| 1. |
- Berggren, Kristina, 1971, et al.
(författare)
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3-Aminopiperidine Based Peptide Analogues as the First Selective Noncovalent Inhibitors of the Bacterial Cysteine Protease IdeS
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:6, s. 2549-2560
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Tidskriftsartikel (refereegranskat)abstract
- A series of eight peptides corresponding to the amino acid sequence of the hinge region of IgG and 17 newly synthesized peptide analogues containing a piperidine moiety as a replacement of a glycine residue were tested as potential inhibitors of the bacterial IgG degrading enzyme of Streptococcus pyogenes, IdeS. None of the peptides showed any inhibitory activity of IdeS, but several piperidine-based analogues were identified as inhibitors. Two different analysis methods were used: an SDS-PAGE based assay to detect IgG cleavage products and a surface plasmon resonance spectroscopy based assay to quantify the degree of inhibition. To investigate the selectivity of the inhibitors for IdeS, all compounds were screened against two other related cysteine proteases (SpeB and papain). The selectivity results show that larger analogues that are active inhibitors of IdeS are even more potent as inhibitors of papain, whereas smaller analogues that are active inhibitors of IdeS inhibit neither SpeB nor papain. Two compounds were identified that exhibit high selectivity against IdeS and will be used for further studies.
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| 2. |
- Berggren, Kristina, 1971, et al.
(författare)
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Synthesis and biological evaluation of reversible inhibitors of IdeS, a bacterial cysteine protease and virulence determinant
- 2009
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 17:9, s. 3463-3470
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Tidskriftsartikel (refereegranskat)abstract
- Analogues of the irreversible protease inhibitors TPCK and TLCK have been synthesized and tested as inhibitors of the bacterial cysteine protease IdeS excreted by Streptococcus pyogenes. Eight compounds were identified as inhibitors of IdeS in an in vitro assay. The most potent compounds contained an aldehyde function, thus acting as efficient reversible inhibitors, nitrile and azide derivatives showed moderate activity. (C) 2009 Elsevier Ltd. All rights reserved.
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| 3. |
- Ahlström, M. M., et al.
(författare)
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CYP2C9 structure-metabolism relationships: Optimizing the metabolic stability of COX-2 inhibitors
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:18, s. 4444-4452
-
Tidskriftsartikel (refereegranskat)abstract
- The cytochrome P450 (CYP) family is composed of a large group of monooxygenases that mediate the metabolism of xenobiotics and endogenous compounds. CYP2C9, one of the major isoforms of the CYP family, is responsible for the phase I metabolism of a variety of drugs. The aim of the present investigation is to use rational design together with MetaSite, a metabolism site prediction program, to synthesize compounds that retain their pharmacological effects but that are metabolically more stable in the presence of CYP2C9. The model compound for the study is the nonsteroidal anti-inflammatory drug celecoxib, a COX-2 selective inhibitor and known CYP2C9 substrate. Thirteen analogs of celecoxib were designed, synthesized, and evaluated with regard to their metabolic properties and pharmacologic effects. The docking solutions and the predictions from MetaSite gave useful information leading to the design of new compounds with improved metabolic properties.
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| 4. |
- Ahlström, Marie M, et al.
(författare)
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Virtual screening and scaffold hopping based on GRID molecular interaction fields.
- 2005
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Ingår i: Journal of chemical information and modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 45:5, s. 1313-23
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Tidskriftsartikel (refereegranskat)abstract
- In this study, a set of strategies for structure-based design using GRID molecular interaction fields (MIFs) to derive a pharmacophoric representation of a protein is reported. Thrombin, one of the key enzymes involved in the blood coagulation cascade, was chosen as the model system since abundant published experimental data are available related to both crystal structures and structurally diverse sets of inhibitors. First, a virtual screening methodology was developed either using a pharmacophore representation of the protein based on GRID MIFs or using GRID MIFs from the 3D structure of a set of chosen thrombin inhibitors. The search was done in a 3D multiconformation version of the Available Chemical Directory (ACD) database, which had been spiked with 262 known thrombin inhibitors (multiple conformers available per compound). The model managed to find 80% of the known thrombin inhibitors among the 74,291 conformers in the ACD by only searching 5% of the database; hence, a 15-fold enrichment of the library was achieved. Second, a scaffold hopping methodology was developed using GRID MIFs, giving the scaffold interaction pattern and the shape of the scaffold, together with the distance between the anchor points. The scaffolds reported by Dolle in the Journal of Combinatorial Chemistry summaries (2000 and 2001) and scaffolds built or derived from ligands cocomplexed with the thrombin enzyme were parameterized using a new set of descriptors and saved into a searchable database. The scaffold representation from the database was then compared to a template scaffold (from a thrombin crystal structure), and the thrombin-derived scaffolds included in the database were found among the top solutions. To validate the usefulness of the methodology to replace the template scaffold, the entire molecule was built (scaffold and side chains) and the resulting compounds were docked into the active site of thrombin. The docking solutions showed the same binding pattern as the cocomplexed compound, hence, showing that this method can be a valuable tool for medicinal chemists to select interchangeable core structures (scaffolds) in an easy manner and retaining the binding properties from the original ligand.
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| 5. |
- Andresen Bergström, Moa, 1978, et al.
(författare)
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Conjugated dienes as prohaptens in contact allergy: in vivo and in vitro studies of structure-activity relationships, sensitizing capacity, and metabolic activation.
- 2006
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 19:6, s. 760-9
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Tidskriftsartikel (refereegranskat)abstract
- There is a great interest in developing in vitro/in silico methods for the prediction of contact allergenic activity. However, many proposed methods do not take the activation of prohaptens to sensitizers by skin metabolism into account. As a consequence, consumer products containing potent sensitizers could be marketed. To identify prohaptens, studies regarding their structure-activity relationships and the mechanisms of their activation must be conducted. In the present investigation, we have studied the structure-activity relationships for alkene prohaptens. A series of seven alkenes (1-7), all of the same basic structure but with variation in the number and position(s) of the double bond(s), were designed and screened for sensitizing capacity using the murine local lymph node assay. Compounds 1-7 were also incubated with liver microsomes in the presence of glutathione to trap and identify reactive metabolites. The metabolic conversion of three alkenes (9-11) to epoxides (12-15) was also studied along with comparison of their sensitizing capacity. Our results show that conjugated dienes in or in conjunction with a six-membered ring are prohaptens that can be metabolically activated to epoxides and conjugated with GSH. Related alkenes containing isolated double bonds and an acyclic conjugated diene were shown to be weak or nonsensitizers. For the first time, the naturally occurring monoterpenes alpha-phellandrene, beta-phellandrene, and alpha-terpinene were demonstrated to be prohaptens able to induce contact allergy. The difference in sensitizing capacity of conjugated dienes as compared to alkenes with isolated double bonds was found to be due to the high reactivity and sensitizing capacity of the allylic epoxides metabolically formed from conjugated dienes. We recommend that these structure-activity relationship rules are incorporated into in silico predictive databases and propose that the prediction of contact allergenic activity of suspected prohaptens is based on assessment of susceptibility to metabolic activation and chemical reactivity of potential metabolites.
