scholarly journals Model Amphipathic Peptide Coupled with Tacrine to Improve Its Antiproliferative Activity

2020 ◽  
Vol 22 (1) ◽  
pp. 242
Author(s):  
Sara Silva ◽  
Cláudia Alves ◽  
Diana Duarte ◽  
Ana Costa ◽  
Bruno Sarmento ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Drug Repurposing ◽  
Parent Drug ◽  
Ache Inhibitor ◽  
Amphipathic Peptide ◽  
Reference Drug ◽  
Mcf 7

Drug repurposing and drug combination are two strategies that have been widely used to overcome the traditional development of new anticancer drugs. Several FDA-approved drugs for other indications have been tested and have demonstrated beneficial anticancer effects. In this connection, our research group recently reported that Tacrine, used to treat Alzheimer’s Disease, inhibits the growth of breast cancer MCF-7 cells both alone and in combination with a reference drug. In this view, we have now coupled Tacrine with the model amphipathic cell-penetrating peptide (CPP) MAP, to ascertain whether coupling of the CPP might enhance the drug’s antiproliferative properties. To this end, we synthesized MAP through solid-phase peptide synthesis, coupled it with Tacrine, and made a comparative evaluation of the parent drug, peptide, and the conjugate regarding their permeability across the blood-brain barrier (BBB), ability to inhibit acetylcholinesterase (AChE) in vitro, and antiproliferative activity on cancer cells. Both MAP and its Tacrine conjugate were highly toxic to MCF-7 and SH-SY5Y cells. In turn, BBB-permeability studies were inconclusive, and conjugation to the CPP led to a considerable loss of Tacrine function as an AChE inhibitor. Nonetheless, this work reinforces the potential of repurposing Tacrine for cancer and enhances the antiproliferative activity of this drug through its conjugation to a CPP.

scholarly journals Design of PSMA ligands with modifications at the inhibitor part: an approach to reduce the salivary gland uptake of radiolabeled PSMA inhibitors?

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Veronika Barbara Felber ◽  
Manuel Amando Valentin ◽  
Hans-Jürgen Wester
Keyword(s):  
Salivary Gland ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
In Vivo Studies ◽  
Tumor Xenograft ◽  
Tumor Uptake ◽  
Lncap Cells ◽  
High Affinity

Abstract Aim To investigate whether modifications of prostate-specific membrane antigen (PSMA)-targeted radiolabeled urea-based inhibitors could reduce salivary gland uptake and thus improve tumor-to-salivary gland ratios, several analogs of a high affinity PSMA ligand were synthesized and evaluated in in vitro and in vivo studies. Methods Binding motifs were synthesized ‘on-resin’ or, when not practicable, in solution. Peptide chain elongations were performed according to optimized standard protocols via solid-phase peptide synthesis. In vitro experiments were performed using PSMA+ LNCaP cells. In vivo studies as well as μSPECT/CT scans were conducted with male LNCaP tumor xenograft-bearing CB17-SCID mice. Results PSMA ligands with A) modifications within the central Zn2+-binding unit, B) proinhibitor motifs and C) substituents & bioisosteres of the P1′-γ-carboxylic acid were synthesized and evaluated. Modifications within the central Zn2+-binding unit of PSMA-10 (Glu-urea-Glu) provided three compounds. Thereof, only natLu-carbamate I (natLu-3) exhibited high affinity (IC50 = 7.1 ± 0.7 nM), but low tumor uptake (5.31 ± 0.94% ID/g, 1 h p.i. and 1.20 ± 0.55% ID/g, 24 h p.i.). All proinhibitor motif-based ligands (three in total) exhibited low binding affinities (> 1 μM), no notable internalization and very low tumor uptake (< 0.50% ID/g). In addition, four compounds with P1′-ɣ-carboxylate substituents were developed and evaluated. Thereof, only tetrazole derivative natLu-11 revealed high affinity (IC50 = 16.4 ± 3.8 nM), but also this inhibitor showed low tumor uptake (3.40 ± 0.63% ID/g, 1 h p.i. and 0.68 ± 0.16% ID/g, 24 h p.i.). Salivary gland uptake in mice remained at an equally low level for all compounds (between 0.02 ± 0.00% ID/g and 0.09 ± 0.03% ID/g), wherefore apparent tumor-to-submandibular gland and tumor-to-parotid gland ratios for the modified peptides were distinctly lower (factor 8–45) than for [177Lu]Lu-PSMA-10 at 24 h p.i. Conclusions The investigated compounds could not compete with the in vivo characteristics of the EuE-based PSMA inhibitor [177Lu]Lu-PSMA-10. Although two derivatives (3 and 11) were found to exhibit high affinities towards LNCaP cells, tumor uptake at 24 h p.i. was considerably low, while uptake in salivary glands remained unaffected. Optimization of the established animal model should be envisaged to enable a clear identification of PSMA-targeting radioligands with improved tumor-to-salivary gland ratios in future studies.

