| 1. |
- Ekebergh, Andreas, 1984, et al.
(author)
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Oxidative Coupling as a Biomimetic Approach to the Synthesis of Scytonemin
- 2011
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In: Organic Letters. - : American Chemical Society (ACS). - 1523-7052 .- 1523-7060. ; 13:16, s. 4458-4461
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Journal article (peer-reviewed)abstract
- The first total synthesis of the dimeric alkaloid pigment scytonemin is described. The key transformations In Its synthesis from 3-indole acetic acid are a Heck carbocyclization and a Suzuki-Miyaura cross-coupling, orchestrated In a stereospecific tandem fashion, followed by a biosynthetically inspired oxidative dimerization. The tandem sequence generates a tetracyclic (E)-3-(arylidene)-3,4-dihydrocyclopenta[b]indol-2(1H)-one that is subsequently dimerized into the unique homodimeric core structure of scytonemin.
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| 2. |
- Karlsson, Isabella, 1980
(author)
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Chemical and Dermatological Aspects of UV-absorbing Compounds
- 2011
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Doctoral thesis (other academic/artistic)abstract
- ABSTRACT The sun’s UV radiation is necessary for the existence of life on earth. However, too much UV exposure can lead to the development of skin cancer. Therefore, sunscreens are often used by the general population as protection from excessive UV radiation. Unfortunately, many of the chemical UV-filters that are used in sunscreens today have the ability to induce contact and photocontact allergy. In this work two different chemical UV-filters together with the anti-inflammatory drug ketoprofen, all known to induce allergic reactions, have been studied to better understand the reason for these adverse effects. In addition, a synthetic route to the natural UV-filter scytonemin has been developed. One of the most commonly used UVA-filters today is the well known photoallergen 4-tert-butyl-4’-methoxy dibenzoylmethane. We showed that it degrades when irradiated with UV light and that several different photodegradation products are formed. Of particular interest were arylglyoxals and benzils because they were unexplored as potential contact allergens. The benzils were found to be cytotoxic rather than allergenic, whereas the arylglyoxals were found to be strong sensitizers in the murine local lymph node assay (LLNA) used to assess their allergenic potency. Photocontact allergy to dibenzoylmethanes is therefore probably caused by the arylglyoxals that are formed upon photodegradation. Chemical reactivity experiments showed that the arylglyoxals have the ability to form immunogenic complexes via an electrophilic-nucleophilic reaction with the amino acid arginine. A relatively new UV-filter on the market is octocrylene that has grown in popularity, due to its ability to stabilize other UV-filters such as 4-tert-butyl-4’-methoxy dibenzoylmethane. However, recent clinical reports suggest that it is the UV-filter that causes most allergic reactions. Patch and photopatch testing of 172 patients with suspected skin reactions to sunscreens or ketoprofen was performed and 23 of these patients displayed a positive test reaction to octocrylene. Five patients were diagnosed with contact allergy and 18 with photocontact allergy. Notably, many of these patients also displayed a photoinduced reaction to ketoprofen. Without UV radiation, octocrylene was classified as a moderate allergen in the murine LLNA and it was shown to reacted with amines like lysine via a retro-aldol condensation. In presence of UV radiation, octocrylene also reacted with amines but via acyl substitution resulting in a different product outcome than the reaction in the dark. Both the clinical studies and the chemical reactivity experiments thereby indicate that octocrylene has the ability to induce both contact and photocontact allergy. The apparent photocross-reactivity between octocrylene and ketoprofen observed in the clinical study could not be explained by the previous reactivity studies of octocrylene. Furthermore, according to other clinical reports, photosensitization to ketoprofen also leads to photocontact allergy to many other compounds. Ketoprofen was therefore irradiated in presence of five amino acid analogs and interestingly a reaction between the tryptophan and lysine analogs was substantially enhanced by ketoprofen. We believe that ketoprofen generates singlet molecular oxygen which activates the tryptophan analog that subsequently reacts with the lysine analog. The formation of an immunogenic complex not containing the allergen itself can explain many of the observed photocross allergies between ketoprofen and other structurally different compounds. In theory all compounds that are able to generate singlet molecular oxygen can promote the formation of the same immunogenic complex. Finally, the first total synthesis of the dimeric alkaloid scytonemin was developed. This natural occurring UV-filter enables the survival of different species of cyanobacteria in areas of intense solar radiation. The planed structure activity studies of scytonemin and derivatives thereof will hopefully lead to the development of a stable UV-filter that does not cause contact or photocontact allergy.