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| 6. |
- Andresen Bergström, Moa, 1978, et al.
(författare)
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Metabolic epoxidation of an alpha,beta-unsaturated oxime generates sensitizers of extreme potency. Are nitroso intermediates responsible?
- 2007
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 20:6, s. 927-936
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic activation of inherently nonprotein-reactive compounds (prohaptens) in the skin can lead to development of contact allergy, a chronic skin disease. The prohapten hypothesis has existed for more than 20 years; yet, detailed knowledge regarding the mechanisms of activation as well as what structural moieties can be transformed to protein-reactive sensitizers is still limited. Today, the consideration of cutaneous bioactivation is important when developing nonanimal-based assays for prediction of contact allergenic activity, as only methods that include skin metabolism are able to detect prohaptens as sensitizers. We have studied the mechanism of activation of the prohapten carvoxime (1), a strongly sensitizing but in itself poorly protein-reactive alpha,beta-unsaturated oxime. alpha,beta-Unsaturated oximes represent a novel class of prohaptens, which previously have never been investigated for potential metabolic activation. To identify reactive metabolites formed from (1), liver microsomal incubations in the presence of glutathione were carried out. Putative reactive metabolites were synthesized, and their allergenic activity, chemical reactivity toward nucleophiles, and ability to elicit a contact allergenic response in animals induced with 1 were assessed. We found that 1 is metabolically activated by epoxidation of the allylic carbon-carbon double bond. The alpha,beta-epoxy oxime metabolites were found to be sensitizers of extreme potency in the local lymph node assay and highly reactive toward nucleophilic amino acids and a model peptide. One of the two diastereomeric epoxy metabolites also elicited an allergic reaction in mice sensitized to 1, in the mouse ear swelling test. Furthermore, this study presents strong indications that the basis of the high reactivity and sensitizing capacity observed for the alpha,beta-unsaturated oximes is related to their ability to form highly reactive nitroso intermediates by tautomerization. To our knowledge, the formation of nitrosoalkenes by oxidative metabolism of alpha,beta-unsaturated oximes has not been shown so far.
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| 7. |
- Andresen Bergström, Moa, 1978, et al.
(författare)
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Oximes: Metabolic Activation and Structure−Allergenic Activity Relationships
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:8, s. 2541-2550
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic activation of chemicals (prohaptens) in the skin can cause allergic contact dermatitis. We have explored structure−allergenic activity relationships for seven potential oxime prohaptens using the local lymph node assay and a GSH trapping screen with liver microsomes. The general structure−allergenic activity relationships found were that an α,β-unsaturation is necessary for an oxime to be a prohapten and that increased steric hindrance around this double bond leads to reduction in sensitizing capacity. We also found that sensitizing oximes can be distinguished in vitro from nonsensitizers by monitoring of mono-oxidized (+16 Da) GSH conjugates in the GSH trapping screen. However, care should be taken when interpreting data from GSH trapping screens, as nonsensitizers may also form GSH conjugates via alternative mechanisms. This investigation emphasizes the importance of considering cutaneous bioactivation in toxicity assessment of chemicals used in contact with the skin.
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| 8. |
- Ankner, Tobias, 1976, et al.
(författare)
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KHMDS enhanced SmI(2)-mediated reformatsky type alpha-cyanation.
- 2010
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Ingår i: Organic letters. - : American Chemical Society (ACS). - 1523-7052 .- 1523-7060. ; 12:10, s. 2210-3
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Tidskriftsartikel (refereegranskat)abstract
- A novel combination of SmI(2), KHMDS, and TsCN can be utilized to introduce a cyano group into structurally diverse and highly sensitive 2-alkyl-chroman-4-ones. Subsequent oxidation allows the formed 2-alkyl-3-cyanochromones to be isolated in yields ranging from 49 to 77%. In addition, alpha-bromoketones and esters were found to undergo equally effective alpha-cyanation.
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| 9. |
- Artursson, Per, et al.
(författare)
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Caco-2 monolayers in experimental and theoretical predictions of drug transport
- 2012
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Ingår i: Advanced Drug Delivery Reviews. - : Elsevier BV. - 0169-409X .- 1872-8294. ; 64:S, s. 280-289
-
Forskningsöversikt (refereegranskat)abstract
- This review examines the use of Caco-2 monolayers in the prediction of intestinal drug absorption. First, the different routes of drug transport in Caco-2 monolayers are compared with those seen in vivo. Second, the prediction of drug absorption in vivo from transport experiments in cell monolayers is discussed for different classes of drugs. Finally, the use of Caco-2 monolayers as a reference model in physico-chemical and theoretical predictions of drug absorption is discussed. We conclude that Caco-2 monolayers can be used to identify drugs with potential absorption problems, and possibly also to select drugs with optimal passive absorption characteristics from series of pharmacologically active molecules generated in drug discovery programs.
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| 10. |
- Berglundh, Sofia, et al.
(författare)
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C-reactive protein, bone loss, fracture, and mortality in elderly women: a longitudinal study in the OPRA cohort.
- 2015
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X. ; 26:2, s. 727-735
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Tidskriftsartikel (refereegranskat)abstract
- This longitudinal study investigates the association between C-reactive protein (CRP), osteoporosis, fractures, and mortality in 1044 elderly women. CRP was not an indicator for low bone mineral density (BMD), bone loss, or fracture in elderly women; however, women with elevated CRP levels over a prolonged period lost more bone over the 10-year follow-up, although fracture risk was not increased.
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| 11. |
- Bergström, Christel A S, et al.
(författare)
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Accuracy of calculated pH-dependent aqueous drug solubility.
