Revised Structures for the Kinamycin Antibiotics: 5-Diazobenzo[b]fluorenes Rather Than Benzo[b]carbazole Cyanamides

Gould, Steven J.; Tamayo, Nuria; Melville, Chris R.; Cone, Martha C.

doi:10.1021/ja00084a096

Cited by 119 publications

(72 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For the biosynthetic sequence leading to landomycin A in So cyanogenus it is assumed that either the disaccharide oliv-oliv is formed prior to its glycosylation or, more likely, that the glycosylation steps which transfer a D-olivose moiety are much faster than the glycosyltransfers with L-rhodinose. Interesting oxygenases are important biosynthetic enzymes for the formation of the kinamycins [3,177,178,183,199,225] and the jadomycins [195,196,197,200]. Both biosyntheses involve an angucyclinone intermediate (257) that undergoes, in a key step, an oxidative ring B fission (presumably into 285) before decarboxylation, ring closure and a condensation reaction with molecular nitrogen (or hydrazine, or transamination and subsequent reaction with NO.…”

Section: Gene Clusters Of the Biosynthesis Of Angucyclin(on)es And Stmentioning

confidence: 99%

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

Krohn

Rohr

1997

Topics in Current Chemistry

182

148

View full text Add to dashboard Cite

General and recent aspects of chemical syntheses on angucyclinones and selected related natural products are summarized here. In the first part of this review on angucyclines, the chemical reaction used as a key step for the construction of the angucyclinone frame is discussed. In the second part, new members of the angucycline group of antibiotics, their bioactivity and recent biosynthetic studies including modern aspects of molecular biology (genetics) are reviewed.

show abstract

Section: Gene Clusters Of the Biosynthesis Of Angucyclin(on)es And Stmentioning

confidence: 99%

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

Krohn

Rohr

1997

Topics in Current Chemistry

182

148

View full text Add to dashboard Cite

show abstract

“…The kinamycins were initially assigned an N-cyanocarbazole structure. However, we [4] and another group [5] independently determined that the structures assigned to the kinamycins were incorrect and that the kinamycins are in fact derivatives of diazobenzo [b]fluorene, rather than of N-cyanobenzo [b]carbazole. The novel antitumor antibiotic lomaiviticin A isolated from a marine actinomycete named Micromonospora lomaivitiensis has also recently been found to be extraordinarily potent (low picomolar IC 50 values) against the modified NCI 24-cancer cell line panel [6].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

O’Hara

Patel

et al. 2007

Free Radical Biology and Medicine

View full text Add to dashboard Cite

The bacterial metabolite kinamycin F, which is being investigated as a potent antitumor agent, contains an unusual and potentially reactive diazo group as well as a paraquinone and a phenol functional group. Kinamycin F reacted with glutathione (GSH) in a complex series of reactions which suggested that kinamycin F may have its cytotoxicity modulated by GSH. Consistent with this idea 2-oxo-4-thiazolidinecarboxylic acid treatment to increase cellular GSH levels and buthionine sulfoximine treatment to decrease GSH levels resulted in decreased and increased kinamycin F cytotoxicity, respectively, in K562 leukemia cells. Kinamycin F weakly bound to DNA and induced DNA damage in K562 cells that was independent of GSH levels. The GSH-promoted DNA nicking induced by kinamycin F in vitro was attenuated by deferoxamine, dimethyl sulfoxide, and by catalase, which indicated that DNA damage initiated by this agent occurred in an iron-, hydrogen peroxideand hydroxyl radical-dependent manner. Electron paramagnetic resonance spectroscopy experiments showed that the GSH/kinamycin F system produced a semiquinone free radical and that the hydrogen peroxide/peroxidase/kinamycin F system generated a phenoxyl free radical. In conclusion, the results indicated that kinamycin F cytotoxicity may be due to reductive and/or peroxidative activation to produce DNA-and protein-damaging species.