scholarly journals Pyrrole-Mediated Peptide Cyclization Identified through Genetically Reprogrammed Peptide Synthesis

Biomedicines ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 99 ◽  
Author(s):  
Klaas Decoene ◽  
Willem Vannecke ◽  
Toby Passioura ◽  
Hiroaki Suga ◽  
Annemieke Madder
Keyword(s):  
Peptide Synthesis ◽  
Cyclic Peptide ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Screening Method ◽  
In Vitro Translation ◽  
Side Chain ◽  
One Pot ◽  
Depth Analysis

Flexible in vitro translation (FIT) was used as a screening method to uncover a new methodology for peptide constraining based on the attack of a nucleophilic side-chain functionality onto an oxidized furylalanine side chain. A set of template peptides, each containing furylalanine as furan-modified amino acid and a nucleophilic residue (Cys, His, Lys, Arg, Ser, or Tyr), was produced through FIT. The translation mixtures were treated with N-bromosuccinimide (NBS) to achieve selective furan oxidation and subsequent MALDI analysis demonstrated Lys and Ser as promising residues for cyclisation. Solid-phase peptide synthesis (SPPS) was used to synthesize suitable amounts of material for further in-depth analysis and characterisation. It was found that in the case of the peptide containing lysine next to a furylalanine residue, a one-pot oxidation and reduction reaction leads to the generation of a cyclic peptide featuring a pyrrole moiety as cyclisation motif, resulting from the attack of the lysine side chain onto the oxidized furylalanine side chain. Structural evidence was provided via NMR and the generality of the methodology was explored. We hereby expand the scope of our previously developed furan-based peptide labeling and crosslinking strategy.

New binuclear Ni(ii) metallates containing ONS chelators: synthesis, characterisation, DNA binding, DNA cleavage, protein binding, antioxidant activity, antimicrobial and in vitro cytotoxicity

2017 ◽  
Vol 41 (7) ◽  
pp. 2543-2560 ◽  
Author(s):  
G. Kalaiarasi ◽  
Ruchi Jain ◽  
H. Puschman ◽  
S. Poorna Chandrika ◽  
K. Preethi ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Dna Binding ◽  
Protein Binding ◽  
Hela Cell ◽  
Antiproliferative Activity ◽  
Dna Cleavage ◽  
In Vitro Cytotoxicity ◽  
Hela Cell Lines ◽  
Mcf 7

Four new binuclear nickel(ii) metallates showed promising antiproliferative activity against MCF-7 and HeLa cell lines and were much less toxic against HaCaT.

scholarly journals Composition and Biological Activity of Volatile Oil from Salvia judaica and S. multicaulis from Jordan

2016 ◽  
Vol 11 (4) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Fatma U. Afifi ◽  
Violet Kasabri ◽  
Hala I. Al-Jaber ◽  
Barakat E. Abu-Irmaileh ◽  
Mahmoud A. Al-Qudah ◽  
...  
Keyword(s):  
Pancreatic Lipase ◽  
Solid Phase ◽  
Volatile Oil ◽  
Positive Control ◽  
Proliferative Potential ◽  
Reference Drug ◽  
Oxygenated Monoterpenes ◽  
Sesquiterpene Hydrocarbons ◽  
Colorectal Cancer Cell Lines

