Dorrigocin B

Iso-Migrastatin (10) has been shown to be the main natural product of Streptomyces platensis, which undergoes a facile, H2O-mediated rearrangement into dorrigocin A (2), 13-epi-dorrigocin A (11), dorrigocin B (3), and migrastatin (1). Eight new congeners (12-19) of 10 were characterized. They can undergo the same H2O-mediated rearrangement into the corresponding 1, 2, 3, and 11 analogues (20-43) or 1,4-Michael addition with cysteine to afford the corresponding analogues (44-51) of NK30424 A and B (5, 6). This study generated a 47-member library of glutarimide polyketides, setting the stage to investigate the SAR for this family of natural products. These results also established the absolute stereochemistry of 5 and 6 and shed new light into the post-polyketide synthase steps for 10 biosynthesis.

The dorrigocins are unique glutarimide antibiotics which were found to reverse the morphology of ras-transformed NIH/3T3 cells from a transformed phenotype to a normal one. The compounds also inhibited the release of yeast mating pheromone, a-factor. The activity of these compounds was not dependent on inhibition of prenylation or protein synthesis. Dorrigocin A was instead found to inhibit the carboxyl methylation in K-ras transformed cells.

Streptomyces platensis (strain NRRL 18993), a producer of dorrigocins, was shown to produce migrastatin, a cyclic congener of dorrigocin A previously reported from a different organism. Additionally a new compound isomeric to migrastatin, isomigrastatin, was also isolated and its structure was determined to be a cyclic form of dorrigocin B. Both compounds were fully characterized from MS and NMR data. Product titers of both were improved by the addition of XAD-16 resin to the fermentation medium.