| 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
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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. |
- 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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| 10. |
- 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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| 11. |
- 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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| 12. |
- 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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| 13. |
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| 14. |
- 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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| 15. |
- 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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| 16. |
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| 17. |
- 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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| 18. |
- 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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| 19. |
- 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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| 20. |
- 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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| 21. |
- 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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| 22. |
- Flaten, Gøril Eide, et al.
(författare)
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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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| 23. |
- Flaten, G. E., et al.
(författare)
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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
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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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| 24. |
- Flaten, Goril Eide, et al.
(författare)
-
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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| 25. |
- Flaten, Gøril Eide, et al.
(författare)
-
Drug permeability across a phospholipid vesicle based barrier: a novel approach for studying passive diffusion.
- 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. ; 27:1, s. 80-90
-
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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| 26. |
- Flaten, Gøril Eide, et al.
(författare)
-
The Phospholipid Vesicle-Based Drug Permeability Assay: 5. Development Toward an Automated Procedure for High-Throughput Permeability Screening
- 2009
-
Ingår i: Journal of the Association for Laboratory Automation. - : SAGE Publications. - 1535-5535. ; 14, s. 12-21
-
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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| 27. |
- 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
-
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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| 28. |
- 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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| 29. |
- 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
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:16, s. 7104-7113
-
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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| 30. |
- Fridén-Saxin, Maria, 1979, et al.
(författare)
-
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
-
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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| 31. |
- 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
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Ingår i: Investigational new drugs. - 0167-6997. ; 22:4, s. 411-20
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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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| 32. |
- 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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| 33. |
- Hagvall, Lina, 1978, et al.
(författare)
-
Can the epoxides of cinnamyl alcohol and cinnamal show new cases of contact allergy?
- 2018
-
Ingår i: Contact dermatitis. - : Wiley. - 1600-0536 .- 0105-1873. ; 78:6, s. 399-405
-
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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| 34. |
- Hubatsch, Ina, et al.
(författare)
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Beta- and gamma-di- and tripeptides as potential substrates for the oligopeptide transporter hPepT1
- 2007
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:21, s. 5238-5242
-
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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| 35. |
- 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
-
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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| 36. |
- Jerlhag, Elisabeth, 1978, et al.
(författare)
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Role of the subunit composition of central nicotinic acetylcholine receptors for the stimulatory and dopamine-enhancing effects of ethanol.
- 2006
-
Ingår i: Alcohol and Alcoholism. ; 41:5, s. 486-493
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: The stimulatory, rewarding, and dopamine (DA)-enhancing effects of ethanol may involve central nicotinic acetylcholine receptors (nAChR), especially those located in the ventral tegmental area (VTA). Identifying the subunit composition that mediates these effects of ethanol would increase the understanding of the neurochemical basis underlying the addictive properties of ethanol. In the present series of experiments, the role of the alpha(3)beta(2)(*) and/or beta(3)(*) and/or alpha(6)(*) subunits of the nAChR for the stimulatory and DA-enhancing effects of ethanol was investigated by using alpha-conotoxin MII (alphaCtxMII), selective to the alpha(3)beta(2)(*) and/or beta(3)(*) and/or the alpha(6)(*) subunits of the nAChR, and the alpha-conotoxin PIA-analogue (alphaCtxPIA-analogue), suggested to be selective to the alpha(6)(*) subunits. METHODS: alphaCtxMII and the alphaCtxPIA-analogue were synthesized using a modified literature procedure. The purity and identity of the peptides were confirmed with HPLC and FAB-MS analyses, respectively. Locomotor activity and in vivo microdialysis in freely moving mice were used. RESULTS: alphaCtxMII and the alphaCtxPIA-analogue were synthesized in good yields (>95%; >90%). In addition, we found that synthesized alphaCtxMII antagonized ethanol-induced locomotor stimulation, which confirms our previous results with the commercially available alphaCtxMII. Furthermore, the synthesized alphaCtxPIA-analogue, assumably also selective for alpha(6)(*) subunits of the nAChR, did neither antagonize the stimulatory nor the accumbal DA-enhancing effects of ethanol. CONCLUSION: These results indicate that alphaCtxMII- but not alphaCtxPIA-analogue-sensitive receptors, i.e. the alpha(3)beta(2)(*) and/or beta(3)(*) rather than the alpha(6)(*) subunits of the nAChR, appear to be of greater importance for these effects of ethanol and that these subunits could constitute neurochemical targets for developing new drugs for the treatment of alcohol dependence.
