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The molecular hybridization concept has recently emerged as a powerful approach in drug discovery. A series of novel indole derivatives linked to the pyrazole moiety were designed and developed via a molecular hybridization protocol as antitumor agents. The target compounds (5a–j and 7a–e) were prepared by the reaction of 5-aminopyrazoles (1a–e) with N-substituted isatin (4a,b) and 1H-indole-3-carbaldehyde (6), respectively. All products were characterized via several analytical and spectroscopic techniques. Compounds (5a–j and 7a–e) were screened for their cytotoxicity activities in vitro against four human cancer types [human colorectal carcinoma (HCT-116), human breast adenocarcinoma (MCF-7), human liver carcinoma (HepG2), and human lung carcinoma (A549)] using the MTT assay. The obtained results showed that the newly synthesized compounds displayed good-to-excellent antitumor activity. For example, 5-((1H-indol-3-yl)methyleneamino)-N-phenyl-3-(phenylamino)-1H-pyrazole-4-carboxamide (7a) and 5-((1H-indol-3-yl)methyleneamino)-3-(phenylamino)-N-(4-methylphenyl)-1H-pyrazole-4-carboxamide (7b) provided excellent anticancer inhibition performance against the HepG2 cancer cell line with IC50 values of 6.1 ± 1.9 and 7.9 ± 1.9 μM, respectively, compared to the standard reference drug, doxorubicin (IC50 = 24.7 ± 3.2 μM). The two powerful anticancer compounds (7a and 7b) were further subjected to cell cycle analysis and apoptosis investigation in HepG2 using flow cytometry. We have also studied the enzymatic assay of these two compounds against some enzymes, namely, caspase-3, Bcl-2, Bax, and CDK-2. Interestingly, the molecular docking study revealed that compounds 7a and 7b could well embed in the active pocket of the CDK-2 enzyme via different interactions. Overall, the prepared pyrazole–indole hybrids (7a and 7b) can be proposed as strong anticancer candidate drugs against various cancer cell lines.

I den här studien har metoder för att separera immunoglobulin (IgG) utvecklats med hjälp av kapillärelektrofores (CE) och Ultra högupplösande vätskekromatografi-Mass spektrometri (UHPLC-MS). Vid analysen av peptider från IgG spjälkat av trypsin (IgG TD) detekterades 26 glykopepeptider med UHPLC-MS genom att använda olika gradienter och mobilfaser. Dessutom analyserades fyra olika koncentrations av IgG TD för att testa detektionsgränsen. Resultatet visade att glykopeptider kunde detekteras i alla fyra koncentrationer men antalet detekterade glykopeptider minskade med minskande koncentration. Den sista delen av UHPLC-MS analysen var en selektivitetsanalys där en blandning av bovint serumalbumin spjälkat av trypsin (BSA TD) och IgG TD analyserades i olika koncentrationer. Selektivitetsanalysen visade att ungefär samma antal IgG glykopeptider detekterades som vid analys av IgG TD. Vid CE-analysen användes tre olika kapillärer, varav två av dem var polyvinylalkohol-coated och olika buffertlösningar (BGE) användes. De slutgiltiga resultaten visade 5 toppar som skulle kunna representera IgG gykopeptider men eftersom ingen MS utfördes kunde inga slutsatser dras. Slutligen, användes Matrix-Assisted Laser desorption/ionisation-time-of-flight (MALDI-TOF) för att analysera proverna innan analys och för att jämföra resultaten med UHPLC-MS. In this study, methods to separate immunoglobulin G (IgG) glycopeptides were developed using capillary electrophoresis (CE) and ultra-high-performance liquid chromatography-Mass spectrometry (UHPLC-MS). In the UHPLC-MS- analysis, 26 glycopeptides were detected during the analysis of trypsin digested IgG (IgG TD) using different gradients and mobile phases. Moreover, a limit of detection study with four different concentrations (0.01, 0.1, 0.5 and 2mg/mL) was performed. Although the number of detected glycopeptides decreased with decreasing concentration, glycopeptides were detected in the 0.01 mg/mL IgG TD sample. Lastly, a selectivity study was performed, in which two trypsin digested Bovine serum albumin (BSA TD) and IgG TD mixtures with different concentrations were analysed. The results showed that approximately the same number glycopeptides were detected as in the IgG sample suggesting that the BSA sample did not interfere with the detection of glycopeptides. Moreover, the CE-analysis included three different capillaries and several background electrolytes (BGEs). Two of the capillaries were polyvinyl alcohol (PVA) coated. The final electropherogram showed five peaks possibly representing IgG glycopeptides but no MS were performed on the CE part leading to no conclusions for the CE-part. Matrix-Assisted Laser Desorption/Ionisation- time-of flight (MALDI-TOF) was performed throughout the project to control the samples and for comparison to the UHPLC-MS analysis.