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| 3. |
- Karlsson, Isabella, 1980, et al.
(author)
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Clinical and experimental studies of octocrylene's allergenic potency
- 2011
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In: Contact Dermatitis. - : Wiley. - 1600-0536 .- 0105-1873. ; 64:6, s. 343-52
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Journal article (peer-reviewed)abstract
- Background. Reports of positive patch test and photopatch test reactions to the chemical ultraviolet filter octocrylene have increased during the last decade. Little is known about the reason for octocrylene's allergenic activity. Objectives. To present and discuss the results of patch tests and photopatch tests with octocrylene, and to investigate the possible cause of its allergenic properties. Methods. Results of patch tests and photopatch tests with octocrylene in patients with adverse skin reactions to sunscreen products and/or ketoprofen were collected. The allergenic potency of octocrylene was investigated in the murine local lymph node assay (LLNA). Chemical reactivity assays were used to mimic octocrylene's interaction with biomolecules. Results. We report 23 cases of positive test reactions to octocrylene (5 patch test and 18 photopatch). Notably, many of these patients also had positive photopatch test reactions to ketoprofen and benzophenone-3. Octocrylene was shown to be a moderate sensitizer in the LLNA, and it reacted with amines such as lysine, but not with thiols such as cysteine. Conclusions. The clinical studies show that octocrylene is both a photocontact allergen and a contact allergen. Octocrylene's ability to cause contact allergy is probably attributable to its reactivity towards lysine. To be able to understand why octocrylene causes photocontact allergy, further studies are needed.
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| 4. |
- Karlsson, Isabella, 1980, et al.
(author)
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Investigation of the Sunscreen Octocrylene's Interaction with Amino Acid Analogs in the Presence of UV Radiation
- 2012
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In: Photochemistry and Photobiology. - : Wiley. - 0031-8655 .- 1751-1097. ; 88:4, s. 904-912
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Journal article (peer-reviewed)abstract
- Octocrylene is an organic UV filter, commonly used in sunscreens and cosmetics, which can give rise to both contact and photocontact allergy. Our aim was to investigate octocrylenes interaction with amino acid analogs in the presence of UV radiation to better understand the reason for octocrylenes photoallergenic capacity. The amino acid analogs were photolysed in presence and absence of octocrylene for 1 h in cyclohexane. The rate of degradation was considerably slower for all amino acid analogs when octocrylene was present in the mixture. Benzylamine, the lysine analog, did react with octocrylene during the photolysis and the corresponding amide was formed in an acylation reaction. By varying the benzylamine concentration and keeping the octocrylene concentration fixed the reaction rate was shown to be independent of the amine concentration. The same type of acylation reaction took place when octocrylene alone was photolysed in ethanol in which the ethyl ester was formed from octocrylene and ethanol. Our results suggest that octocrylenes ability to cause photocontact allergy could be due to its photoinduced reactivity toward primary amines and alcohols.
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| 5. |
- Karlsson, Isabella, 1980, et al.