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| 37. |
- Karlberg, Ann-Therese, 1947, et al.
(författare)
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Allergic Contact Dermatitis––Formation, Structural Requirements, and Reactivity of Skin Sensitizers
- 2008
-
Ingår i: Chem. Res. Toxicol.. - : American Chemical Society (ACS). ; 21:1, s. 53-69
-
Tidskriftsartikel (refereegranskat)abstract
- Contact allergy is caused by a wide range of chemicals after skin contact. Its clinical manifestation, allergic contact dermatitis (ACD), is developed upon repeated contact with the allergen. This perspective focuses on two areas that have yielded new useful information during the last 20 years: (i) structure–activity relationship (SAR) studies of contact allergy based on the concept of hapten-protein binding and (ii) mechanistic investigations regarding activation of nonsensitizing compounds to contact allergens by air oxidation or skin metabolism. The second area is more thoroughly reviewed since the full picture has previously not been published. Prediction of the sensitizing capacity of a chemical is important to avoid outbreaks of ACD in the population. Much research has been devoted to the development of in vitro and in silico predictive testing methods. Today, no method exists that is sensitive enough to detect weak allergens and that is robust enough to be used for routine screening. To cause sensitization, a chemical must bind to macromolecules (proteins) in the skin. Expert systems containing information about the relationship between the chemical structure and the ability of chemicals to haptenate proteins are available. However, few designed SAR studies based on mechanistic investigations of prohaptens have been published. Many compounds are not allergenic themselves but are activated in the skin (e.g., metabolically) or before skin contact (e.g., via air oxidation) to form skin sensitizers. Thus, more basic research is needed on the chemical reactions involved in the antigen formation and the immunological mechanisms. The clinical importance of air oxidation to activate nonallergenic compounds has been demonstrated. Oxidized fragrance terpenes, in contrast to the pure terpenes, gave positive patch test reactions in consecutive dermatitis patients as frequently as the most common standard allergens. This shows the importance of using compounds to which people are exposed when screening for ACD in dermatology clinics.
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| 38. |
- Karlsson, Isabella, et al.
(författare)
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Nature-Derived Epoxy Resin Monomers with Reduced Sensitizing Capacity-Isosorbide-Based Bis-Epoxides
- 2023
-
Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 36:2, s. 281-290
-
Tidskriftsartikel (refereegranskat)abstract
- Epoxy resin systems (ERSs) are a class of thermosetting resins that become thermostable and insoluble polymers upon curing. They are widely used as components of protective surfaces, adhesives, and paints and in the manufacturing of composites in the plastics industry. The diglycidyl ether of bisphenol A (DGEBA) is used in 75-90% of ERSs and is thus by far the most used epoxy resin monomer (ERM). Unfortunately, DGEBA is a strong skin sensitizer and it is one of the most common causes of occupational contact dermatitis. Furthermore, DGEBA is synthesized from bisphenol A (BPA), which is a petroleum-derived chemical with endocrine-disruptive properties. In this work, we have used isosorbide, a renewable and nontoxic sugar-based material, as an alternative to BPA in the design of ERMs. Three different bisepoxide isosorbide derivatives were synthesized: the diglycidyl ether of isosorbide (1) and two novel isosorbide-based bis-epoxides containing either a benzoic ester (2) or a benzyl ether linkage (3). Assessment of the in vivo sensitizing potency of the isosorbide bis-epoxides in the murine local lymph node assay (LLNA) showed that all three compounds were significantly less sensitizing than DGEBA, especially 2 which was nonsensitizing up to 25% w/v. The peptide reactivity showed the same order of reactivity as the LLNA, i.e., 2 being the least reactive, followed by 3 and then 1, which displayed similar peptide reactivity as DGEBA. Skin permeation of 2 and 3 was compared to DGEBA using ex vivo pig skin and static Franz cells. The preliminary investigations of the technical properties of the polymers formed from 1-3 were promising. Although further investigations of the technical properties are needed, all isosorbide bis-epoxides have the potential to be less sensitizing renewable replacements of DGEBA, especially 2 that had the lowest sensitizing potency in vivo as well as the lowest peptide reactivity.
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| 39. |
- Lehmann, Fredrik, 1976, et al.