- 2004
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Ingår i: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987. ; 22:5, s. 387-98
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate the extent to which the Henderson-Hasselbalch (HH) relationship can be used to predict the pH-dependent aqueous solubility of cationic drugs. The pH-dependent solubility for 25 amines, carrying a single positive charge, was determined with a small-scale shake flask method. Each sample was prepared as a suspension in 150 mM phosphate buffer. The pH-dependent solubility curves were obtained using at least 10 different pH values. The intrinsic solubility, the solubility at the pKa and the solubility at pH values reflecting the pH of the bulk and acid microclimate in the human small intestine (pH 7.4 and 6.5, respectively) were determined for all compounds. The experimental study revealed a large diversity in slope, from -0.5 (celiprolol) to -8.6 (hydralazine) in the linear pH-dependent solubility interval, which is in sharp contrast to the slope of -1 assumed by the HH equation. In addition, a large variation in the range of solubility between the completely uncharged and completely charged drug species was observed. The range for disopyramide was only 1.1 log units, whereas that for amiodarone was greater than 6.3 log units, pointing at the compound specific response to counter-ion effects. In conclusion, the investigated cationic drugs displayed compound specific pH-dependent solubility profiles, indicating that that the HH equation in many cases will only give rough estimations of the pH-dependent solubility of drugs in divalent buffer systems.
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| 12. |
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| 13. |
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| 14. |
- Bergström, Christel A S, et al.
(författare)
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Global and local computational models for aqueous solubility prediction of drug-like molecules.
- 2004
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Ingår i: Journal of chemical information and computer sciences. - : American Chemical Society (ACS). - 0095-2338 .- 1520-5142. ; 44:4, s. 1477-88
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to develop in silico protocols for the prediction of aqueous drug solubility. For this purpose, high quality solubility data of 85 drug-like compounds covering the total drug-like space as identified with the ChemGPS methodology were used. Two-dimensional molecular descriptors describing electron distribution, lipophilicity, flexibility, and size were calculated by Molconn-Z and Selma. Global minimum energy conformers were obtained by Monte Carlo simulations in MacroModel and three-dimensional descriptors of molecular surface area properties were calculated by Marea. PLS models were obtained by use of training and test sets. Both a global drug solubility model (R(2) = 0.80, RMSE(te) = 0.83) and subset specific models (after dividing the 85 compounds into acids, bases, ampholytes, and nonproteolytes) were generated. Furthermore, the final models were successful in predicting the solubility values of external test sets taken from the literature. The results showed that homologous series and subsets can be predicted with high accuracy from easily comprehensible models, whereas consensus modeling might be needed to predict the aqueous drug solubility of datasets with large structural diversity.
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| 15. |
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| 16. |
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| 17. |
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| 18. |
- Carlsson, Anna-Carin, 1976, et al.
(författare)
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Microwave-assisted synthesis of the Schollkopf chiral auxiliaries: (3S)- and (3R)-3,6-dihydro-2,5-diethoxy-3-isopropyl-pyrazine
- 2006
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Ingår i: Tetrahedron Letters. - : Elsevier BV. - 0040-4039. ; 47:29, s. 5199-5201
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Tidskriftsartikel (refereegranskat)abstract
- A practical and efficient methodology for the laboratory scale preparation of Schollkopf's bis-lactim ether chiral auxiliaries (3S)- and (3R)-3,6-dihydro-2,5-diethoxy-3-isopropyl-pyrazine has been developed. The key step is the preparation of the 2,5diketopiperazine derivative by microwave-assisted heating in water. The protocol avoids reactions at low temperature and the use of high boiling solvents. Only inexpensive and readily available starting materials are required. The bis-lactim ethers were produced in high yields on a multigram scale. (c) 2006 Elsevier Ltd. All rights reserved.
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| 19. |
- Dahlén, Kristian, 1973, et al.
(författare)
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A scaffold approach to 3,6,8-trisubstituted flavones
- 2006
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Ingår i: Synlett. - : Georg Thieme Verlag KG. - 0936-5214 .- 1437-2096. ; :6, s. 897-900
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Tidskriftsartikel (refereegranskat)abstract
- An efficient synthetic approach to 3,6,8-trisubstituted flavone scaffolds has been developed based on Pd-mediated coupling reactions.
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| 20. |
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| 21. |
- Dahlén, Kristian, 1973, et al.
(författare)
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Synthesis of 2,3,6,8-tetrasubstituted chromone scaffolds.
- 2006
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Ingår i: The Journal of organic chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 71:18, s. 6863-6871
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Tidskriftsartikel (refereegranskat)abstract
- A useful and efficient synthetic strategy to 2,3,6,8-tetrasubstituted chromone derivatives has been developed. 2-Aryl/styryl-8-bromo-6-chloro-3-hydroxychromone derivatives were synthesized and used as scaffolds by introducing a variety of substituents in the 3-, 6-, and 8-positions using palladium-mediated reactions. Excellent regioselectivity in all positions could be obtained by performing reactions in the 8-position first, in which Stille, Heck, Suzuki, and Sonogashira reactions gave good to excellent yields of product (63-98%). Stille and Heck reactions in the 6-position also gave the desired products in good yields (64-86%). The hydroxy group in the 3-position was activated as a triflate and used in productive Stille reactions (63-94%). This hydroxyl group was also used in O-alkylation reactions with different functionalized alkyl bromides (57-88%). The flavonoids, which are based on the chromone structure, and other related ring systems, have several interesting biological activities. The chromones are also interesting structural scaffolds, and they have for example been designed to be used as mimetics of short peptides. The versatile applicability of chromone derivatives and especially their potential use in drug discovery implicates the importance of access to efficient synthetic routes to such compounds.
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| 22. |
- Delaine, Tamara, 1981, et al.
(författare)
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A structure activity relationship study of geranial derivatives
- 2012
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Ingår i: Contact Dermatitis 11th congress of the European society of contact dermatitis (ESCD) 13-16 june 2012, Malmö, Sweden. - : Wiley. ; 66:Suppl. 2
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Konferensbidrag (refereegranskat)abstract
- Background: Fragrances are common causes of contact allergy. Skin exposure to geranial is frequent since citral (mixture of geranial and neral) is commonly used in fragrances and flavors and is considered as a moderate allergen. Previous studies according to the local lymphnodeassay (LLNA)in micehaverevealed large variations in the sensitizing capacity of different geranial derivatives. Objectives: For a better understanding of these variations, a structure-activity relationship (SAR) study on a series of derivatives of geranial was carried out. Methods: The chemical reactivity of the compounds towards a model peptide was investigated using LC-MS. The adduct formation and the non-reacted peptide depletion were monitored. Adducts formed with model amino acids were investigated and structural determination was performed. Additional derivatives were synthesized and their sensitization potencies were evaluated in relation to their physicochemical and reactivity properties. Results: Most of the derivatives were shown to bind covalently to the cysteine residue of the model peptide. The percentage of depletion of the non-reacted peptide ranged from 0% to 100% after 24 hr, constant rate of depletion revealed a large difference between the fastest and lowest reacting derivatives. These resultswere congruent with the skin sensitization potencies obtained with the LLNA. Conclusions: A good correlation between the reactivity and the sensitizing potency was observed. Small changes in the chemical structure of geranial result in significant differences in sensitizing capacity and chemical reactivity. Conflicts of interest: The authors have declared no conflicts.
