Biological activities of pyrazoline-indole based Re(I) carbonyls: DNA interaction, antibacterial, anticancer, ROS production, lipid peroxidation, in vivo and in vitro cytotoxicity studies

AbstractNanoparticles consisting of different biocompatible materials are attracting a lot of interest in the biomedical area as useful tools for drug delivery, photo-therapy and contrast enhancement agents in MRI, fluorescence and confocal microscopy. This work mainly focuses on the synthesis of polymeric/inorganic multifunctional nanoparticles (PIMN) based on biocompatible di-block copolymer poly(L,L-lactide-co-ethylene glycol) (PLLA-PEG) via an emulsion-evaporation method. Besides containing a hydrophobic drug (Indomethacin), these polymeric nanoparticles incorporate different visualization agents such as superparamagnetic iron oxide nanoparticles (SPION) and fluorescent Quantum Dots (QDs) that are used as contrast agents for Magnetic Resonance Imaging (MRI) and fluorescence microscopy together. Gold Nanorods are also incorporated in such nanostructures to allow simultaneous visualization and photodynamic therapy. MRI studies are performed with different loading of SPION into PIMN, showing an enhancement in T2 contrast superior to commercial contrast agents. Core-shell QDs absorption and emission spectra are recorded before and after their loading into PIMN. With these polymeric/inorganic multifunctional nanoparticles, both MRI visualization and confocal fluorescence microscopy studies can be performed. Gold nanorods are also synthesized and incorporated into PIMN without changing their longitudinal absorption peak usable for lased excitation and phototherapy. In-vitro cytotoxicity studies have also been performed to confirm the low cytotoxicity of PIMN for further in-vivo studies.

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Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: a phase I trial of daily bolus infusion

Blood ◽

10.1182/blood.v79.3.576.bloodjournal793576 ◽

1992 ◽

Vol 79 (3) ◽

pp. 576-585 ◽

Cited By ~ 1

Author(s):

ML Grossbard ◽

AS Freedman ◽

J Ritz ◽

F Coral ◽

VS Goldmacher ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Maximum Tolerated Dose ◽

In Vitro Cytotoxicity ◽

Bolus Infusion ◽

Protein Toxin ◽

Cytotoxicity Studies ◽

Ricin A

Anti-B4-blocked Ricin (Anti-B4-bR) is an immunotoxin comprised of the anti-B4 monoclonal antibody (MoAb) and the protein toxin “blocked ricin.” The anti-B4 MoAb is directed against the B-lineage-restricted CD19 antigen expressed on more than 95% of normal and neoplastic B cells. Blocked ricin is an altered ricin derivative that has its nonspecific binding eliminated by chemically blocking the galactose binding domains of the B chain. In vitro cytotoxicity studies demonstrate that the IC37 of Anti-B4-bR is 2 x 10(-11) mol/L compared with 4 x 10(-12) mol/L for native ricin. A phase I dose escalation clinical trial was conducted in 25 patients with refractory B-cell malignancies. Anti-B4-bR was administered by daily 1-hour bolus infusion for 5 consecutive days at doses ranging from 1 microgram/kg/d to 60 micrograms/kg/d. Serum levels above 1 nmol/L were achieved transiently in the majority of patients treated at the maximum tolerated dose of 50 micrograms/kg/d for 5 days for a total dose of 250 micrograms/kg. The dose-limiting toxicity was defined by transient, reversible grade 3 elevations in hepatic transaminases, without impaired hepatic synthetic function. Minor toxicities included transient hypoalbuminemia, thrombocytopenia, and fevers. Human antimouse antibody and human anti-ricin antibody were detected in nine patients. One complete response, two partial responses, and eight mixed or transient responses were observed. These results show the in vitro and in vivo cytotoxicity of Anti-B4-bR and indicate that this immunotoxin can be administered as a daily bolus infusion for 5 days with tolerable, reversible toxicity.