(author)
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Ketoprofen-Induced Formation of Amino Acid Photoadducts: Possible Explanation for Photocontact Allergy to Ketoprofen
- 2014
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In: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 27:7, s. 1294-1303
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Journal article (peer-reviewed)abstract
- Photocontact allergy is a well-known side effect of topical preparations of the nonsteroidal anti-inflammatory drug ketoprofen. Photocontact allergy to ketoprofen appears to induce a large number of photocross allergies to both structurally similar and structurally unrelated compounds. Contact and photocontact allergies are explained by structural modification of skin proteins by the allergen. This complex is recognized by the immune system, which initiates an immune response. We have studied ketoprofen's interaction with amino acids to better understand ketoprofen's photoallergenic ability. Irradiation of ketoprofen and amino acid analogues resulted in four different ketoprofen photodecarboxylation products (6-9) together with a fifth photoproduct (5). Dihydroquinazoline 5 was shown to be a reaction product between the indole moiety of 3-methylindole (Trp analogue) and the primary amine benzylamine (Lys analogue). In presence of air, dihydroquinazoline 5 quickly degrades into stable quinazolinone 12. The corresponding quinazolinone (17) was formed upon irradiation of ketoprofen and the amino acids N-acetyl-L-Trp ethyl ester and L-Lys ethyl ester. The formation of these models of an immunogenic complex starts with the ketoprofen-sensitized formation of singlet oxygen, which reacts with the indole moiety of Trp. The formed intermediate subsequently reacts with the primary amino functionality of Lys, or its analogue, to form a Trp Lys adduct or a mimic thereof. The formation of a specific immunogenic complex that does not contain the allergen but that can still induce photocontact allergy would explain the large number of photocross allergies with ketoprofen. These allergens do not have to be structurally similar as long as they can generate singlet oxygen. To the best of our knowledge, there is no other suggested explanation for ketoprofen's photoallergenic properties that can account for the observed photocross allergies. The formation of a specific immunogenic complex that does not contain the allergen is a novel hypothesis in the field of contact and photocontact allergy.
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| 6. |
- Karlsson, Isabella, 1980, et al.
(author)
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Photodegradation of Dibenzoylmethanes: Potential Cause of Photocontact Allergy to Sunscreens
- 2009
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In: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 22:11, s. 1881-1892
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Journal article (peer-reviewed)abstract
- One of the most frequently observed photoallergens today is the sunscreen agent 4-tert-butyl-4′-methoxy dibenzoylmethane (1a). The structurally similar compound, 4-isopropyldibenzoylmethane (1b), was a common cause of sunscreen allergy in the eighties and early nineties but was removed from the market in 1993 and replaced with dibenzoylmethane 1a. We have studied the photodegradation of the dibenzoylmethane 1a, to better understand how these substances cause an immune reaction. Several expected degradation products were formed and identified. Of these, arylglyoxals and benzils were of particular interest because they were unexplored as potential contact allergens. The allergenic potential of photodegraded 1a was evaluated by screening the formed arylglyoxals and benzils for their sensitizing capacity in the murine local lymph node assay. The arylglyoxals were found to be strong sensitizers. They were also found to be highly reactive toward the nucleophile arginine, which indicates that the immunogenic hapten-protein complex could be formed via an electrophilic-nucleophilic pathway. By varying the electron-withdrawing or -donating capacity of the substituent in the para position of the arylglyoxal, the electronic effects were shown to have no significant impact on either the sensitizing or the electrophilic power of arylglyoxals. Thus, a change in the substitution pattern of the parent dibenzoylmethane will not influence the sensitizing capacity of the products formed from them upon photodegradation. Furthermore, the combined studies of benzils, using the local lymph node assay and a cell proliferation assay, indicate that the benzils are cytotoxic rather than allergenic. Taken together, this study presents strong indication that photocontact allergy to dibenzoylmethanes is caused by the arylglyoxals that are formed upon photodegradation.
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| 7. |
- Ndreu, Lorena, 1990-, et al.