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| 23. |
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| 24. |
- Delaine, Tamara, 1981, et al.
(författare)
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Epoxyalcohols: bioactivation and conjugation required for skin sensitization.
- 2014
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 27:10, s. 1860-70
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Tidskriftsartikel (refereegranskat)abstract
- Allylic alcohols, such as geraniol 1, are easily oxidized by varying mechanisms, including the formation of both 2,3-epoxides and/or aldehydes. These epoxides, aldehydes, and epoxy-aldehydes can be interconverted to each other, and the reactivity of them all must be considered when considering the sensitization potential of the parent allylic alcohol. An in-depth study of the possible metabolites and autoxidation products of allylic alcohols is described, covering the formation, interconversion, reactivity, and sensitizing potential thereof, using a combination of in vivo, in vitro, in chemico, and in silico methods. This multimodal study, using the integration of diverse techniques to investigate the sensitization potential of a molecule, allows the identification of potential candidate(s) for the true culprit(s) in allergic responses to allylic alcohols. Overall, the sensitization potential of the investigated epoxyalcohols and unsaturated alcohols was found to derive from metabolic oxidation to the more potent aldehyde where possible. Where this is less likely, the compound remains weakly or nonsensitizing. Metabolic activation of a double bond to form a nonconjugated, nonterminal epoxide moiety is not enough to turn a nonsensitizing alcohol into a sensitizer, as such epoxides have low reactivity and low sensitizing potency. In addition, even an allylic 2,3-epoxide moiety is not necessarily a potent sensitizer, as shown for 2, where formation of the epoxide weakens the sensitization potential.
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| 25. |
- Delaine, Tamara, 1981, et al.
(författare)
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Skin Sensitization of Epoxyaldehydes: Importance of Conjugation.
- 2013
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 26:5, s. 674-684
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Tidskriftsartikel (refereegranskat)abstract
- Structure-activity relationship (SAR) models are important tools for predicting the skin sensitization potential of new compounds without animal testing. In compounds possessing a structural alert (aldehyde) and an activation alert (double bond), it is important to consider bioactivation/autoxidation (e.g., epoxidation). In the present study, we have explored a series of aldehydes with regard to contact allergy. The chemical reactivity of these 6 aldehydes toward a model hexapeptide was investigated, and their skin sensitization potencies were evaluated using the local lymph node assay (LLNA). Overall, we observed a similar trend for the in vitro reactivity and the in vivo sensitization potency for the structural analogues in this study. The highly reactive conjugated aldehydes (α,β-unsaturated aldehydes and 2,3-epoxyaldehydes) are sensitizing moieties, while nonconjugated aldehydes and nonterminal aliphatic epoxides show low reactivity and low sensitization potency. Our data show the importance of not only double bond conjugation to aldehyde but also epoxide-aldehyde conjugation. The observations indicate that the formation of nonconjugated epoxides by bioactivation or autoxidation is not sufficient to significantly increase the sensitization potency of weakly sensitizing parent compounds.
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| 26. |
- Delaine, Tamara, 1981, et al.
(författare)
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Structure-Activity Relationship between the in Vivo Skin Sensitizing Potency of Analogues of Phenyl Glycidyl Ether and the Induction of Nrf2-Dependent Luciferase Activity in the KeratinoSens in Vitro Assay.
- 2011
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Ingår i: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 24:8, s. 1312-8
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Tidskriftsartikel (refereegranskat)abstract
- Because of regulatory constraints and ethical considerations, research on alternatives to animal testing to predict the skin sensitization potential of novel chemicals has become a high priority. Ideally, these alternatives should not only predict the hazard of novel chemicals but also rate the potency of skin sensitizers. Currently, no alternative method gives reliable potency estimations for a wide range of chemicals in differing structural classes. Performing potency estimations within specific structural classes has thus been proposed. Detailed structure-activity studies for the in vivo sensitization capacity of a series of analogues of phenyl glycidyl ether (PGE) were recently published. These studies are part of an investigation regarding the allergenic activity of epoxy-resin monomers. Here we report data on the same chemicals in the KeratinoSens in vitro assay, which is based on a stable transgenic keratinocyte cell line with a luciferase gene under the control of an antioxidant response element. A strong correlation between the EC3 values in the local lymph node assay (LLNA) and both the luciferase-inducing concentrations and the cytotoxicity in the cell-based assay was established for six analogues of PGE. This correlation allowed the potency in the LLNA of two novel structurally closely related derivatives to be predicted by read-across with errors of 1.4- and 2.6-fold. However, the LLNA EC3 values of two structurally different bifunctional monomers were overpredicted on the basis of this data set, indicating that accurate potency estimation by read-across based on in vitro data might be restricted to a relatively narrow applicability domain.
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| 27. |
- Dyrager, Christine, 1975, et al.
(författare)
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2,6,8-Trisubstituted 3-hydroxychromone derivatives as fluorophores for live-cell imaging.
- 2009
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Ingår i: Chemistry (Weinheim an der Bergstrasse, Germany). - : Wiley. - 1521-3765 .- 0947-6539. ; 15:37, s. 9417-23
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Tidskriftsartikel (refereegranskat)abstract
- We present the synthesis and photophysical characterisation of a series of structurally diverse, fluorescent 2,6,8-trisubstituted 3-hydroxychromone derivatives with high fluorescence quantum yields and molar extinction coefficients. Two of these derivatives (9 and 10 a) have been studied as fluorophores for cellular imaging in HeLa cells and show excellent permeability and promising fluorescence properties in a cellular environment. In addition, we have demonstrated by photophysical characterisation of 3-isobutyroxychromone derivatives that esterification of the 3-hydroxyl group results in acceptable and useful fluorescence properties.
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| 28. |
- Dyrager, Christine, 1975, et al.
(författare)
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Inhibitors and promoters of tubulin polymerization : Synthesis and biological evaluation of chalcones and related dienones as potential anticancer agents
- 2011
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 19:8, s. 2659-2665
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Tidskriftsartikel (refereegranskat)abstract
- A series of dihalogenated chalcones and structurally related dienones were synthesized and evaluated for their antiproliferative activity in 10 different cancer cell lines and for their effect on microtubule assembly. All compounds showed cytotoxic activity, with IC50 values in the 5-280 mu M range depending on the chalcone structure and the cell line. Five of the compounds were found to be tubulin polymerization inhibitors. In contrast, one of the compounds was found to stabilize tubulin to the same extent as the anticancer drug docetaxel. Molecular modeling suggested that the tubulin inhibitors bind to the colchicine binding site of beta-tubulin while the novel tubulin stabilization agent seems to interact with the paclitaxel binding site.