(författare)
-
Design, parallel synthesis and SAR of novel urotensin II receptor agonists
- 2007
-
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 42, s. 276-285
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Tidskriftsartikel (refereegranskat)abstract
- A 30-membered library of amides based on the potent urotensin II (UII) receptor agonist FL104, has been synthesized from ten different carboxylic acids and three amines. A synthetic protocol producing the amides in 47-98% yield has been developed in which the purification involved only extractions and in a few cases filtration through an ion-exchange resin. It was found that 5 mg of starting material was enough to obtain reproducible results and excellent purities. Thus, the procedure is estimated to be transferable to fully automated systems. The synthesized compounds were evaluated for their UII receptor agonistic activities using a cell-based assay (R-SAT). The most active compounds were the 4-trifluoromethylcinnamic amides of 1-(4-chlorophenyl)-3-dimethylamino-propylamine and 1-(2-naphthyl)-3-dimethylamino-propylamine, both showed EC50 values of 130 nM. © 2006 Elsevier Masson SAS. All rights reserved.
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| 40. |
- Lehmann, Fredrik, 1976, et al.
(författare)
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Isochromanone-based urotensin-II receptor agonists.
- 2005
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Ingår i: Bioorganic & medicinal chemistry. - : Elsevier BV. - 0968-0896. ; 13:8, s. 3057-68
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Tidskriftsartikel (refereegranskat)abstract
- A series of analogues of the selective non-peptide urotensin II (UII) receptor agonist 3-(4-chlorophenyl)-3-(2-dimethylaminoethyl)-isochroman-1-one (AC-7954, 1) was synthesized and evaluated for UII agonist activity using a functional cell-based assay. The introduction of a methyl group in the 4-position resulted in a complete loss of activity, whereas substituents in the aromatic rings were beneficial. Sterically demanding amino groups were also detrimental to the activity. Several potent agonists were identified, six compounds being equally or more potent than 1. The most potent compound in the series was the 6,7-dimethyl analogue of 1 (16, pEC50 6.87). The racemate of 16 was resolved into the pure enantiomers using preparative straight phase HPLC. It was shown that the potency resides in the (+)-enantiomer (pEC50 7.11). The synthesized compounds seem to be selective for the UII receptor as no activities were observed at the closely related SSTR3 and 5 receptors.
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| 41. |
- Lehmann, Fredrik, 1976, et al.
(författare)
-
Novel and potent small-molecule urotensin II receptor agonists
- 2009
-
Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 17:13, s. 4657-4665
-
Tidskriftsartikel (refereegranskat)abstract
- A series of analogs of the non-peptidic urotensin II receptor agonist N-[1-(4-chlorophenyl)-3-(dimethylamino)propyl]-4-phenylbenzamide (FL104) has been synthesized and evaluated pharmacologically. The enantiomers of the two most potent racemic analogues were obtained from the corresponding diastereomeric mandelic amides. In agreement with previously observed SAR, most of the agonist potency resided in the (S) enantiomers. The most potent UII receptor agonist in the new series was (S)-N-[3-dimethylamino-1-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide (EC50 = 23 nM at the urotensin II receptor).
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| 42. |
- Lehmann, Fredrik, 1976, et al.
(författare)
-
Novel potent and efficacious nonpeptidic urotensin II receptor agonists
- 2006
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49, s. 2232-2240
-
Tidskriftsartikel (refereegranskat)abstract
- Six different series of nonpeptidic urotensin II receptor agonists have been synthesized and evaluated for their agonistic activity in a cell-based assay (R-SAT). The compounds are ring-opened analogues of the isochromanone-based agonist AC-7954 with different functionalities constituting the linker between the two aromatic ring moieties. Several of the compounds are highly potent and efficacious, with N-[1-(4-chlorophenyl)-3-(dimethylamino)- propyl]-4-phenylbenzamide oxalate (5d) being the most potent. The pure enantiomers of 5d were obtained from the corresponding diastereomeric amides. It was shown by a combination of X-ray crystallography and chemical correlation that the activity resides in the S-enantiomer of 5d (pEC50 7.49). © 2006 American Chemical Society.
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| 43. |
- Lehmann, Fredrik, 1976, et al.
(författare)
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Optimization of isochromanone based urotensin II receptor agonists.
- 2010
-
Ingår i: Bioorganic & medicinal chemistry. - : Elsevier BV. - 1464-3391 .- 0968-0896. ; 18:13, s. 4844-4854
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Tidskriftsartikel (refereegranskat)abstract
- A series of novel isochromanone based urotensin II receptor agonists have been synthesized and evaluated for their activity using a functional cell based assay (R-SAT). Several potent and efficacious derivatives were identified with 3-(3,4-dichlorophenyl)-6,7-dimethyl-3-(2-dimethylaminoethyl)isochroman-1-one (28) being the most potent compound showing an EC(50)-value of 51nM, thereby being the most potent compound so far within the isochromanone series. In addition, two other heterocyclic systems (isochromanes and tetrahydroisoquinolinones) were investigated and these derivatives were found to be both potent and efficacious. The activity of the isochromane derivatives implies that the carbonyl group of the isochromanone is not necessary for activity. Furthermore it was found that the geometry of the heterocycles was more important for receptor interaction than the composition of the heteroatoms present.
