Fungal Metabolites with Immunosuppressive Activities

1 Cyclosporins, Fungal Metabolites with Immunosuppressive Activities 

Pharmaceutical Division, Preclinical Research, Sandoz Ltd., CH-4002 Basel, Switzerland 

Synthesis of (25, 3R,4/ ,6 )-3-hydroxy-4-methyl-2-methylamino-6-octenoic acid (MeBmt) 19 

Parallel with chemical investigations, microbiological studies were intensified, especially the search for high producing mutants, as well as the improvement of media and culture conditions to enhance yields. A substantial feedback resulted from examination of the biosynthesis of cyclosporins. Yields and the composition of the metabolite mixture were significantly influenced by exogenously supplied amino-acid precursors. 

Complementary research activities deal with the development of suitable galenical formulations, the elaboration of analytical methods for monitoring cyclosporin levels, the study of pharmacokinetics and metabolism and, last but not least, the elucidation of the intriguing mechanism of action of cyclosporin A. 

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Von Wartburg, A., Traber, R. Cyclosporins, fungal metabolites with immunosuppressive activities. Progr. Med. Chem. 1988, 25, 1-33. 

A variety of macrocyclic natural products, either peptides or peptide-mimetic structures with HD AC inhibitory activity and promising pharmacological effects, have been reported. Some of them are shown in Fig. 5 for illustration for instance, romidepsin 9 (FK228) exhibits excellent class I inhibitory activity and has recently been approved by the FDA for the treatment of cutaneous T-cell lymphoma patients [58, 59]. Similarly, the marine natural product largazole 10 that demonstrates potent antiproliferative activity [60] and HC-toxin 11, a fungal metabolite with immunosuppressant activity, have been investigated as cytostatic agents [61, 62]. 

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