(author)
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Investigation into Propolis Components Responsible for Inducing Skin Allergy : Air Oxidation of Caffeic Acid and Its Esters Contribute to Hapten Formation
- 2023
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In: Chemical Research in Toxicology. - 0893-228X .- 1520-5010. ; 36:6, s. 859-869
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Journal article (peer-reviewed)abstract
- Propolis is a resin-like material produced by bees fromthe budsof poplar and cone-bearing trees and is used in beehive construction.Propolis is a common additive in various biocosmetics and health-relatedproducts, despite the fact that it is a well-known cause of contactallergy. Caffeic acid and its esters have been the primary suspectsbehind the sensitization potency of propolis-induced contact allergy.However, the chemical structures of the protein adducts formed betweenthese haptens and skin proteins during the process of skin sensitizationremain unknown. In this study, the reactivity of three main contactallergens found in propolis, namely, caffeic acid (CA), caffeic acid1,1-dimethylallyl ester (CAAE), and caffeic acid phenethyl ester (CAPE),was investigated. These compounds were initially subjected to thekinetic direct peptide reactivity assay to categorize the sensitizationpotency of CA, CAAE, and CAPE, but the data obtained was deemed toounreliable to confidently classify their skin sensitization potentialbased on this assay alone. To further investigate the chemistry involvedin generating possible skin allergy-inducing protein adducts, modelpeptide reactions with CA, CAAE, and CAPE were conducted and analyzedvia liquid chromatography-high-resolution mass spectrometry.Reactions between CA, CAAE, and CAPE and a cysteine-containing peptidein the presence of oxygen, both in closed and open systems, were monitoredat specific time points. These studies revealed the formation of twodifferent adducts, one corresponding to thiol addition to the & alpha;,& beta;-unsaturatedcarbonyl region of the caffeic structure and the second correspondingto thiol addition to the catechol, after air oxidation to o-quinone.Observation of these peptide adducts classifies these compounds asprehaptens. Interestingly, no adduct formation was observed when thesame reactions were performed under oxygen-free conditions, highlightingthe importance of air oxidation processes in CA, CAAE, and CAPE adductformation. Additionally, through NMR analysis, we found that thioladdition occurs at the C-2 position in the aromatic ring of the CAderivatives. Our results emphasize the importance of air oxidationin the sensitization potency of propolis and shed light on the chemicalstructures of the resultant haptens which could trigger allergic reactionsin vivo.
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| 8. |
- Ponting, David J., et al.
(author)
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Development of New Epoxy Resin Monomers - A Delicate Balance between Skin Allergy and Polymerization Properties
- 2019
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In: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 32:1, s. 57-66
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Journal article (peer-reviewed)abstract
- Epoxy resin monomers (ERMs) are used as building blocks for thermosetting polymers in applications where strong, flexible, and lightweight materials are required. Most epoxy resins are polymers of diglycidyl ether of bisphenol A (DGEBA). It is highly allergenic and causes occupational allergic contact dermatitis and contact allergy in the general population. Thus, measures to prevent exposure by protective clothing and education are not enough. This work describes a continuation of our research aiming at reducing the skin-sensitizing potency of ERMs while maintaining the ability to form polymers. Alternative ERMs were designed and synthesized whereafter the sensitizing potency was determined using the murine local lymph node assay (LLNA). The reactivity of the diepoxides toward a nucleophilic peptide was investigated, and the differences in reactivity explained using computational studies. The diepoxides were reacted with triethylenetetramine, and the formed polymers were tested for technical applicability using thermogravimetric analysis. We had previously shown that the absence of an oxygen atom in the side chains or removal of aromaticity reduced the sensitizing potency compared to that of DGEBA. Thus, a cycloaliphatic analogue 1 of DGEBA without ether oxygen in the side chains was considered promising and was synthesized. As predicted, the sensitizing potency was considerably reduced (10 times) compared to that of DGEBA. However, the technical properties of the polymer of this compound were not considered sufficient. More polar aromatic analogues were investigated, but they could not compete with our previously described ERMs regarding polymerization properties and with 1 regarding low skin sensitization properties. Development of alternative epoxy materials is a delicate balance between allergenic activity and polymerization properties. Tuning of structural properties together with investigation of polymerization conditions combined with skin sensitization studies should be used in industrial research and development. ERM 1 could be used as a lead compound for further studies of aliphatic ERMs.