The aim of this work was to determine the composition of the hydro-distilled essential oil of Salvia judaica Boiss. and S. multicaulis Vahl. (Lamiaceae) from Jordan by GC and GC-MS and to report the actual composition of their fresh leaves and flowers using SPME (Solid Phase Micro-Extraction). Their dual alpha-amylase/alpha glucosidase and pancreatic lipase inhibitory activities as well as their anti-proliferative potential were screened. The aroma profile of the leaves, flowers, and flowers at pre-flowering stages of S. judaica, obtained through SPME was composed of sesquiterpene hydrocarbons (87.7 %, 71.8 %, and 86.2 %, respectively) while the hydro-distilled oil of the dry leaves was rich in oxygenated sesquiterpenes (50.8%). Fresh leaves of S. multicaulis were rich in oxygenated monoterpenes (58.1%), while monoterpene hydrocarbons dominated the blooming flowers (57.2%) and the flowers at the pre-flowering stage (64.7%). The hydro-distilled oil of the dry leaves was rich in oxygenated monoterpenes (77.6%). With doxorubicin as a positive control, no anti-proliferative activity was observed against colorectal cancer cell lines HT29, HCT116, and SW620 using SRB assay for either Salvia spp. In vitro enzymatic starch digestion was evaluated with Acarbose (IC50: 0.2± 0.0 μg /mL) as the reference drug. The respective IC50 (mg/mL) values of S. judaica and S. multicaulis aqueous extracts were 4.9 ± 0.4 and 10.3 ± 0.9. Modulation of pancreatic lipase activity (PL) was determined by colorimetry and compared with Orlistat (IC50: 0.11 ± 0.0 μg/mL). PL-IC50 values (μg/mL) obtained for S. judaica and S. multicaulis were 108.5±6.4 and 31.8 ± 0.8, respectively.

scholarly journals Primaquine and Chloroquine Fumardiamides as Promising Antiplasmodial Agents

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2812 ◽  
Author(s):  
Beus ◽  
Fontinha ◽  
Held ◽  
Rajić ◽  
Uzelac ◽  
...  
Keyword(s):  
Parent Drug ◽  
Breast Adenocarcinoma ◽  
Kidney Cells ◽  
In Vitro Activity ◽  
Human Breast ◽  
Human Hepatoma Cells ◽  
Starting Point ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Mcf 7

This paper describes a continuation of our efforts in the pursuit of novel antiplasmodial agents with optimized properties. Following our previous discovery of biologically potent asymmetric primaquine (PQ) and halogenaniline fumardiamides (1–6), we now report their significant in vitro activity against the hepatic stages of Plasmodium parasites. Furthermore, we successfully prepared chloroquine (CQ) analogue derivatives (11–16) and evaluated their activity against both the hepatic and erythrocytic stages of Plasmodium. Our results have shown that PQ fumardiamides (1–6) exert both higher activity against P. berghei hepatic stages and lower toxicity against human hepatoma cells than the parent drug and CQ derivatives (11–16). The favourable cytotoxicity profile of the most active compounds, 5 and 6, was corroborated by assays performed on human cells (human breast adenocarcinoma (MCF-7) and non-tumour embryonic kidney cells (HEK293T)), even when glucose-6-phosphate dehydrogenase (G6PD) was inhibited. The activity of CQ fumardiamides on P. falciparum erythrocytic stages was higher than that of PQ derivatives, comparable to CQ against CQ-resistant strain PfDd2, but lower than CQ when tested on the CQ-sensitive strain Pf3D7. In addition, both sets of compounds showed favourable drug-like properties. Hence, quinoline fumardiamides could serve as a starting point towards the development of safer and more effective antiplasmodial agents.

scholarly journals Small peptide-based GLP-1R ligands: an approach to reduce the kidney uptake of radiolabeled GLP-1R-targeting agents?

