Streptonigrin biosynthesis. 7. Incorporation of oxygen from oxygen-18: evidence for an oxidative .beta.-carboline cleavage

Abstract

Some years ago we reported results2 on the biosynthesis of streptonigrin (1), a potent anticancer antibiotic obtained from Streptomyces flocculus, which indicated that the 4-phenylpicolinic acid moiety was derived by cleavage of a /3-carboline intermediate. Two mechanisms were presented, illustrative of chemically rational possibilities, that involved oxidation of the D ring. In one the C-8' phenolic oxygen was derived from 02 while in the other it was derived from H20. Subsequently, we characterized lavendamycin, 2,3 from S. lavendulae, clearly a member of the streptonigrin family, and containing the putative /3-carboline moiety. Recently, Rickards et al.4,5 reported the structure of streptonigrone (3) and proposed a third mechanism for the /3-carboline cleavage that was formally nonoxidative and involved a covalent hydration6 at C-8' followed by a 1,6-elimination of the original indole nitrogen. By this mechanism the C-8' phenolic oxygen would be derived from H20. This paper prompts us to report data that clearly indicate the oxygen in question is derived from molecular oxygen rather than from water.A seed culture of S. flocculus was prepared7 and used to inoculate four production broths7 (250 mL in 1-L Erlenmeyer flasks). These were connected in series via two sterile filters to a closed system containing a burette which was refillable with 1802 4 gas (50% enriched, obtained from Cambridge Isotopes, Inc.), a small aquarium pump, and a C02 trap (aqueous KOH). Air was

Angucyclines: Total syntheses, new structures, and biosynthetic studies of an emerging new class of antibiotics

“…The 1sO label may be washed out in the aqueous fermentation medium via the hydrate. For instance, expected labels in one or the other feeding experiment were decreased in the 7-position of dehydrorabelomycin (257) and could neither be detected at the 12-position in urdamycinone A (4, aquayamycin), emycin A and in ochromycinone (35), nor in the 7-or 12-positions of PD 116740 (279) and PD 116198 (218, see below) [54,96,157,159,204,206,213,214].…”

Novel Lavendamycin Analogues as Antitumor Agents: Synthesis, in Vitro Cytotoxicity, Structure−Metabolism, and Computational Molecular Modeling Studies with NAD(P)H:Quinone Oxidoreductase 1

“…25,27 Lavendamycin (1a), a bacterially derived quinolinedione antibiotic, was isolated from the fermentation broth of Streptomyces lavendulae in 1981. 29 Lavendamycin is structurally 29,30 and biosynthetically [31][32][33] related to streptonigrin (SN) (2), another potent 7-aminoquinoline-5,8-dione antitumor antibiotic. Earlier work has shown that the use of both of these antitumor agents as potential drugs has been precluded due to their high degree of toxicity.…”

“…Lavendamycin ( 1a ), a bacterially derived quinolinedione antibiotic, was isolated from the fermentation broth of Streptomyces lavendulae in 1981 . Lavendamycin is structurally , and biosynthetically − related to streptonigrin (SN) ( 2 ), another potent 7-aminoquinoline-5,8-dione antitumor antibiotic. Earlier work has shown that the use of both of these antitumor agents as potential drugs has been precluded due to their high degree of toxicity. ,, However, in contrast to the parent compound, we have found that a significant number of lavendamycin derivatives have low animal toxicity but show strong antitumor activity or are potent inhibitors of the HIV-reverse transcriptase. − These studies have been possible only through our success in developing short and efficient syntheses for a variety of lavendamycin analogues possessing the full pentacyclic structure.…”

Incorporation of Two Oxygens from 18O2 in the Epoxyquinone from the Dihydroxyacetanilide Epoxidase Reaction: Evidence for a Dioxygenase Mechanism

“…We had previously observed that the ketone carbonyl of 1 undergoes rapid exchange with water, and have observed partial and complete , washout of 18 O-labels from quinone carbonyls that had initially been biosynthetically labeled by 18 O 2 during in vivo feeding studies. It was thus necessary to determine the integrity of the quinone carbonyls of 3 .…”