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see https://doi.org/10.1021/acs.jmedchem.9b01006. In this work, we demonstrate that the indole-oxazole-pyrrole framework of the breitfussin family of natural products is a promising scaffold for kinase inhibition. Six new halogenated natural products, breitfussin C–H (3 – 8) were isolated and characterized from the Arctic, marine hydrozoan Thuiaria breitfussi. The structures of two of the new natural products were also confirmed by total synthesis. Two of the breitfussins (3 and 4) were found to selectively inhibit the survival of several cancer cell lines, with the lowest IC50 value of 340 nM measured against the drug-resistant triple negative breast cancer cell line MDA-MB-468, while leaving the majority of the tested cell lines not or significantly less affected. When tested against panels of protein kinases, 3 gave IC50 and Kd values as low as 200 and 390 nM against the PIM1 and DRAK1 kinases, respectively. The activity was confirmed to be mediated through ATP competitive binding in the ATP binding pocket of the kinases. Furthermore, evaluation of potential off-target and toxicological effects, as well as relevant in vitro ADME parameters for 3 revealed that the breitfussin scaffold holds promise for the development of selective kinase inhibitors.

Kræft er en af de førende årsager til sygdom og dødelighed over hele verden. Ifølge WHO døde 8,8 millioner mennesker af kræft i 2015, hvilket betyder at 1 ud af 6 dødsfald skyldtes kræft. Malign melanoma er en af de hurtigst voksende kræftformer med anslået 91.270 nye tilfælde i 2018 alene i USA. Behandlingen i dag inkluderer kirurgi, kemoterapi, stråling, hormonelle behandlinger og immunterapi. Disse behandlinger har mange bivirkninger, risiko for resistensudvikling og er generelt ekstremt dyre. Antimikrobielle peptider (AMP'er) er gode potentielle kandidater til kræftbehandling da de har høj specificitet mod kræftceller, gode penetreringsevner og en høj nedbrydningshastighed, hvilket mindsker risikoen for udvikling af resistens. Derudover har de også lav toksicitet samt minimal akkumulering i væv. I dette studie blev tre AMP’er (GN2, GN4 of GN6) undersøgt for deres anticancer potentiale på cellelinjen Ma-Mel-51. Resultaterne blev opnået ved MTS- og hæmolyse-analyser og viste, at alle GN-peptider undersøgt havde lovende anticancerpotentiale mod melanomcellelinjen Ma-Mel-51, og kan være potentielle kandidater til fremtidige undersøgelser, idet de havde høj selektivitet over for kræftceller med lav selektivitet mod ikke-maligne HaCaT celler og røde blodlegemer., Cancer is one of the leading causes of morbidity and mortality worldwide. Acording to World Health Organization 8.8 million people died of cancer alone in 2015 wich means 1 out of 6 deaths being due to cancer. Malignant melanoma is one of the fastest growing types of cancers worldwide with an estimated 91,270 new cases in 2018 in the U.S. only. Today’s treatment involve surgery, chemotherapy, radiation, hormonal treatments and immunotherapeutics. These treatments have adverse side effects, resistance development and a high expense. Antimicrobial peptides (AMPs) serve as good candidates for cancer treatment due to their high specificity, ability to penetrate membrane and high speed of degradation with decreased risk of resistance, low toxicity and low accumulation in tissue. In this study the anticancer potencies of the three AMPs; GN2, GN4 and GN6 were investigated. The results were obtained by MTS and hemolysis assays and showed all investigated GN-peptides to have promising anticancer potencies towards the melanoma cell line Ma-Mel-51 and could serve as promising candidates for future investigations as they also exhibited high selectivity to cancer cells with low selectivity to the non-malignant HaCaT cell line and HRBC.

