Dorrigocins: Novel antifungal antibiotics that change the morphology of ras-transformed NIH/3T3 cells to that of normal cells. II. Isolation and elucidation of structures.

Abstract

Two novel antifungal antibiotics, named dorrigocin A and B have been isolated fermentation broth and myceliumof Streptomyces platensis subsp. rosaceus. These close compoundswere separated from one another by countercurrent chromatographyon ai planet centrifuge. The structures of the dorrigocins were determined by NMRand IR spe and mass spectrometry. Each is a putative propionate -acetate derived straight chain terminating in cycloheximide. The dorrigocins differ from one another only in their oxidatioIn the course of screening for antifungal antibiotics, two novel glutarimide compoundsdesignated dorrigocin A (1) and B (2) were isolated from Streptomyces platensis subsp. rosaceus. These antibiotics are most closely related to the recently described glutarimide antibiotic BU-4146T(3)1}. This paper will describe the isolation and separation of the dorrigocins and the elucidation of their structures. Two companion papers2'3) describe the isolation, identification and fermentation of the producing culture and a biological evaluation of the dorrigocins. Isolation of the Dorrigocins Upon completion of fermentation, 30 liters of whole broth was treated with XAD-16(3 liters) which was washed with water and eluted with methanol (12liters). The methanol eluate was concentrated to dryness and triturated sequentially with 1 liter portions of; ethyl acetate, methanol, and water. The methanol soluble material was partitioned between hexane, ethyl acetate, methanol and water (0.2 liters of each).The lower layer from this partition was concentrated to dryness and chromatographed over a Sephadex LH-20 column developed with methanol. Active fractions from this column were combined and concentrated to a pale oil. This oil was subjected to countercurrent chromatography on an Ito multilayered coil planet centrifuge in a solvent system of chloroform-methanol-water (1 : 1 : 1) with the lower layer stationary.Active fractions from this columnwere combinedand concentrated to an oil. This oil was subjected to countercurrent chromatography on an Ito multi-layered coil planet centrifuge

Challenges and opportunities for natural product discovery, production, and engineering in native producers versus heterologous hosts

“…Dorrigocins A and B, first isolated in 1994 from Streptomyces platensis subsp. rosaceus strain AB1981F-75 to inhibit a carboxyl methyltransferase involved in cellular signal transduction via processing of Ras-related proteins [18,22], belong to the glutarimidecontaining polyketide family of natural products. Other members of this family of natural products include migrastatin (MGS), isolated from Streptomyces sp.…”

A Long‐Range Acting Dehydratase Domain as the Missing Link for C17‐Dehydration in Iso‐Migrastatin Biosynthesis

“…Members of this family feature varying oxidation states such as lactimidomycin (LTM, 2 ), different polyketide chain lengths as exemplified by streptimidone ( 3 ), 9‐methylstreptimidone ( 4 ), and cycloheximide ( 5 ), an enlarged 14‐membered macrolide like migrastatin (MGS, 6 ), and acyclic dorrigocin‐type polyketides (e.g. dorrigocin A, 7 ) (Figure ). While 1 , 6 , and 7 were originally isolated from the same S. platensis NRRL 18993 strain independently, it was subsequently established that 6 and 7 resulted from 1 , via a H 2 O‐mediated ring expansion and ring‐opening rearrangement, respectively, revealing a common biosynthetic origin for iso‐MGS, MGS, and the dorrigocins…”

“…dorrigocin A, 7 ) (Figure ). While 1 , 6 , and 7 were originally isolated from the same S. platensis NRRL 18993 strain independently, it was subsequently established that 6 and 7 resulted from 1 , via a H 2 O‐mediated ring expansion and ring‐opening rearrangement, respectively, revealing a common biosynthetic origin for iso‐MGS, MGS, and the dorrigocins…”

Natural Product Inspired Topology Directed Synthesis of Hybrid Macrocyclic Compounds: A Simple Approach to Natural Product Analogues

“…MK929‐43F1 and revealed its structure as a 14‐membered macrolide with a glutarimide side chain –. Karwowski and co‐workers first isolated Dorrigocin A ( 10 ) and Dorrigacin B ( 12 ) from S. platensis NRRL18993 ,. Migrastatin ( 7 ) is a shunt metabolite of isomigrastatin ( 8 ) (Figure ), Isomigrastatin transforms into migrastatin by a strain relief driven [3, 3]‐sigmatropic rearrangement that does not need any enzyme catalysis ,.…”