1451070-60-2Relevant academic research and scientific papers
Ketoprofen-induced formation of amino acid photoadducts: Possible explanation for photocontact allergy to ketoprofen
Karlsson, Isabella,Persson, Elin,Ekebergh, Andreas,M?rtensson, Jerker,B?rje, Anna
, p. 1294 - 1303 (2014/08/05)
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.
Isocyanide cyclization reactions: 4-methylene-4H-benzo[d][1,3]oxazine, 3-benzyl-4-methylene-3,4-dihydroquinazolines and 3-(4-benzyl)-3H-quinazolin-4- ones - Experiment and theory
Neue, Benedikt,Reiermann, Ralph,Froehlich, Roland,Wibbeling, Birgit,Bergander, Klaus,Wuerthwein, Ernst-Ulrich
, p. 4944 - 4952 (2013/08/23)
2-Isocyanoacetophenone (3a) was found to be an easily accessible starting material for the unexpected formation of various heterocyclic systems. Thus, a hitherto unknown rather unstable 4-methylene-4H-benzoxazine derivative 4, which could be characterized by NMR spectroscopy, was formed in situ by the reaction of 3a in the presence of weak acids. In the presence of benzylamines, a new class of 3,4-dihydroquinazoline derivatives 6 and their oxidation products, quinazolin-4-ones 9, were obtained. The starting materials and products were completely characterized by spectroscopic and X-ray analysis. The scope and limitations of these cyclization reactions were investigated under various reaction conditions. High-level quantum chemical calculations were carried out to elucidate the mechanisms leading to scaffolds 4 and 6. The calculations suggest that the formation of 4 and 6 involves the generation of an unusual six-membered N-heterocyclic carbene or its C-protonated form as a reaction intermediate, followed by tautomerisation. This mechanism might also be applicable to other isocyanide cyclization reactions. Copyright