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Preparation, Cytotoxicity, and In Vitro Bioimaging of Water Soluble and Highly Fluorescent Palladium Nanoclusters

Bioengineering ◽

10.3390/bioengineering7010020 ◽

2020 ◽

Vol 7 (1) ◽

pp. 20 ◽

Cited By ~ 6

Author(s):

Suresh Thangudu ◽

Poliraju Kalluru ◽

Raviraj Vankayala

Keyword(s):

In Vitro Cytotoxicity ◽

Molecular Probes ◽

Water Soluble ◽

Quantum Yields ◽

Cell Labelling ◽

Metal Nanoclusters ◽

Extinction Coefficients ◽

Cytotoxicity Studies

Fluorescent probes offer great potential to identify and treat surgical tumors by clinicians. To this end, several molecular probes were examined as in vitro and in vivo bioimaging probes. However, due to their ultra-low extinction coefficients as well as photobleaching problems, conventional molecular probes limit its practical utility. To address the above mentioned challenges, metal nanoclusters (MNCs) can serve as an excellent alternative with many unique features such as higher molar extinction coefficients/light absorbing capabilities, good photostability and appreciable fluorescence quantum yields. Herein, we reported a green synthesis of water soluble palladium nanoclusters (Pd NCs) and characterized them by using various spectroscopic and microscopic characterization techniques. These nanoclusters showed excellent photophysical properties with the characteristic emission peak centered at 500 nm under 420 nm photoexcitation wavelength. In vitro cytotoxicity studies in human cervical cancer cells (HeLa) cells reveal that Pd NCs exhibited good biocompatibility with an IC50 value of >100 µg/mL and also showed excellent co-localization and distribution throughout the cytoplasm region with a significant fraction translocating into cell nucleus. We foresee that Pd NCs will carry huge potential to serve as a new generation bioimaging nanoprobe owing to its smaller size, minimal cytotoxicity, nucleus translocation capability and good cell labelling properties.

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Palmitic Acid Curcumin Ester Facilitates Protection of Neuroblastoma against Oligomeric Aβ40 Insult

Cellular Physiology and Biochemistry ◽

10.1159/000485117 ◽

2017 ◽

Vol 44 (2) ◽

pp. 618-633 ◽

Cited By ~ 7

Author(s):

Zhangyang Qi ◽

Meihao Wu ◽

Yun Fu ◽

Tengfei Huang ◽

Tingting Wang ◽

...

Keyword(s):

Lipid Peroxidation ◽

Protective Effect ◽

Palmitic Acid ◽

Cell Membranes ◽

Direct Interaction ◽

Association Constants ◽

Ros Production ◽

Ros Scavenging

Background/Aims: The generation of reactive oxygen species (ROS) caused by amyloid-β (Aβ) is considered to be one of mechanisms underlying the development of Alzheimer’s disease. Curcumin can attenuate Aβ-induced neurotoxicity through ROS scavenging, but the protective effect of intracellular curcumin on neurocyte membranes against extracellular Aβ may be compromised. To address this issue, we synthesized a palmitic acid curcumin ester (P-curcumin) which can be cultivated on the cell membrane and investigated the neuroprotective effect of P-curcumin and its interaction with Aβ. Methods: P-curcumin was prepared through chemical synthesis. Its structure was determined via nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). An MTT assay was used to assess Aβ cytotoxicity and the protective effect of P-curcumin on SH-SY5Y cells. The effect of P-curcumin on Aβ-induced ROS production in vitro and in vivo were assessed based on changes in dichlorofluorescein (DCF) fluorescence. A spectrophotometric method was employed to detect lipid peroxidation. To mimic the interaction of P-curcumin on cell membranes with Aβ, liposomes were prepared by thin film method. Finally, the interactions between free P-curcumin and P-curcumin cultivated on liposomes and Aβ were determined via spectrophotometry. Results: A novel derivative, palmitic acid curcumin ester was prepared and characterized. This curcumin, cultivated on the membranes of neurocytes, may prevent Aβ-mediated ROS production and may inhibit the direct interaction between Aβ and the cellular membrane. Furthermore, P-curcumin could scavenge Aβ-mediated ROS as curcumin in vitro and in vivo, and had the potential to prevent lipid peroxidation. Morphological analyses showed that P-curcumin was better than curcumin at protecting cell shape. To examine P-curcumin’s ability to attenuate direct interaction between Aβ and cell membranes, the binding affinity of Aβ to curcumin and P-curcumin was determined. The association constants for free P-curcumin and curcumin were 7.66 × 104 M-1 and 7.61 × 105 M-1, respectively. In the liposome-trapped state, the association constants were 3.71 × 105 M-1 for P-curcumin and 1.44× 106 M-1 for curcumin. With this data, the thermodynamic constants of P-curcumin association with soluble Aβ (ΔH, ΔS, and ΔG) were also determined. Conclusion: Cultivated curcumin weakened the direct interaction between Aβ and cell membranes and showed greater neuroprotective effects against Aβ insult than free curcumin.