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| 29. |
- Ebrahimi, Parvaneh, et al.
(författare)
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Epigenome-wide cross-tissue correlation of human bone and blood DNA methylation–can blood be used as a surrogate for bone?
- 2021
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 16:1, s. 92-105
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Tidskriftsartikel (refereegranskat)abstract
- Difficulty in obtaining bone tissue is an obstacle to studying epigenetics to understand gene–environment interactions, and their role in disease pathogenesis. Blood is an obvious alternative and in this proof of principle study, our aim was to systematically investigate whether blood is a viable surrogate for bone. We measured epigenome-wide DNA methylation at 850 K CpG sites in matched trabecular bone and peripheral blood collected from the same patients at the same time-point (n = 12 women; 66–85y), to investigate the between-tissue correspondence. What constituted a CpG site with corresponding methylation in both tissues was stringently defined. Only sites highly correlated (r2 > 0.74; FDR q-value <0.05) and at least 80% similarity in methylation level (Δβ <0.2) between paired samples were retained. In total, 28,549 CpG sites were similarly methylated in bone and blood. Between 33% and 49% of loci associated with bone phenotypes through GWAS were represented among these sites, and major pathways relevant to bone regulation were enriched. The results from this study indicate that blood can mirror the bone methylome and capture sites related to bone regulation. This study shows that in principal, peripheral blood is a feasible surrogate for bone tissue in DNA methylation investigations. As the first step, this will provide a platform for future studies in bone epigenetics, and possibly for larger-scale epidemiological studies.
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| 30. |
- Flaten, Gøril Eide, et al.
(författare)
-
Drug permeability across a phospholipid vesicle-based barrier 2. Characterization of barrier structure, storage stability and stability towards pH changes.
- 2006
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Ingår i: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987. ; 28:4, s. 336-43
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Tidskriftsartikel (refereegranskat)abstract
- Recently we reported on the development of a phospholipid vesicle-based barrier as a medium throughput method for screening of drug permeability. The aim of this present study is to characterize the barrier structure, including an estimation of the amount of phospholipid within it, its storage stability and its stability over various pH ranges found in different parts of the gastrointestinal tract. The amount of lipid in the barrier was quantified using a colorimetric phospholipase D-based assay. The total amount averaged 3.30mg phospholipid per barrier. The preparation process comprises the consecutive deposition of two types of liposomes on a filter support. We estimated that the smallest liposomes, with a mean diameter of 298nm, would fill the pore volume of the filter when tightly packed. The volume of the bigger liposomes, deposited on top of the filter, was calculated to generate a 0.1mm thick layer. Visualisation of fluorescently labelled liposomes by confocal laser-scanning microscopy confirmed that the pores of the filter were completely filled with liposomes and that there was a liposome layer on top. Small angle X-ray scattering (SAXS) analysis was used to study the lamellarity of the liposomes. The liposomes contained oligo- and/or multilamellar structures before and after deposition. The functionality of the barriers during storage at three different temperatures was examined for a period of up to 4 weeks by measuring the permeability of the hydrophilic marker calcein across them. The conclusion was that the phospholipid vesicle-based barriers could be stored at -80 degrees Celsius for up to 2 weeks without significant changes. The stability of the barriers in a pH range from 2.0 to 8.0 was investigated by performing permeation studies with fluorescein at different pH values. It was found that the phospholipid vesicle-based barrier did not lose its integrity within this range. Thus, the barriers appear suitable for further studies to provide insight into segmental absorption in the human gastrointestinal tract. Furthermore, because the phospholipid vesicle-based barrier can be stored, larger batches can be produced. This makes the phospholipid vesicle-based barrier more appropriate for high throughput screening.
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| 31. |
- Flaten, G. E., et al.
(författare)
-
Drug permeability across a phospholipid vesicle based barrier: 3. Characterization of drug-membrane interactions and the effect of agitation on the barrier integrity and on the permeability
- 2007
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987. ; 30:3-4, s. 324-332
-
Tidskriftsartikel (refereegranskat)abstract
- Recently, we reported on the development and structural characterization of a phospholipid vesicle based barrier useful for medium throughput screening of passive drug permeability. Here, we investigate the physical and functional integrity of the phospholipid vesicle based barriers to agitation by stirring or shaking, and whether agitation affects drug permeability of sulpiride, metoprolol and testosterone. In addition, three drugs (caffeine, naproxen and sulphasalazine) which were shown in a previous study to affect the electrical resistance of the barriers, were investigated for their influence on the permeability of a simultaneously applied hydrophilic marker (calcein), and on the thermotropic phase transition of the phospholipid bilayers using differential scanning calorimetry (DSC). Electrical resistance measurements indicated that the barriers should withstand shaking speeds up to 150 rpm without losing their integrity, but significant release of phospholipids from the membrane barriers to the donor and acceptor chambers was observed under agitation >= 150 rpm. When using agitation up to 100 rpm no increase in permeability was observed for sulpiride, metoprolol and testosterone. The phospholipid vesicle-based barrier thus differ from other permeability models in that agitation does not lead to an increase in permeability, not even for highly lipophilic drugs such as testosterone. This is explained by the different morphology of the vesicle-based barrier which is containing a 100 mu m thick layer of mostly aqueous compartments immobilised within a matrix of phospholipids vesicles. Sulphasalazine and naproxen were shown to decrease the electrical resistance and increase the permeability of the hydrophilic marker calcein. The DSC experiments showed that these two drugs probably interact with the head groups of the phospholipids. In contrast, caffeine gave an increase in electrical resistance and a decrease in permeability of calcein. From the DSC experiments no signs of interaction of caffeine with the phospholipid bilayer could be observed. (c) 2006 Elsevier B.V. All rights reserved.
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| 32. |
- Flaten, Goril Eide, et al.
