New Cyanocyclines from a Cyanide-Treated Broth of Streptomyces lusitanus

Abstract

Organic extracts of Streptomyces lusitanus, the producer of the anticancer antibiotic naphthyridinomycin [1], were found to contain two additional compounds active in an antibiotic screen. As with 1, these reacted with NaCN added at the end of the fermentation. One of the addition products has been named cyanocycline B [3] and is derived from N-desmethylnaphthyridinomycin [4], while the other has been named cyanocycline C [5], and is derived from the hydroquinone 6 of 1. Cyanocycline C is unstable and was characterized after conversion to the dimethyl derivative with CH2N2 in the presence of TFA. The implications of these metabolites for the biosynthesis of 1 are discussed. A third new antibiotic, cyanocycline D [8] was isolated from the cyanide-treated broth and proved to be an artifact in which the oxazolidine ring had been opened by cyanide. The potential relevance of the formation of 8 to the reaction of 1 with DNA is also discussed.

Biosynthesis of the angiogenesis inhibitor borrelidin by Streptomyces parvulus Tü4055: insights into nitrile formation†

“…Among the actinomycetes, several nitrile‐containing compounds with different chemical structures have been isolated. Saframycin A, cyanocycline A and Dnacin A1 are heterocyclic quinone compounds produced by Streptomyces lavendulae , Streptomyces lusitanus and Actinosynnema pretiosum respectively (Arai et al ., 1980; Hayashi et al ., 1983; Gould et al ., 1993; Hida et al ., 1994). All these compounds exhibit antibiotic and antitumour activities.…”

“…For the microbial metabolites saframycin A and cyanocycline A, biosynthesis most probably takes place through a different pathway as their production was increased in certain fermentation experiments through the addition of sodium cyanide to the culture medium (Arai et al ., 1980; Gould et al ., 1993). It is unclear whether these strains biosynthesize cyanide de novo , or whether they sequester it from their environment.…”

Recent progress in the total synthesis of naphthyridinomycin and lemonomycin tetrahydroisoquinoline antitumor antibiotics (TAAs)

“…10 In 1993, Gould and co-workers isolated three other TAAs from the fermentation broth of Streptomyces lusitanus. 11 These highly unstable alkaloids were derivatized by cyanation to furnish the new stable cyanocyclines B (5) and C (7), along with cyanocycline D (9). Their original structures were assigned to be 6 and 8, respectively (Fig.…”

“…If guanine is replaced by inosine, no significant alkylation takes place, leading to the assumption that naphthyridinomycin alkylates the primary amino group of guanine. 23 Whereas the biological activities of naphthyridinomycin and cyanocycline A are about equal, bioxalomycin a 2 (11) is extraordinarily effective against Gram-positive bacteria 12 (Table 1). Bioxalomycin a 2 shows cross-linking to duplex DNA by double alkylation of the N-2 of guanine, presumably at the C-7 and C-13b positions.…”

“…It was also shown that bioxalomycin a 2 (11), just like the TAAs quinocarcin and tetrazomine, spontaneously converts dioxygen to superoxide in a Cannizarro-like mechanism. In this respect, 11 is several orders of magnitude more effective than any other member of the TAA family, probably due to the presence of two oxazolidine moieties and the redox-labile hydroquinone ring.…”