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Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: a phase I trial of daily bolus infusion

Blood ◽

10.1182/blood.v79.3.576.576 ◽

1992 ◽

Vol 79 (3) ◽

pp. 576-585 ◽

Cited By ~ 123

Author(s):

ML Grossbard ◽

AS Freedman ◽

J Ritz ◽

F Coral ◽

VS Goldmacher ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Maximum Tolerated Dose ◽

In Vitro Cytotoxicity ◽

Bolus Infusion ◽

Protein Toxin ◽

Cytotoxicity Studies ◽

Ricin A

Abstract Anti-B4-blocked Ricin (Anti-B4-bR) is an immunotoxin comprised of the anti-B4 monoclonal antibody (MoAb) and the protein toxin “blocked ricin.” The anti-B4 MoAb is directed against the B-lineage-restricted CD19 antigen expressed on more than 95% of normal and neoplastic B cells. Blocked ricin is an altered ricin derivative that has its nonspecific binding eliminated by chemically blocking the galactose binding domains of the B chain. In vitro cytotoxicity studies demonstrate that the IC37 of Anti-B4-bR is 2 x 10(-11) mol/L compared with 4 x 10(-12) mol/L for native ricin. A phase I dose escalation clinical trial was conducted in 25 patients with refractory B-cell malignancies. Anti-B4-bR was administered by daily 1-hour bolus infusion for 5 consecutive days at doses ranging from 1 microgram/kg/d to 60 micrograms/kg/d. Serum levels above 1 nmol/L were achieved transiently in the majority of patients treated at the maximum tolerated dose of 50 micrograms/kg/d for 5 days for a total dose of 250 micrograms/kg. The dose-limiting toxicity was defined by transient, reversible grade 3 elevations in hepatic transaminases, without impaired hepatic synthetic function. Minor toxicities included transient hypoalbuminemia, thrombocytopenia, and fevers. Human antimouse antibody and human anti-ricin antibody were detected in nine patients. One complete response, two partial responses, and eight mixed or transient responses were observed. These results show the in vitro and in vivo cytotoxicity of Anti-B4-bR and indicate that this immunotoxin can be administered as a daily bolus infusion for 5 days with tolerable, reversible toxicity.

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Phytochemical Profile, Antioxidant Activity, and Cytotoxicity Assessment of Tagetes erecta L. Flowers

Molecules ◽

10.3390/molecules26051201 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1201

Author(s):

Ana Flavia Burlec ◽

Łukasz Pecio ◽

Solomiia Kozachok ◽

Cornelia Mircea ◽

Andreia Corciovă ◽

...