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Veronika Barbara Felber ◽  
Hans-Jürgen Wester
Keyword(s):  
Renal Excretion ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Cross Coupling ◽  
Solution Synthesis ◽  
Small Peptides ◽  
Small Peptide ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Aim Elevated kidney uptake in insulinoma patients remains a major limitation of radiometallated exendin-derived ligands of the glucagon-like peptide 1 receptor (GLP-1R). Based on the previously published potent GLP-1R-activating undecapeptide 1, short-chained GLP-1R ligands were developed to investigate whether kidney uptake can be reduced by means of direct 18F-labeling (nuclide-based accelerated renal excretion) or the reduction of the overall ligand charge (ligand-based reduced kidney uptake). Materials & methods GLP-1R ligands were prepared according to optimized standard protocols via solid-phase peptide synthesis (SPPS) or, when not practicable, via fragment coupling in solution. Synthesis of (2‘-Et, 4‘-OMe)4, 4’-L-biphenylalanine ((2′-Et, 4′-OMe)BIP), required for the preparation of 1, was accomplished by Suzuki-Miyaura cross-coupling. In vitro experiments were performed using stably transfected GLP-1R+ HEK293-hGLP-1R cells. Results In contrast to the three reference ligands glucagon-like peptide 1 (GLP-1, IC50 = 23.2 ± 12.2 nM), [Nle14, Tyr(3-I)40]exendin-4 (IC50 = 7.63 ± 2.78 nM) and [Nle14, Tyr40]exendin-4 (IC50 = 9.87 ± 1.82 nM), the investigated GLP-1R-targeting small peptides (9–15 amino acids), including lead peptide 1, exhibited only medium to low affinities (IC50 > 189 nM). Only SiFA-tagged undecapeptide 5 (IC50 = 189 ± 35 nM) revealed a higher affinity than 1 (IC50 = 669 ± 242 nM). Conclusion The investigated small peptides, including lead peptide 1, could not compete with favorable in vitro characteristics of glucagon-like peptide 1 (GLP-1), [Nle14, Tyr(3-I)40]exendin-4 and [Nle14, Tyr40]exendin-4. The auspicious EC50 values of 1 provided by the literature could not be transferred to competitive binding experiments. Therefore, the use of 1 as a basic scaffold for the design of further GLP-1R-targeting radioligands cannot be recommended. Further investigations might include the scaffold of 5, although substantial optimizations concerning affinity and lipophilicity would be required. In sum, GLP-1R-targeting radioligands with reduced kidney uptake could not be obtained in this work, which emphasizes the need for further ligands addressing this particular issue.

scholarly journals THE CYTOTOXIC EFFECT OF CHELIDONIUM MAJUS IN VITRO

2015 ◽  
Vol 8 (2) ◽  
Author(s):  
Vladimíra Tomečková ◽  
Veronika Tkáčová ◽  
Peter Urban ◽  
Marek Stupák
Keyword(s):  
Tumor Cells ◽  
Hela Cells ◽  
Antiproliferative Activity ◽  
Cytotoxic Effect ◽  
Lymphoblastic Leukemia ◽  
Mammary Adenocarcinoma ◽  
Chelidonium Majus ◽  
Mcf 7 ◽  
Lipophilic Substances

The effect of aqueous and ether Chelidonium majus haulms extract on cervical HeLa tumor cells, mammary adenocarcinoma MCF 7 tumor cells and acute lymphoblastic leukemia CEM tumor cells in vitro have been studied. The purpose of this research was to compare the effect of aqueous and ether Chelidonium majus haulms extract on selected tumor cells. Colorimetric MTT assay have been used for the study of the antiproliferative effect of aqueous and ether haulms extract of Chelidonium majus on cell viability in vitro. The results of the experiments have shown the cytotoxic effect of the aqueous and the ether Chelidonium majus haulms extract on the individual tumor cells. The aqueous Chelidonium majus haulms extract was the most effective on CEM cells, it was less effective on MCF 7 cells and it was the least effective on HeLa cells. The ether haulms extract of Chelidonium majus was the most effective at all of studied concentrations on CEM cells and MCF 7 cells in comparison with HeLa cells, where it was significantly effective only at the highest concentration. Aqueous and ether haulms extract of Chelidonium majus tested in vitro indicated their cytotoxic activity. Both haulms extract of Chelidonium majus were more efficient on CEM cells. It is assumed that higher antiproliferative activity of ether haulms extract of Chelidonium majus is the result of higher antiproliferative activity of lipophilic substances. The lipophilic substances pass through membrane and bind to various proteins and change their biological activity.