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| 44. |
- Malo, Marcus, et al.
(författare)
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Development of 7TM receptor-ligand complex models using ligand-biased, semi-empirical helix-bundle repacking in torsion space: application to the agonist interaction of the human dopamine D-2 receptor
- 2013
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Ingår i: Journal of Computer-Aided Molecular Design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 27:3, s. 277-291
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Tidskriftsartikel (refereegranskat)abstract
- Prediction of 3D structures of membrane proteins, and of G-protein coupled receptors (GPCRs) in particular, is motivated by their importance in biological systems and the difficulties associated with experimental structure determination. In the present study, a novel method for the prediction of 3D structures of the membrane-embedded region of helical membrane proteins is presented. A large pool of candidate models are produced by repacking of the helices of a homology model using Monte Carlo sampling in torsion space, followed by ranking based on their geometric and ligand-binding properties. The trajectory is directed by weak initial restraints to orient helices towards the original model to improve computation efficiency, and by a ligand to guide the receptor towards a chosen conformational state. The method was validated by construction of the β1 adrenergic receptor model in complex with (S)-cyanopindolol using bovine rhodopsin as template. In addition, models of the dopamine D2 receptor were produced with the selective and rigid agonist (R)-N-propylapomorphine ((R)-NPA) present. A second quality assessment was implemented by evaluating the results from docking of a library of 29 ligands with known activity, which further discriminated between receptor models. Agonist binding and recognition by the dopamine D2 receptor is interpreted using the 3D structure model resulting from the approach. This method has a potential for modeling of all types of helical transmembrane proteins for which a structural template with sequence homology sufficient for homology modeling is not available or is in an incorrect conformational state, but for which sufficient empirical information is accessible.
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| 45. |
- Malo, Marcus, et al.
(författare)
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Investigation of D1 receptor-agonist interactions and D1/D2 agonist selectivity using a combination of pharmacophore and receptor homology modelling
- 2012
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:3, s. 483-494
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D1 receptor agonism and D1/D2 agonist selectivity. A 3D structure model of the D1 receptor in its agonist-bound state was constructed with a full D1 agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D1 agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor-based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D1 and D2 receptors revealed differences in shape and ligand-interacting features that determine selectivity of D1 and D2 receptor agonists. A hydrogen bond pharmacophoric feature (Ser-TM5) was shown to contribute most to the selectivity. Non-conserved residues in the binding pocket that strongly contribute to D1/D2 receptor agonist selectivity were also identified; those were Ser/Cys3.36, Tyr/Phe5.38, Ser/Tyr5.41, and Asn/His6.55 in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D1 and D2 agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand–protein interactions for which experimental information is limited.
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| 46. |
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| 47. |
- Malo, Marcus, et al.
(författare)
-
Selective pharmacophore models of dopamine D(1) and D(2) full agonists based on extended pharmacophore features.
- 2010
-
Ingår i: ChemMedChem. - : Wiley. - 1860-7187 .- 1860-7179. ; 5:2, s. 232-46
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Tidskriftsartikel (refereegranskat)abstract
- This study is focused on the identification of structural features that determine the selectivity of dopamine receptor agonists toward D(1) and D(2) receptors. Selective pharmacophore models were developed for both receptors. The models were built by using projected pharmacophoric features that represent the main agonist interaction sites in the receptor (the Ser residues in TM5 and the Asp in TM3), a directional aromatic feature in the ligand, a feature with large positional tolerance representing the positively charged nitrogen in the ligand, and sets of excluded volumes reflecting the shapes of the receptors. The sets of D(1) and D(2) ligands used for modeling were carefully selected from published sources and consist of structurally diverse, conformationally rigid full agonists as active ligands together with structurally related inactives. The robustness of the models in discriminating actives from inactives was tested against four ensembles of conformations generated by using different established methods and different force fields. The reasons for the selectivity can be attributed to both geometrical differences in the arrangement of the features, e.g., different tilt angels of the pi system, as well as shape differences covered by the different sets of excluded volumes. This work provides useful information for the design of new D(1) and D(2) agonists and also for comparative homology modeling of D(1) and D(2) receptors. The approach is general and could therefore be applied to other ligand-protein interactions for which no experimental protein structure is available.