Keyword(s):

Biological Activities ◽

In Vitro Cytotoxicity ◽

In Vitro Assays ◽

Tagetes Erecta ◽

Phytochemical Analysis ◽

Total Extract ◽

Tagetes Erecta L ◽

Cytotoxicity Assessment

Tagetes erecta L. is a popular ornamental plant of the Asteraceae family, which is widely cultivated not only for its decorative use, but also for the extraction of lutein. Besides carotenoid representatives, which have been extensively studied, other important classes of secondary metabolites present in the plant, such as polyphenols, could exhibit important biological activities. The phytochemical analysis of a methanolic extract obtained from T. erecta inflorescences was achieved using liquid chromatography–mass spectrometry (LC-MS) techniques. The extract was further subjected to a multistep purification process, which allowed the separation of different fractions. The total extract and its fractions contain several polyphenolic compounds, such as hydroxybenzoic and hydroxycinnamic acid derivatives, flavonols (especially quercetagetin glycosides), and several aglycons (e.g., quercetin, patuletin). One of the fractions, containing mostly quercetagitrin, was subjected to two different antioxidant assays (metal chelating activity and lipoxygenase inhibition) and to in vitro cytotoxicity assessment. Generally, the biological assays showed promising results for the investigated fraction compared to the initial extract. Given the encouraging outcome of the in vitro assays, further purification and structural analysis of compounds from T. erecta extracts, as well as further in vivo investigations are justified.

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Experimental Validation of a Mathematical Model to Describe the Drug Cytotoxicity of Leukemic Cells

Symmetry ◽

10.3390/sym13101760 ◽

2021 ◽

Vol 13 (10) ◽

pp. 1760

Author(s):

Ekaterina Guzev ◽

Galia Luboshits ◽

Svetlana Bunimovich-Mendrazitsky ◽

Michael A. Firer

Keyword(s):

Mathematical Model ◽

Drug Efficacy ◽

In Vitro Cytotoxicity ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Logistic Growth ◽

Treatment Schedule ◽

Cytotoxicity Studies

Chlorambucil (Chl), Melphalan (Mel), and Cytarabine (Cyt) are recognized drugs used in the chemotherapy of patients with advanced Chronic Lymphocytic Leukemia (CLL). The optimal treatment schedule and timing of Chl, Mel, and Cyt administration remains unknown and has traditionally been decided empirically and independently of preclinical in vitro efficacy studies. As a first step toward mathematical prediction of in vivo drug efficacy from in vitro cytotoxicity studies, we used murine A20 leukemic cells as a test case of CLL. We first found that logistic growth best described the proliferation of the cells in vitro. Then, we tested in vitro the cytotoxic efficacy of Chl, Mel, and Cyt against A20 cells. On the basis of these experimental data, we found the parameters for cancer cell death rates that were dependent on the concentration of the respective drugs and developed a mathematical model involving nonlinear ordinary differential equations. For the proposed mathematical model, three equilibrium states were analyzed using the general method of Lyapunov, with only one equilibrium being stable. We obtained a very good symmetry between the experimental results and numerical simulations of the model. Our novel model can be used as a general tool to study the cytotoxic activity of various drugs with different doses and modes of action by appropriate adjustment of the values for the selected parameters.

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Abstract 28: Carboxyalkyl-pyrrole Phosphatidylethanolamine Adducts Are Present In Vivo And Induce Platelet Activation Via Toll-like Receptor

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a28 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Sudipta Biswas ◽

