Cyclosporins--new analogues by precursor directed biosynthesis.
Cyclosporin A (ciclosporin), a potent and clinically important immunosuppressive drug (Sandimmun), represents the main component of a group of over 25 closely related, cyclic undecapeptides produced by the fungus Tolypocladium inflatum. By feeding experiments using DL-alpha-allylglycine as precursor, specific incorporation in position 2 was attained leading to [Allylgly2]cyclosporin A. Exogenously supplied L-beta-cyclohexylalanine results in the almost exclusive production of [MeCyclohexylala1]cyclosporin A (replacement of methylbutenyl-methylthreonine-1). D-Alanine in position 8 can be successfully substituted by D-serine. The new [D-Ser8] analogues of the cyclosporins A, C, D and G as well as [Allylgly2]cyclosporin A exhibit high immunosuppressive effects.
Traber
R
R
SANDOZ Ltd., Preclinical Research, Biotechnology, Basel, Switzerland.
Hofmann
H
H
Kobel
H
H
D000596:Amino Acids / Q000378:metabolism*; D003524:Cyclosporins / Q000096:biosynthesis* / Q000302:isolation & purification / Q000494:pharmacology; D003904:Mitosporic Fungi / Q000378:metabolism*; D015394:Molecular Structure
D000596:Amino Acids; D003524:Cyclosporins