(författare)
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Drug permeability across a phospholipid vesicle-based barrier: 4. The effect of tensides, co-solvents and pH changes on barrier integrity and on drug permeability
- 2008
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987. ; 34:2-3, s. 173-180
-
Tidskriftsartikel (refereegranskat)abstract
- In this study the integrity of the recently developed phospholipid vesicle-based permeability barrier in the presence of a variety of co-solvents and tensides has been investigated. Also included are studies of the influence of these additives on drug permeation and the effect of pH changes on the permeability of ionogenic drug compounds. Permeability experiments using the hydrophilic model compound calcein together with polysorbate 80 (Tween 80), polyoxyl 35 castor oil (Cremophor EL), macrogol lauryl ether (Brij 35), sorbitan monolaurate (Span 20), polyethylene glycol 400 (PEG 400), ethanol and dimethylsulphoxide (DMSO) were performed to determine whether the barriers were affected by the presence of these additives in the donor compartment. It was found that the integrity of the phospholipid vesicle-based barriers did not seem to be influenced by Span 20 up to a concentration of 5 mg/ml, PEG 400 up to a concentration of 40 mg/ml and ethanol and DMSO up to a concentration of 20 mg/ml, respectively. Brij 35, Tween 80 and Cremophor EL were however found to be incompatible with the model at all concentrations as the barriers became leaky. Appearance of phospholipid in the donor chamber in presence of these three tensides indicated that the loss of integrity was due to partial dissolution of the phospholipid vesicles from the barrier. The permeability of testosterone was not significantly improved by the presence of the different co-solvents, except for 40 mg/ml PEG 400 and 20 mg/ml DMSO where the permeability was increased.
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| 33. |
- Flaten, Gøril Eide, et al.
(författare)
-
Drug permeability across a phospholipid vesicle based barrier: a novel approach for studying passive diffusion.
- 2006
-
Ingår i: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987. ; 27:1, s. 80-90
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to develop a novel predictive medium-throughput screening method for drug permeability, with use of a tight barrier of liposomes on a filter support. To our knowledge no one has succeeded in depositing membrane barriers without the use of an inert solvent such as hexadecane. The first part of the study involved development of a protocol for preparation of these barriers, which were made of liposomes from egg phosphatidylcholin in phosphate buffer pH 7.4 with 10 % (v/v) ethanol. The liposomes were deposited into the pores and onto the surface of a filter support (mixed cellulose ester) by use of centrifugation. Solvent evaporation and freeze-thaw cycling were then used to promote fusion of liposomes. A tight barrier could thus be obtained as shown with calcein permeability and electrical resistance. In the second part of the study the model was validated using 21 drug compounds, which cover a wide range of physicochemical properties and absorption (F(a)) in humans (13-100%). The drug permeation studies were carried out at room temperature with phosphate buffer (pH 7.4) in both acceptor and donor chambers. The apparent permeability coefficients obtained from the phospholipid vesicle based model correlated well with literature data on human absorption in vivo, which suggests that its performance is adequate and that the method is suitable for rapid screening of passive transport of new chemical entities. The results obtained from our model were compared with polar surface area (PSA) and experimental logD and with results obtained by established permeability screening methods such as immobilized liposome chromatography (ILC), the PAMPA models and the Caco-2 model. Our approach seems to model the in vivo absorption better than PSA, experimental logD, the ILC and PAMPA models, when similar conditions are used as in our assay, and equally well as the Caco-2 model and the Double Sink PAMPA (DS-PAMPA) model.
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| 34. |
- Flaten, Gøril Eide, et al.
(författare)
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The Phospholipid Vesicle-Based Drug Permeability Assay: 5. Development Toward an Automated Procedure for High-Throughput Permeability Screening
- 2009
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Ingår i: Journal of the Association for Laboratory Automation. - : SAGE Publications. - 1535-5535. ; 14, s. 12-21
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Tidskriftsartikel (refereegranskat)abstract
- In vitro screening for oral absorption has become an essential part of drug discovery and development. Recently, a new phospholipid vesicle-based permeation assay was developed which has shown to satisfyingly predict passive absorption of drugs in humans. The purpose of the current study was to investigate whether the assay may be further developed into a high-throughput tool by automating its most time-consuming steps. The following challenges were addressed: (1) to design, build, and test a heat-sealing machine for mounting of the desired type of filter support onto both single wells and 24-well titer plate inserts and (2) to transfer the permeability assay to a robotic workstation with attached ultraviolet (UV) reader. The workstation is able to pipette and transport both plates and filter inserts and perform on-line photometric quantification of the amount of drug permeated. To enable the robot to move single (Standard Transwell; Corning Inc, Lowell, MA) filter inserts, an extension of the gripping arm was designed, built, and tested. Furthermore, in an alternative approach 24-well filter plates (Millicell; Millipore, Billerica, MA) were used instead of single filter inserts. The latter turned out to be more suitable in terms of error-free high-throughput robotic handling. The permeability values of drugs gained by the two automated procedures were compared with those measured by manual handling of the assay. Only neglectable differences in permeability values were seen. In conclusion, the most time-consuming steps of the assay were shown to be eligible for automation. This represents an interesting addition to the toolbox of in vitro permeability screening assays running in a medium- to high-throughput format due to its easiness, its transferability to other laboratories, and its good correlation with in vivo data on fraction absorbed of drugs in humans.
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| 35. |
- Fridén-Saxin, Maria, 1979, et al.
(författare)
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Chroman-4-one and chromone based somatostatin beta-turn mimetics
- 2016
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234. ; 114, s. 59-64
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Tidskriftsartikel (refereegranskat)abstract
- A scaffold approach has been used to develop somatostatin beta-turn mimetics based on chroman-4-one and chromone ring systems. Such derivatives could adopt conformations resembling type II or type II' beta-turns. Side chain equivalents of the crucial Trp8 and Lys9 in somatostatin were introduced in the 2- and 8-positions of the scaffolds using efficient reactions. Interestingly, this proof-of-concept study shows that 4 and 9 have K-i-values in the low mu M range when evaluated for their affinity for the sst2 and sst4 receptors. (C) 2016 Elsevier Masson SAS. All rights reserved.
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| 36. |
- Fridén-Saxin, Maria, 1979, et al.
(författare)
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Proline-mediated formation of novel chroman-4-one tetrahydropyrimidines
- 2012
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 68:35, s. 7035-7040
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Tidskriftsartikel (refereegranskat)abstract
- Novel tricyclic N-benzylated chroman-4-one tetrahydropyrimidine derivatives have been prepared through a multi-component reaction between various 2-substituted chroman-4-one derivatives, N-methylenebenzylamine and a catalytic amount of proline under mild reaction conditions. The tricyclic structure of 1a was determined by NMR spectroscopy and confirmed by X-ray crystallography. An additional product, 2a, was isolated from the reaction mixture and its structure and conformation were determined by a combination of theoretical (Monte Carlo conformational search) and NMR-based (NOE and (3)J(HH) couplings) conformational analysis. The NMR analysis revealed one preferred geometry for 1a and 2a in CHCl3 solution. (C) 2012 Elsevier Ltd. All rights reserved.