scholarly journals Synthesis of new 3-(substituted-phenyl)-N-(2-hydroxy-2-(substituted-phenyl)ethyl)-N-methylthiophene-2-sulfonamide derivatives as antiproliferative agents

2018 ◽  
Vol 9 (1) ◽  
pp. 13-21 ◽  
Author(s):  
Chandrakant Pawar ◽  
Dattatraya Pansare ◽  
Devanand Shinde
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
1H Nmr ◽  
13C Nmr ◽  
Antiproliferative Activity ◽  
Positive Control ◽  
Antiproliferative Agents ◽  
Ic50 Values ◽  
Mcf 7

In the present work, we report the synthesis of a series of 3-(substituted phenyl)-N-(2-hydroxy-2-(substituted-phenyl)ethyl)-N-methylthiophene-2-sulfonamide derivatives through Suzuki and Buchwald reaction. We have optimized methodology for targets from milligram to multi-gram scale. The newly synthesized compounds were characterized by 1H NMR, 19F NMR, 13C NMR, LC-MS techniques and purity was further checked by HPLC. The compounds were evaluated for their in-vitro antiproliferative activity against MCF-7, HeLa, A-549 and Du-145 cancer cell lines by CCK-8 assay. The preliminary bioassay suggests that most of the compounds show antiproliferation with different degrees and 5-fluorouracil was used as positive control. Among these compounds 2d, 2g, 2i, 4e, 4h and 4k are most active compared to the standard. All the synthesized compounds show IC50 values from 1.82-9.52 µM in different cell lines. Amongst these, compounds 2d, 2g, 2i, 4e, 4h and 4k were most potent, with IC50 values ranging from 1.82-4.28 µM in different cell lines.

scholarly journals Corrigendum to: Screening of Ipomoea tuba Leaf Extract for Identification of Bioactive Compounds and Evaluation of Its in vitro Antiproliferative Activity Against MCF-7 and HeLa Cells (Published: Food Technol. Biotechnol. 58 (1) 71-75 (2020) https://doi.org/10.17113/ftb.58.01.20.6351)

2020 ◽  
Vol 58 (3) ◽  
pp. 356-356
Author(s):  
Thirupati Chinna Venkateswarulu ◽  
Gaddam Eswaraiah ◽  
Srirrama Krupanidhi ◽  
Karlapudi Abraham Peele ◽  
Indira Mikkili ◽  
...  
Keyword(s):  
Cell Lines ◽  
Bioactive Compounds ◽  
Hela Cells ◽  
Antiproliferative Activity ◽  
Leaf Extract ◽  
Mcf 7

The authors requested the replacement of Fig. 1. Morphology of MCF-7 cells after the treatment with the extract of Ipomoea tuba leaf: a) untreated MCF-7 cell lines, and b-g) treated with different concentrations (5, 10, 25, 50, 75 and 100 μg/mL respectively) of the leaf extract The change includes the replacemend of images 1c-1g.

Synthesis and Characterization of Bradykinin Derivatives Based on a β-Cyclodextrin Core

2016 ◽  
Vol 69 (3) ◽  
pp. 328 ◽  
Author(s):  
Rachel J. Stephenson ◽  
Fran Wolber ◽  
Paul G. Plieger ◽  
David R. K. Harding
Keyword(s):  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Synthesis And Characterization ◽  
Structure Activity ◽  
Fmoc Spps ◽  
Model Drug ◽  
Sulfonamide Group ◽  
Important Structure

Mono-6A-fluorenylmethyloxycarbonylamino-mono-6X-succinyl-β-cyclodextrin (1), an amino acid-based bi-functionalized derivative of β-cyclodextrin (β-CD), has been functionalized with the bioactive peptide, bradykinin and/or sulfonamides using fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis (SPPS). The all-in-one molecule contains a carrier (cyclodextrin), targeting agent (bradykinin), and/or model drug (sulfonamide). Varying combinations of these bradykinin-focussed molecules have been synthesized using Fmoc SPPS on Rink amide resin. The positioning of the sulfonamide group, the bradykinin peptide and the cyclodextrin carrier are essential for biological activity. The inclusion of spacers is also important. Structure–activity studies performed on three cancer cell lines in vitro support these conclusions.

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