Summary. Water-soluble peptides/proteins with molecular weight below 10 kDa were isolated from residual material of cod (liver, skin, and cod mix i.e. skin, frames, and viscera), and salmon (skin, and salmon mix i.e. skin, frames, and viscera) by cut-off filtration. Peptide motifs with reported bioactivity were identified in all samples by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) (Orbitrap), bioinformatics, and database search. Peptides with potential type 2 diabetes, cardio system, immunomodulation, prolyl endopeptidase (PEP), and antioxidant activity were detected. The potential antioxidant activity in the samples was confirmed by two antioxidant assays, namely hydroxyl radical scavenging activity (HRSA), and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical cation decolorization assay. In these assays the salmon samples were found to possess higher antioxidant activity than the cod samples. All samples except the cod skin were found to have higher antioxidant activity than alanine-histidine (AH), a dipeptide with known antioxidant activity. Industrial relevance. Residual material from fisheries and aquaculture makes up large quantities of material. Although previously regarded as waste this material has valuable components that are of interest for the biotech industry. The fractionation process utilized in this work offers the possibility for simple isolation of interesting peptides with antioxidant activity. This method should be of interest for the food industry and biotech industry for product development.

Attention Deficit Hyperactivity Disorder (ADHD) is becoming a more common diagnosis of younger children. In recent years the perception that some ingredients in our food may have a negative effect regarding the symptoms in children with ADHD has grown stronger. Children with ADHD often suffer from irritated bowel syndromes which affect their ability to digest food. This may result in malnutrition as well as a release of substances that are harmful.The purpose of this report is to compile and illustrate the knowledge of how special food, particular milk protein and gluten, may affect the symptoms of children with ADHD. Also, the report aims to evaluate if there should be changes made in Kindergarten to increase the well-being of these children. The report is a summary of research results on the effects milk protein and gluten have on children with ADHD.The majority of children with ADHD demonstrate decreased symptoms if they receive a diet without milk protein and gluten.If children with ADHD would be given a special diet excluding milk protein and gluten it is realistic to assume that their ADHD-symptoms might be reduced with a greater sense of well-being and quality of life as a result. Attention Deficit Hyperactivity Disorder (ADHD) är en allt mer vanligt förekommande diagnos hos förskolebarn. Uppfattningen om att en anpassad kosthållning kan lindra symtomen hos barn med ADHD har växt sig starkare de senaste åren. Barn med ADHD lider ofta av en irriterad tarm som har en störd matspjälkningsfunktion, vilket kan leda till att näringsämnen bryts ner ofullständigt och resulterar i näringsbrister och frisättning av ämnen som kan påverka oss negativt.Syftet med rapporten är att sammanställa och belysa kunskapen om hur kosten kan påverka symtomen hos barn med ADHD, med särskild inriktning på påverkan från mjölkprotein och gluten. Samt att belysa vilken nytta skolverksamheten kan ha av dagens forskning inom ämnet.Rapporten är en sammanställning av de forskningsresultat som finns inom ämnet ADHD-anpassad kost där mjölkprotein och gluten utesluts.Majoriteten av barn med ADHD påvisar en minskade symtom om de får en anpassad kost utan mjölkprotein och gluten.Om förskolan skulle erbjuda barn med ADHD en anpassad kost är det realistiskt att anta att deras ADHD-symtom skulle kunna minska med ett ökat välbefinnande som följd.