Soumya Panigrahi ◽

Alejandro Zimman ◽

Eugene Podrez

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Platelet Activation ◽

Platelet Reactivity ◽

Biological Activities ◽

Direct Interaction ◽

Covalent Modification ◽

Downstream Signaling

A prothrombotic state and increased platelet reactivity are common in pathophysiological conditions associated with oxidative stress. Lipid peroxidation, a major consequence of oxidative stress generates highly reactive products capable of modifying autologous proteins as well as lipids. Hydroxy-ω-oxoalkenoic acids and their carboxyalkylpyrrole (CAP) protein adducts are recently described products of lipid peroxidation with strong biological activity mediated by Toll like receptors (TLR). Phosphatidylethanolamine (PE) is the second most abundant phospholipid in the living organisms. While recent studies suggest that PE is a major target for covalent modification by reactive products of lipid peroxidation, the presence of such products in vivo, their biological activities and receptors involved are not established. We now report that CAP-PE adducts are present in vivo in circulation and are significantly elevated in plasma of hyperlipidemic apoE-/- mice. In vitro experiments demonstrated that CAP-PE adducts induce platelet integrin αIIbβ3 activation, P-selectin expression and promote platelet aggregation. Multiple complimentary approaches demonstrated that platelet activation by CAP-PE is mediated by TLR2 and TLR1. Furthermore, direct interaction of CAP-PE and TLR2 was demonstrated. CAP-PE induced assembly of TLR2/TLR1 receptor complex in platelets leading to downstream signaling via MyD88/TIRAP-dependent pathway. CAPs-PE induced signaling included phosphorylation and activation of IRAK4 and subsequent activation of TRAF6, Src family kinase, Syk and PLCγ2. Thus, our study identified carboxyalkylpyrrole adducts of phosphatidylethanolamine as novel end products accumulating in circulation in hyperlipidemia that can induce platelet activation via innate immunity signaling pathway.

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Synthesis and Cytotoxic Evaluation of Novel Benzimidazole Fused Condensed Thienopyrimdines Derivatives

Current Bioactive Compounds ◽

10.2174/1573407214666180808124802 ◽

2020 ◽

Vol 16 (2) ◽

pp. 133-141

Author(s):

S. Kaliraj ◽

Muthu K. Kathiravan

Keyword(s):

Good Yield ◽

Biological Activities ◽

In Vitro Cytotoxicity ◽

Cytotoxic Action ◽

Moderate Activity ◽

Quinazoline Derivative ◽

Cellular Division ◽

Major Health Problem ◽

Cytotoxicity Studies

Background: Cancer is a major health problem acting as a global killer and one of the leading causes of death. Most cancer chemotherapeutic drugs currently in clinical use are to kill malignant tumour cells by inhibiting some of the mechanisms implied in cellular division. Thienopyrimidines occupy a special position among the fused pyrimidines, along with other pyrimidines containing an annelated five membered hetero aromatic ring; forms a significant class of drugs which exhibit an array of various biological activities. One of the important current anticancer agent gefitinib acts as tyrosine kinase inhibitors is a quinazoline derivative. The thieno[2,3-d]pyrimidine ring system, is considered as a bioisostere of quinazoline moiety and have attracted great attention due to their broad bioactivities, including antitumor. Methods: Novel thienopyrimidine derivatives were synthesized by cyclization of thiophene o-amino esters with lactam salts such as pyrrolidin-2-one, piperidin-2-one and caprolactam by treating using phosphorous oxychloride. The next set of compounds thieno[2,3-d]pyrimidin-4(3H)-one were synthesised by Niementowski condensations between 2-aminothiophene carboxylate and formamide under reflux condition, followed by its chlorination in good yield. Microwave Fusion of 4-chlorothieno[2,3-d] pyrimidines with o-phenylenediamine afforded target compounds. The target compounds were tested on MCF-7 and HEK293 cell line. Results: The synthesized thirty compounds structures were established by IR, 1H NMR and Mass spectroscopy. The synthesized compounds were obtained in the good yield ranging from 45-70%. The synthesized compounds were subjected to cytotoxicity studies. Among the twenty compounds only one compound showed moderate activity. One of the compound 2c bearing acetyl group had IC50 48.93 μM. However decrease in the size of the lactam ring from six to five member ring or increase to seven member ring resulted in the loss of activity. The IC50 value of 5a was found to be 70.86μg/ml. The compound 5i have more cytotoxic action among the series. Conclusion: A series of thirty compounds belonging to novel pyyrolo, pyrido and benzimidazole fused thienopyrimidines were synthesized, characterized and were evaluated for their in vitro cytotoxicity. The compounds bearing bulky group such as terbutyl group and chloro substitution had the best activity. In conclusion, these structures seems to have biological properties and further investigation on this group could provide a lead.

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