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| 37. |
- Fridén-Saxin, Maria, 1979, et al.
(författare)
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Synthesis and Evaluation of Substituted Chroman-4-one and Chromone Derivatives as Sirtuin 2-Selective Inhibitors
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:16, s. 7104-7113
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Tidskriftsartikel (refereegranskat)abstract
- A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC50 of 1.5 mu M. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.
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| 38. |
- Fridén-Saxin, Maria, 1979, et al.
(författare)
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Synthesis of 2-alkyl-substituted chromone derivatives using microwave irradiation.
- 2009
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Ingår i: The Journal of organic chemistry. - : American Chemical Society (ACS). - 1520-6904 .- 0022-3263. ; 74:7, s. 2755-9
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Tidskriftsartikel (refereegranskat)abstract
- A base-promoted condensation between 2-hydroxyacetophenones and aliphatic aldehydes has been studied. The reaction has been optimized to afford 2-alkyl-substituted 4-chromanones in an efficient manner using microwave heating. Performing the reaction using diisopropylamine in EtOH at 170 degrees C for 1 h gave moderate to high yields (43-88%). The 4-chromanones could be further converted into highly functionalized 2,3,6,8-tetrasubstituted chromones in which a 3-substituent (acetate, amine, or bromine) was introduced via straightforward chemical transformations.
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| 39. |
- Garg, Gaurav, et al.
(författare)
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Glucose-dependent insulinotropic polypeptide (GIP) and GIP receptor (GIPR) genes : An association analysis of polymorphisms and bone in young and elderly women
- 2016
-
Ingår i: Bone Reports. - : Elsevier BV. - 2352-1872. ; 4, s. 23-27
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: The gastro-intestinal hormone glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-induced insulin secretion, with bone anabolic effects through GIP receptor (GIPR) in animal models. We explore its potential in humans by analyzing association between polymorphisms (SNPs) in the GIP and GIPR genes with bone phenotypes in young and elderly women. Methods: Association between GIP (rs2291725) and GIPR (rs10423928) and BMD, bone mineral content (BMC), bone microarchitecture, fracture and body composition was analyzed in the OPRA (75y, n. =. 1044) and PEAK-25 (25y; n. =. 1061) cohorts and serum-GIP in OPRA. Results: The GIP receptor AA-genotype was associated with lower ultrasound values in young women (BUA p=0.011; SI p=0.030), with no association to bone phenotypes in the elderly. In the elderly, the GIP was associated with lower ultrasound (GG vs. AA; SOS padj=0.021) and lower femoral neck BMD and BMC after adjusting for fat mass (padj=0.016 and padj=0.03). In young women, neither GIPR nor GIP associated with other bone phenotypes including spine trabecular bone score. In the elderly, neither SNP associated with fracture. GIP was associated with body composition only in Peak-25; GIPR was not associated with body composition in either cohort. Serum-GIP levels (in elderly) were not associated with bone phenotypes, however lower levels were associated with the GIPR A-allele (β=-6.93; padj=0.03). Conclusions: This first exploratory association study between polymorphisms in GIP and GIPR in relation to bone phenotypes and serum-GIP in women at different ages indicates a possible, albeit complex link between glucose metabolism genes and bone, while recognizing that further studies are warranted.
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| 40. |
- Garg, Gaurav, et al.
(författare)
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Variation in the MC4R Gene Is Associated with Bone Phenotypes in Elderly Swedish Women.
- 2014
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:2
-
Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r(2) = 0.2-0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs.
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| 41. |
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| 42. |
- Gullbo, Joachim, et al.
(författare)
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Antitumor activity of the novel melphalan containing tripeptide J3 (L-prolyl-melphalanyl-p-L-fluorophenylalanine ethyl ester) : Comparison with its m-L-sarcolysin analogue P2
- 2003
-
Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 2:12, s. 1331-1339
-
Tidskriftsartikel (refereegranskat)abstract
- Peptichemio (PTC), a mixture of six oligopeptides all containing m-L-sarcolysin, has previously shown impressive results in clinical trials. The tripeptide P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester) has been suggested as the main contributor to PTC activity. In contrast to its analogue melphalan, m-L-sarcolysin never reached clinical use. To allow a direct comparison, the corresponding melphalan containing tripeptide J3 (L-prolyl-L-melphalanyl-p-L-fluorophenylalanine ethyl ester) was synthesized and its activity was compared with that of P2; the activities of melphalan and m-L-sarcolysin were studied in parallel. Cytotoxic activity in human tumor cell lines and some fresh human tumor specimens were analyzed as well as effects on cellular metabolism, macromolecular synthesis, and preliminary evaluation of the cell death characteristics. The results show that melphalan and m-L-sarcolysin display similar activity in these systems and that the tripeptides were more active than their parent monomers. Surprisingly however, the melphalan containing tripeptide J3 demonstrated a significantly more rapid and stronger activity than the m-L-sarcolysin analogue P2. Finally, the in vivo toxicity and activity of melphalan and J3 were investigated in mice bearing human leukemia cells in s.c. fibers. The in vitro results seem translatable into the in vivo situation, demonstrating better antileukemic effect of J3 but similar side effects as melphalan.
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| 43. |
- Gullbo, Joachim, et al.
(författare)
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Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo.
- 2004
-
Ingår i: Investigational new drugs. - 0167-6997. ; 22:4, s. 411-20
-
Tidskriftsartikel (refereegranskat)abstract
- The novel alkylating dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) was evaluated for acute toxicity and antitumor activity in mice, with melphalan as a reference. To determine a safe and tolerable dose for efficacy studies the acute toxicity following intravenous injection in the tail vein was monitored using a 14-day schedule with up to four doses. The highest tested dose, 25 micromoles/kg, was considered close to this level, with minor effects on body weight gain but significant effects on hematological parameters. Melphalan and J1 appeared equitoxic with no statistically significant differences. Subsequently a mouse hollow fiber model was employed with subcutaneous implantation of fibers containing human tumor cells. Three different human tumor cell lines as well as two samples of primary human tumor cells (ovarian carcinoma and chronic lymphatic leukemia) were used as tumor models. At the dose level tested there was a marked and statistically significant decrease in both T-cell leukemia CCRF-CEM and small cell lung cancer NCI-H69 tumor cell growth and viability in response to J1 as compared with both placebo and melphalan treated groups. In primary ovarian carcinoma cells only J1 treatment resulted in significant tumor regression (net cell kill). In summary the results indicate that, despite an expected short half time in the blood circulation, the promising in vitro data from the previous studies of J1 seems translatable into the in vivo situation. At equal doses of alkylating units J1, compared to melphalan, was more active in the mouse hollow-fiber model, but showed similar general toxicity.