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| 9. |
- Rajczewski, Andrew T., et al.
(author)
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Mass Spectrometry-Based Strategies for Assessing Human Exposure Using Hemoglobin Adductomics
- 2023
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In: Chemical Research in Toxicology. - 0893-228X .- 1520-5010. ; 36:12, s. 2019-2030
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Journal article (peer-reviewed)abstract
- Hemoglobin (Hb) adducts are widely used in human biomonitoring due to the high abundance of hemoglobin in human blood, its reactivity toward electrophiles, and adducted protein stability for up to 120 days. In the present paper, we compared three methods of analysis of hemoglobin adducts: mass spectrometry of derivatized N-terminal Val adducts, mass spectrometry of N-terminal adducted hemoglobin peptides, and limited proteolysis mass spectrometry . Blood from human donors was incubated with a selection of contact allergens and other electrophiles, after which hemoglobin was isolated and subjected to three analysis methods. We found that the FIRE method was able to detect and reliably quantify N-terminal adducts of acrylamide, acrylic acid, glycidic acid, and 2,3-epoxypropyl phenyl ether (PGE), but it was less efficient for 2-methyleneglutaronitrile (2-MGN) and failed to detect 1-chloro-2,4-dinitrobenzene (DNCB). By contrast, bottom-up proteomics was able to determine the presence of adducts from all six electrophiles at both the N-terminus and reactive hemoglobin side chains. Limited proteolysis mass spectrometry, studied for four contact allergens (three electrophiles and a metal salt), was able to determine the presence of covalent hemoglobin adducts with one of the three electrophiles (DNCB) and coordination complexation with the nickel salt. Together, these approaches represent complementary tools in the study of the hemoglobin adductome.
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| 10. |
- Vryonidis, Efstathios, 1989-, et al.
(author)
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Pathways to Identify Electrophiles In Vivo Using Hemoglobin Adducts : Hydroxypropanoic Acid Valine Adduct and Its Possible Precursors
- 2022
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In: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 35:12, s. 2227-2240
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Journal article (peer-reviewed)abstract
- Analytical methods and tools for the characterization of the human exposome by untargeted mass spectrometry approaches are advancing rapidly. Adductomics methods have been developed for untargeted screening of short-lived electrophiles, in the form of adducts to proteins or DNA, in vivo. The identification of an adduct and its precursor electrophile in the blood is more complex than that of stable chemicals. The present work aims to illustrate procedures for the identification of an adduct to N-terminal valine in hemoglobin detected with adductomics, and pathways for the tracing of its precursor and possible exposure sources. Identification of the adduct proceeded via preparation and characterization of standards of adduct analytes. Possible precursor(s) and exposure sources were investigated by measurements in blood of adduct formation by precursors in vitro and adduct levels in vivo. The adduct was identified as hydroxypropanoic acid valine (HPA-Val) by verification with a synthesized reference. The HPA-Val was measured together with other adducts (from acrylamide, glycidamide, glycidol, and acrylic acid) in human blood (n = 51, schoolchildren). The HPA-Val levels ranged between 6 and 76 pmol/g hemoglobin. The analysis of reference samples from humans and rodents showed that the HPA-Val adduct was observed in all studied samples. No correlation of the HPA-Val level with the other studied adducts was observed in humans, nor was an increase in tobacco smokers observed. A small increase was observed in rodents exposed to glycidol. The formation of the HPA-Val adduct upon incubation of blood with glycidic acid (an epoxide) was shown. The relatively high adduct levels observed in vivo in relation to the measured reactivity of the epoxide, and the fact that the epoxide is not described as naturally occurring, suggest that glycidic acid is not the only precursor of the HPA-Val adduct identified in vivo. Another endogenous electrophile is suspected to contribute to the in vivo HPA-Val adduct level.
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