Chemical modification of sorbistin. I. N-acyl analogs of sorbistin.
Sorbistin A1 (1b) and sorbistin B (1a), bioactive components of a new type of aminoglycoside antibiotic produced by a strain of Pseudomonas species, have been converted into a key intermediate 3 by blocking of the 1- and 4-amino groups of sorbistins with dimedone and subsequent deacylation of the 4'-N-acyl group. Some 4'-N-acyl analogs of sorbistin (1e approximately 1t) have been synthesized by 4'-N-acylation of 3 with an appropriate reactive derivative of carboxylic acids (mixed anhydride, acid chloride or activated ester) followed by deblocking of the protected group with bromine or sodium nitrite. Chemical interconversion of three natural sorbistins A1 (1b), A2 (1c) and B (1a) has been performed by this procedure. The 1-N-acyl (4a approximately 4c) and the 1,4'-N,N-diacyl analogs (6a approximately 6c) have been prepared by direct N-acylation of sorbistin D (1d) (the 4'-desacyl derivative) and sorbistin A1, respectively. On the other hand, the 4-N-acyl (5a and 5b) and the 4,4'-N,N-diacyl derivatives (7a and 7b) have been prepared by acylation and subsequent hydrogenolysis of 1-N-Cbz-sorbistin D (4b) and 1-N-Cbz-sorbistin A1 (6b), respectively. Determination of in vitro antimicrobial activity showed that the 4'-N-propionyl (1b) and the 4'-N-cyclopropylcarbonyl (1s) derivatives are the most active members of the 4'-N-acyl derivatives. Elongation and shortening of the side chain and introduction of functional groups decreased the activity. N-Acylation of the amino group at C-1 or at C-4 gave virtually inactive products.
D000215:Acylation; D000617:Aminoglycosides / Q000138:chemical synthesis* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D004352:Drug Resistance, Microbial; D008722:Methods; D013329:Structure-Activity Relationship
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents