Microbial biotransformations of a synthetic immunomodulating agent, HR325.
The microbial biotransformation of HR325 [2-cyano-3-cyclopropyl-3-hydroxy-N-(4'-trifluoromethyl-3'-methylphenyl)- propenamide], a synthetic immunomodulating agent, has been investigated in order to be compared with animal metabolism and to prepare some metabolites which are difficult to obtain by chemical methods. Several fungal strains are able to completely metabolize this drug. Mortierella isabellina NRRL 1757 only achieves a benzylic hydroxylation on the aromatic methyl group, affording in high yield the corresponding hydroxymethyl derivative. In addition, other strains, such as Cunninghamella elegans ATCC 26269 or Beauveria bassiana ATCC 7159 can cleave both cyclopropyl and cyano groups in a new unknown oxidative biochemical reaction, which can be mimicked by m-chloroperbenzoate oxidation. The resulting cyanohydrin is hydrolyzed and reduced to a primary alcohol. In B. bassiana, the final incubation product is a beta-4-O-methylglucoside derivative of this alcohol, and has been fully characterized by independent synthesis. The different metabolic patterns of HR325 in the three fungal strains are discussed, and a mechanistic hypothesis about the oxidative cleavage of the right part of the molecule is proposed. The production of microbial metabolites is compared to animal metabolism in terms of structure and efficiency.
Lacroix
I
I
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Unité associée au CNRS No. 400, Université René Descartes-Paris V, France.
Biton
J
J
Azerad
R
R
D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics*; D000814:Aniline Compounds / Q000493:pharmacokinetics*; D001711:Biotransformation; D005658:Fungi / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D000814:Aniline Compounds; C107042:HR 325