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| 44. |
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| 45. |
- Gullbo, Joachim, et al.
(författare)
-
Structure activity relationship for alkylating dipeptide nitrogen mustard derivatives
- 2003
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Ingår i: Oncology Research. - : Computers, Materials and Continua (Tech Science Press). - 0965-0407 .- 1555-3906. ; 14:3, s. 113-132
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Tidskriftsartikel (refereegranskat)abstract
- The strategy of using small peptides for effective targeting of tumor cells in chemotherapy has proven beneficial. Recently we showed that J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester), an alkylating nitrogen mustard-containing dipeptide, exhibited strong cytotoxic activity in fresh human tumor samples in addition to rapid and pronounced inhibition of macromolecular syntheses and cellular respiration in the human tumor lymphoma cell line U-937 GTB. In this study, an additional series of 17 nitrogen mustard-containing dipeptides has been synthesized and analyzed for cytotoxic activity in a panel of 10 human tumor cell lines. The results were compared to the single amino acid mustard derivative melphalan and its ethyl and isopropyl esters. Also P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester), a tripeptide that previously has shown impressive effects in human tumor cells, was used as reference. The tested compounds displayed various activities in the different cell lines but also showed a high correlation, indicating a similar mechanism of action. Factors like amino acid composition, amino acid sequence, modifications of the C- and N-termini, and to a minor extent the lipophilicity of the dipeptide derivatives appear to influence the in vitro activity. The results indicate that the activity of these compounds not only relies on their chemical reactivity, but also on active biological interactions such as transport across membranes and/or enzymatic liberation of reactive molecular entities.
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| 46. |
- Hagvall, Lina, 1978, et al.
(författare)
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Assessment of cross-reactivity of new less sensitizing epoxy resin monomers in epoxy resin-allergic individuals
- 2016
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Ingår i: Contact Dermatitis. - : Wiley. - 0105-1873. ; 75:3, s. 144-150
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMeasures to prevent occupational exposure to epoxy resins, including education, medical examination, and voluntary agreements between employers and workers, have not been effective enough to protect against skin sensitization. Therefore, alternatives to the major epoxy resin haptens that have been found to be less sensitizing in the local lymph node assay have been developed. ObjectivesTo study the cross-reactivity of two newly designed epoxy resin monomers, with decreased skin-sensitizing potency and good technical properties as compared with diglycidyl ether of bisphenol A (DGEBA), in subjects with known contact allergy to epoxy resin of DGEBA type. Patients and MethodsEleven individuals with previous positive patch test reactions to epoxy resin of DGEBA participated in the study. The two alternative epoxy resin monomers were synthesized and patch tested in dilution series in parallel with epoxy resin of DGEBA from the baseline series (containing 92% DGEBA). ResultsAll participants reacted to epoxy resin of DGEBA on retesting. Three participants reacted to monomer 1. No reactions were seen to monomer 2. ConclusionsThe alternative monomers studied showed little or no cross-reactivity with epoxy resin of DGEBA. Decreasing the risk of sensitization by using less sensitizing compounds is important, as contact allergy to epoxy resins is common in spite of thorough preventive measures.
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| 47. |
- Hagvall, Lina, 1978, et al.
(författare)
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Can the epoxides of cinnamyl alcohol and cinnamal show new cases of contact allergy?
- 2018
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Ingår i: Contact dermatitis. - : Wiley. - 1600-0536 .- 0105-1873. ; 78:6, s. 399-405
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Tidskriftsartikel (refereegranskat)abstract
- Cinnamyl alcohol is considered to be a prohapten and prehapten with cinnamal as the main metabolite. However, many individuals who are allergic to cinnamyl alcohol do not react to cinnamal. Sensitizing epoxides of cinnamyl alcohol and cinnamal have been identified as metabolites and autoxidation products of cinnamyl alcohol.To investigate the clinical relevance of contact allergy to epoxycinnamyl alcohol and epoxycinnamal.Irritative effects of the epoxides were investigated in 12 dermatitis patients. Epoxycinnamyl alcohol and epoxycinnamal were patch tested in 393 and 390 consecutive patients, respectively. In parallel, cinnamyl alcohol and cinnamal were patch tested in 607 and 616 patients, respectively.Both epoxides were irritants, but no more positive reactions were detected than when testing was performed with cinnamyl alcohol and cinnamal. Late allergic reactions to epoxycinnamyl alcohol were observed. In general, patients with late reactions showed doubtful or positive reactions to cinnamal and fragrance mix I at regular patch testing.The investigated epoxides are not important haptens in contact allergy to cinnamon fragrance. The high frequency of fragrance allergy among patients included in the irritancy study showed the difficulty of suspecting fragrance allergy on the basis of history; patch testing broadly with fragrance compounds is therefore important.
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| 48. |
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| 49. |
- Hubatsch, Ina, et al.
(författare)
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Beta- and gamma-di- and tripeptides as potential substrates for the oligopeptide transporter hPepT1
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:21, s. 5238-5242
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Tidskriftsartikel (refereegranskat)abstract
- The hPepT1-mediated transport properties of a series of 11 synthesized beta- and gamma-peptides have been studied in Caco-2 cells. The results show that several of the compounds interact with the peptide transporter, but only two beta-dipeptides act as substrates and are transported across the cell monolayers. These two are less-efficient substrates than alfa-peptides. Larger derivatives than beta-dipeptides do not act as hPepT1 substrates, but instead, they appear to be substrates for P-glycoprotein efflux.
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| 50. |
- Jam, Fariba, 1967, et al.
(författare)
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Microwave assisted synthesis of spiro-2,5-diketopiperazines
- 2007
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 63, s. 9881-9889
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Tidskriftsartikel (refereegranskat)abstract
- A general and efficient method for the synthesis of spiro-2,5-diketopiperazines (spiro-DKPs) is described. Cyclization of Boc-protected dipeptides containing spiro-amino acids by microwave assisted heating in water furnished the corresponding spiro-DKPs. The spiro-amino acids were prepared by combining stereoselective alkylation reactions using the Schöllkopf methodology for amino acid construction with Grubbs ring-closing metathesis (RCM) methodology using ruthenium complexes. The RCM reactions and all subsequent transformations to the spiro-DKPs were run with microwave assisted heating, resulting in high yields and short reaction times for all steps.
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