Chemistry of the Immunomodulatory Macrolide Ascomycin and Related Analogues
Ascomycin and its close homologue tacrolimus are highly complex macrocyclic natural compounds isolated from the fermentation broths of Streptomyces hygroscopicus var. ascomyceticus and Streptomyces tsukubaensis. They are potent T-cell inhibitors of the ph
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Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 1.1. Ascomycin and Related Natural Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 1.2. Ascomycin Derivatives, a Novel Class of Anti-inflammatory Compounds . . . . . . . 62 1.3. Structural Features of Ascomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 2. Synthesis Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 2.1. Synthesis of the Four Diastereomeric “Furano-Ascomycins” . . . . . . . . . . . . . . . . . . . . . 70 2.2. Synthesis of 13C Labeled Ascomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 2.3. Reactivity of the Binding Domain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 2.4. Modifications in the Effector and Cyclohexyl Domains . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1. Introduction This chapter, after giving a short overview of the natural product ascomycin and related analogues, provides a summary of the biological properties and the clinical use of the ascomycin derivative pimecrolimus, a calcineurin inhibitor, developed and registered for topical treatment of the inflammatory skin disease atopic dermatitis. This is followed by an in-depth description of the structural features of ascomycin and synthesis aspects including specific modifications in the binding region, cleavage reactions, semisynthetic approaches, and modifications in the effector and cyclohexyl regions. The literature covers journal articles up to July 2010 with emphasis on chemistry. Structure-activity relationships are mentioned only qualitatively. No attempt has been made to review the patent literature in depth.
M.A.R.C. Bulusu and K. Baumann are former employees of Novartis Institutes for BioMedical Research Vienna. M.A.R.C. Bulusu • K. Baumann • A. Stuetz (*) Novartis Institutes for BioMedical Research Vienna, Muthgasse 11/2, A-1190, Vienna, Austria e-mail: [email protected] A.D. Kinghorn, H. Falk, J. Kobayashi (eds.), Progress in the Chemistry of Organic Natural Products, Vol. 94, DOI 10.1007/978-3-7091-0748-5_2, # Springer-Verlag/Wien 2011
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1.1. Ascomycin and Related Natural Products The successful application of cyclosporin A (CyA, Sandimmune®) in the prevention of transplantation rejectio
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