261759-01-7Relevant academic research and scientific papers
New derivatives of ascomycin with modifications in the amino acid region - Synthesis and biological activities, and X-ray crystal structure of 5,6-dehydroascomycin
Bulusu, Murty A. R. C.,Waldstaetten, Peter,Tricotet, Thomas,Rochais, Christophe,Steck, Andrea,Bacher, Markus,Schulz, Gerhard,Meingassner, Josef G.,Hiestand, Peter,Zenke, Gerhard,Schuler, Walter,Wagner, Trixie
experimental part, p. 839 - 889 (2009/08/14)
The immunomodulatory macrolide ascomycin (1a) inhibits T-cell activation via binding to macrophilin-12 and inhibition of the phosphatase calcineurin. Its structural analogs pimecrolimus and tacrolimus have recently become available as the first novel topical treatments of atopic dermatitis since the introduction of topical corticosteroids in the 1950s. This stimulated the search for novel derivatives with an improved biological profile. Though several derivatives of 1a are known, only a few derivatives with modifications on the amino acid moiety are available because of the chemical inaccessibility of this region. To this end, we present here a new approach using a photochemical reaction as the key step. Thus, irradiation of ascomycin (1a) led to mixtures of the methoxy products 2a and 8, the cleavage product 4a, the but-1-enyl derivative 7, and the oxazolidinone 9 depending on the solvent. The selectivity of the reaction was improved to furnish 2a or 9 in preparatively useful yields. The mechanism and scope of the reaction were investigated. Starting from 2a, several analogs featuring novel modifications on the amino acid moiety, which are not easily accessible through routine methods, were synthesized in a few steps. Further, using the photoreaction key intermediates with potential for broader modifications on the amino acid moiety were synthesized, and their utility was exemplified by the synthesis of vinylpipecolic acid and vinylproline analogs. An interesting photochemical cleavage of the amide bond in the derivatives of ascomycin (1a) is presented. The structural and conformational features of the new analogs together with the X-ray crystal structure of 5,6-dehydroascomycin (6a) are presented, and their biological activities are discussed. Of all the derivatives, 6a showed the best activities in in vitro and in vivo models of allergic contact dermatitis whilst showing a lower risk of immunosuppression.
Novel derivatives of ascomycin through photochemistry
Bulusu, Murty A. R. C.,Haidl, Ewald,Schulz, Gerhard,Waldstaetten, Peter,Grassberger, Maximilian
, p. 1159 - 1164 (2007/10/03)
Irradiation of ascomycin 1 leads to three reaction pathways: (a) [1,3]- sigmatropic shift of the allylic carbonyl group leading to the ring- contracted products 3 and 4, (b) electron-transfer from the amide nitrogen to the caxbonyl group followed by reorganisation leading to a zwitterionic intermediate Z which undergoes either intramolecular cyclisation (leading to 6 in CH3CN) or addition of methanol (leading to 2 in MeOH), and, (c) decarbonylative fragmentation resulting in the acyclic lactone 5. The effects of solvent, wavelength, and the substrate-structure on the product distribution have been examined. Simple transformations of the photoproducts leading to novel derivatives are presented.
