The biochemical pharmacology of nogalamycin and its derivatives

Li, Li H.; Krueger, William C.

doi:10.1016/0163-7258(91)90080-6

Cited by 28 publications

(16 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8 A variety of physicochemical and biochemical techniques have been used to study the structures and sequence selectivity of daunomycin and nogalamycin complexes with duplex DNA. 1,9 The sequence selectivity of daunomycin is more complex than that of simple intercalators owing to the presence of the daunosamine sugar. CpG, GpC and CpA have been suggested as preferred sites for daunomycin.…”

mentioning

confidence: 99%

“…1,2 Daunomycin has found widespread clinical use in the treatment of acute leukaemia, and, recently, efficacy in the treatment of non-small cell lung carcinoma and Kaposi's sarcoma has been suggested. 3,4 The precise mechanism(s) underlying antitumour activity are not known, but anthracycline antibiotics have been shown to interact with proteins such as DNA topoisomerases, and to crosslink DNA.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Observation of daunomycin and nogalamycin complexes with duplex DNA using electrospray ionisation mass spectrometry

Kapur¹,

Beck²,

Sheil³

1999

Rapid Commun. Mass Spectrom.

View full text Add to dashboard Cite

The noncovalent binding of the antitumour drugs daunomycin and nogalamycin to duplex DNA has been studied using electrospray ionisation mass spectrometry (ESI-MS). The conditions for the preparation of drug/duplex DNA complexes and for their detection by ESI-MS have been optimised. Ions corresponding to these complexes were most abundant relative to free DNA when prepared in the pH range 8-9, and using gentle ESI interface conditions. Self-complementary oligonucleotides, 5'-d(GGCTAGCC)-3' or 5'-d(CGGCGCCG)-3', annealed in the presence of a 5-fold molar excess of either nogalamycin or daunomycin gave ESI mass spectra in which the most intense ions corresponded to three molecules of drug bound to duplex DNA, with some evidence for four drug molecules bound. For binding to 5'-d(TGAGCTAGCTCA)(2)-3', complexes containing up to four nogalamycin and six daunomycin molecules were observed. These data are consistent with the neighbour exclusion principle whereby intercalation occurs between every other base pair such that up to four bound drugs would be expected for the 8 mers and up to six for the 12 mer. Competition experiments involving a single drug in an equimolar mixture of two oligonucleotides (5'-d(TGAGCTAGCTCA)(2)-3' with either 5'-d(CGGCGCCG)(2)-3' or 5'-d(GGCTAGCC)(2)-3') showed ions arising from complexes of drug/5'-d(CGGCGCCG)(2)-3' were more intense than complexes of drug/5'-d(GGCTAGCC)(2)-3', relative to those from the 12 mer in each mixture. While this suggests ESI-MS has the potential to detect differences in sequence selectivity, more detailed experiments involving a comparison of the relative ionisation efficiency of different oligonucleotides and a wider range of intercalators are required to establish this definitively. ESI mass spectra from experiments in which both drugs were reacted with the same oligonucleotide were more complex, such that a clear preference for one drug could not be established.

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Observation of daunomycin and nogalamycin complexes with duplex DNA using electrospray ionisation mass spectrometry

Kapur¹,

Beck²,

Sheil³

1999

Rapid Commun. Mass Spectrom.

View full text Add to dashboard Cite

show abstract

“…1) has a particularly interesting chemical structure (5) because one of the carbohydrate units of the molecule, nogalamine, is attached both via a carboncarbon bond and a classical O-glycosidic linkage to the aglycone. The progress of 1 to clinical trials was prevented by unacceptable toxicity (6), but the compound was further developed into a semisynthetic analog, menogaril (7), which improved the original anticancer activity while diminishing the severe acute toxicity (6). Subsequently, menogaril has received favorable recommendations for further studies in phase II clinical trials (8).…”

mentioning

confidence: 99%

Divergent non-heme iron enzymes in the nogalamycin biosynthetic pathway

Siitonen

Selvaraj

Niiranen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Nogalamycin, an aromatic polyketide displaying high cytotoxicity, has a unique structure, with one of the carbohydrate units covalently attached to the aglycone via an additional carbon-carbon bond. The underlying chemistry, which implies a particularly challenging reaction requiring activation of an aliphatic carbon atom, has remained enigmatic. Here, we show that the unusual C5′′-C2 carbocyclization is catalyzed by the non-heme iron α-ketoglutarate (α-KG)-dependent SnoK in the biosynthesis of the anthracycline nogalamycin. The data are consistent with a mechanistic proposal whereby the Fe(IV) = O center abstracts the H5′′ atom from the amino sugar of the substrate, with subsequent attack of the aromatic C2 carbon on the radical center. We further show that, in the same metabolic pathway, the homologous SnoN (38% sequence identity) catalyzes an epimerization step at the adjacent C4′′ carbon, most likely via a radical mechanism involving the Fe(IV) = O center. SnoK and SnoN have surprisingly similar active site architectures considering the markedly different chemistries catalyzed by the enzymes. Structural studies reveal that the differences are achieved by minor changes in the alignment of the substrates in front of the reactive ferryl-oxo species. Our findings significantly expand the repertoire of reactions reported for this important protein family and provide an illustrative example of enzyme evolution.natural product biosynthesis | Streptomyces | crystal structure | α-ketoglutarate-dependent oxygenase | iron-dependent oxygenase

show abstract

“…Actinomycin D is a monofunctional intercalating agent which places bulky cyclic peptides in the DNA minor groove, chromomycin is a minor groove binding agent (Yang et al, 1999) and nogalamycin is a monofunctional threading agent which intercalates with its nogalose sugar lying in the minor groove and its bicyclic amino sugar spearing the duplex making hydrogen bonding interactions with guanines in the major groove (Li and Krueger, 1991). All are known to bind selectively to GC-rich sequences and block RNA polymerase progression by placing a bulky group in the DNA minor groove.…”

Section: Cytotoxicity Of Novel and Established Transcription Inhibitomentioning

confidence: 99%

Considerations for Treatment Development in Rhabdomyosarcoma: In Vitro Assessment of Novel DNA Binding Drugs

Wolf¹,

Wakelin²,

Catchpoole³

2011

Soft Tissue Tumors

View full text Add to dashboard Cite

The biochemical pharmacology of nogalamycin and its derivatives

Cited by 28 publications

References 56 publications

Observation of daunomycin and nogalamycin complexes with duplex DNA using electrospray ionisation mass spectrometry

Observation of daunomycin and nogalamycin complexes with duplex DNA using electrospray ionisation mass spectrometry

Divergent non-heme iron enzymes in the nogalamycin biosynthetic pathway

Considerations for Treatment Development in Rhabdomyosarcoma: In Vitro Assessment of Novel DNA Binding Drugs

Contact Info

Product

Resources

About