibility, as determined by CLSI susceptibility breakpoints, were attained in several MDR clinical isolates, and time-kill assays revealed a synergistic dose-dependent pharmacodynamic relationship. A triple combination of the adjuvant with ceftazidime/avibactam (approved), aztreonam/avibactam (Phase III) and meropenem/avibactam enhances the efficacies of β-lactam/β-lactamase inhibitors against recalcitrant strains, suggesting rapid access of the combination to their periplasmic targets. The newly developed adjuvants, and their combinations, were non-haemolytic and non-cytotoxic, and preliminary in vivo evaluation in G. mellonella suggests therapeutic potential for the double and triple combinations. Non-ribosomal tobramycin-cyclam conjugate mitigates the effect of OprD/OprF porin loss in P. aeruginosa and potentiates β-lactam/β-lactamase inhibitors against carbapenem-resistant clinical isolates, highlighting the complexity of resistance to β-lactam antibiotics. Our strategy presents an avenue to further preserve the therapeutic utility of β-lactam antibiotics.

Synthesis, spectroscopic characterization and biological studies of nano-sized Co(II), Ni(II), Cu(II) and Zn(II) Schiff's base hybrids

A novel series of nano-sized Co(II), Ni(II), Cu(II) and Zn(II) hybrids has been synthesized using the template method, i.e. by the in situ reaction of oxazin–Schiff's base [(E)-3-(2-(4-(diethylamino)-2-mercaptobenzylidene)hydrazineyl)-2H-benzo[b][1,4]oxazin-2-one] (HL) derived from 4-(diethylamino)-2-mercaptobenzaldehyde with 3-hydrazineyl-2H-benzo[b][1,4]oxazin-2-one in the presence of Co(II), Ni(II), Cu(II), Zn(II) chloride in ethanol. The structures and geometry of the optained compounds have been described by using the different analytical and spectroscopic tools such as elemental analysis, UV-VIS, IR, MS, 1H NMR, ESR, CV, TGA, XRD, SEM, AFM, magnetic and molar conductivity measurements. IR spectral studies confirmed the coordination of the ligand to the metal ions through the thiol sulfur, azomethine nitrogen and carbonyl oxygen. The Schiff's base ligand acts as monobasic tridentate OSN donor. The geometrical structures have been found to be octahedral and tetrahedral. The molar conductance measurements of the nano-sized hybrids in DMF and DMSO correspond to be nonelectrolytic nature for all nano-sized metal (II) hybrids. The elemental analyses confirm 1 M: 2 L stoichiometry of the type [ML2] (M = Co(II), Ni(II), Cu(II) and Zn(II)). Electrochemical behaviour of nano-sized metal (II) hybrids were determined by cyclic voltammetry. Degradation pattern of the ligand HL and its nano-sized hybrids is shown by thermal studies. The activation of thermodynamic parameters are calculated using Coast-Redfern (CR) and Horowitz-Metzger (HM) methods. The data obtained from XRD, SEM, TEM and AFM images unequivocally asserted the nano-sized metal chelates. The percentage antioxidant activities are also more for complexes than the ligand. The investigated ligand and metal complexes were screened for their in-vitro antimicrobial activities against different types of fungal and bacterial strains. The resulting data assert on the inspected compounds as a highly promising bactericides and fungicides. The antitumor activities of all synthesized compounds were evaluated towards human liver Carcinoma (HepG2) cell line. DNA-binding, DNA cleavage and fluorescence properties of nano-sized hybrids with this ligand are reported.