show abstract

“…Streptomyces strain WP 4669 produces an angucyclinone, PD 116740, which has activity against L1210 lymphocytic leukemia and HCT-8 colon adenocarcinoma cell lines (47). We have studied the biosynthesis of a number of angucyclinonederived metabolites (15,16,43), including PD 116740 (14). In these pathways, either dehydrorabelomycin (27,43) or TET (13,26), plays a key role (Fig.…”

mentioning

confidence: 99%

Cloning and heterologous expression of the entire gene clusters for PD 116740 from Streptomyces strain WP 4669 and tetrangulol and tetrangomycin from Streptomyces rimosus NRRL 3016

1997

View full text Add to dashboard Cite

The genes for the complete pathways for two polycyclic aromatic polyketides of the angucyclinone class have been cloned and heterologously expressed. Genomic DNAs of Streptomyces rimosus NRRL 3016 and Streptomyces strain WP 4669 were partially digested with MboI, and libraries (ca. 40-kb fragments) in Escherichia coli XL1-Blue MR were prepared with the cosmid vector pOJ446. Hybridization with the actI probe from the actinorhodin polyketide synthase genes identified two clusters of polyketide genes from each organism. After transfer of the four clusters to Streptomyces lividans TK24, expression of one cluster from each organism was established through the identification of pathway-specific products by high-performance liquid chromatography with photodiode array detection. Peaks were identified from the S. rimosus cluster (pks RIM-1 ) for tetrangulol, tetrangomycin, and fridamycin E. Peaks were identified from the WP 4669 cluster (pks WP-2 ) for tetrangulol, 19-hydroxytetrangulol, 8-O-methyltetrangulol, 19-hydroxy-8-O-methyltetrangulol, and PD 116740. Structures were confirmed by 1 H nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.Members of the genus Streptomyces produce well over half of the known antibiotics of natural origin. Of these, polyketidederived metabolites are among the most numerous and diverse and include many clinically important members, such as erythromycin, tetracycline, and doxorubicin. Assembly of the skeletons of such compounds by oligomerization of small precursor fatty acid thioesters to form polyketide backbones is carried out by polyketide synthases (PKSs). These are made up of either large multifunctional enzymes (type I PKSs) or multienzyme complexes (type II PKSs). Molecular genetic analyses have revealed that the genes for each PKS are clustered in a relatively small region of DNA (22). The gene clusters for numerous polyketide pathways have been detected by hybridization with probes derived from genes coding for proteins that catalyze equivalent reactions in different pathways (25,29).Angucyclinones, a name recently given to naturally occurring benz [a]anthraquinones, are a rapidly growing group of polyketide natural products, involving many bioactive compounds (41). They are now the largest class of known aromatic decaketides. Two angucyclinones-tetrangulol (TET) and tetrangomycin-had been isolated from Streptomyces rimosus and were the first identified members of this class of antibiotics (26). Streptomyces strain WP 4669 produces an angucyclinone, PD 116740, which has activity against L1210 lymphocytic leukemia and HCT-8 colon adenocarcinoma cell lines (47). We have studied the biosynthesis of a number of angucyclinonederived metabolites (15, 16, 43), including PD 116740 (14). In these pathways, either dehydrorabelomycin (27, 43) or TET (13, 26), plays a key role (Fig. 1). These studies have revealed that the polyketide assembly common to both of these diverges at a prearomatic stage with an additional ketone reduction (at C-6) leading to TET. We have...

show abstract

Revised Structures for the Kinamycin Antibiotics: 5-Diazobenzo[b]fluorenes Rather Than Benzo[b]carbazole Cyanamides

Cited by 119 publications

References 0 publications

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

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

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

Cloning and heterologous expression of the entire gene clusters for PD 116740 from Streptomyces strain WP 4669 and tetrangulol and tetrangomycin from Streptomyces rimosus NRRL 3016

Contact Info

Product

Resources

About