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| 48. |
- Meinander, K., et al.
(författare)
-
Pseudopeptides with a centrally positioned alkene-based disulphide bridge mimetic stimulate kallikrein-related peptidase 3 activity
- 2013
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Ingår i: Medchemcomm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:3, s. 549-553
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Tidskriftsartikel (refereegranskat)abstract
- Pseudopeptides based on the kallikrein-related peptidase 3 (KLK3) activating bicyclic peptide “C-4” comprising hydrocarbon-based disulphide bridge mimetics have been synthesized. After investigating different synthetic approaches, the pseudopeptides were successfully cyclized from two L-allylglycine side chains via an alkene ring-closing metathesis reaction during the peptide synthesis. The alkene-linker was formed in a 1 : 1 E/Z isomer ratio. The resulting pseudopeptides were almost as potent as the parent peptide, increasing the activity of KLK3 over four-fold at 200 μg ml−1 (130–140 μM) concentrations.
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| 49. |
- Niklasson, Ida B, 1982, et al.
(författare)
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Bioactivation of Cinnamic Alcohol Forms Several Strong Skin Sensitizers
- 2014
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 27:4, s. 568-575
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Tidskriftsartikel (refereegranskat)abstract
- Cinnamic alcohol is a frequent contact allergen, causing allergic contact dermatitis (ACD) in a substantial number of individuals sensitized from contacts with fragrances. Hence, cinnamic alcohol is one of the constituents in fragrance mix I (FM I) used for screening contact allergy in dermatitis patients. Cinnamic alcohol lacks structural alerts for protein reactivity and must therefore be activated by either air oxidation or bioactivation to be able to act as a sensitizer. In the present study, we explored the bioactivation of cinnamic alcohol using human liver microsomes (HLM), and the potential pathways for these reactions were modeled by in silico (DFT) techniques. Subsequently, the reactivity of cinnamic alcohol and its metabolites toward a model hexapeptide were investigated. In addition to cinnamic aldehyde and cinnamic acid, two highly sensitizing epoiddes previously unobserved in studies of bioactivation were detected in the incubations with HLMs. Formation of epoxy cinnamic aldehyde was shown (both by the liver microsomal experiments, in which no depletion of epoxy cinnamic alcohol was observed after initial formation, and by the very high activation energy found for the oxidation thereof by calculations) to proceed via cinnamic aldehyde and not epoxy cinnamic alcohol.
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| 50. |
- Niklasson, Ida B, 1982, et al.
(författare)
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Cinnamyl alcohol oxidizes rapidly upon air exposure
- 2013
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Ingår i: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 68:3, s. 129-138
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Tidskriftsartikel (refereegranskat)abstract
- Background. Cinnamyl alcohol and cinnamal are frequent fragrance contact allergens. Both are included in the European baseline fragrance mix I, which is used for screening of contact allergy in dermatitis patients. Objectives. The aim of this study was to investigate the autoxidation of cinnamyl alcoholandtoidentifytheoxidationproductsformedonairexposure.Wealsowantedto evaluate the effect of autoxidation on the sensitization potency of cinnamyl alcohol. Methods. Samples of commercially available cinnamyl alcohol with and without purificationwereexposedtoair,andtheautoxidationwasfollowedbychemicalanalysis. Theanalysiswasperformedwithmassspectrometry(LC/MS/MS).Sensitizationpotencies ofcompoundsweredeterminedwiththemurinelocallymphnodeassay(LLNA)inmice. Results. Chemical analysis showed that the concentration of cinnamyl alcohol in the air-exposed samples decreased rapidly over time, and that autoxidation products were formed. Cinnamal, epoxy cinnamyl alcohol and cinnamic acid were identified as oxidation products. According to our study, cinnamal and epoxy cinnamyl alcohol were thefirstautoxidation productsformed. Theepoxy cinnamyl alcohol wasshowntobethe oxidation product with the highest sensitization potency. The analysis of our samples of commercially available cinnamyl alcohol showed that there was already a content of 1.5% cinnamal at the start of the autoxidation experiments. Conclusion. Cinnamylalcoholreadilyautoxidizesuponairexposure,andformsstrong sensitizers as determined by the LLNA. Cinnamal was formed in the largest amounts, showingthatcinnamalisnotonlyformedviabioactivation,ashaspreviouslybeenshown. A highly sensitizing epoxide was also identified and quantified in the oxidation mixture.
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