Determination of the Biological Activity and Structure Activity Relationships of Drugs Based on the Highly Cytotoxic Duocarmycins and CC-1065

Determination of the Biological Activity and Structure Activity Relationships of Drugs Based on the Highly Cytotoxic Duocarmycins and CC-1065
Tietze, L. F.; Krewer, B.; von Hof, J. M.; Frauendorf, H. & Schuberth, I. (2009) 
Toxins1(2) pp. 134-150.​

Authors
Tietze, Lutz Friedjan; Krewer, Birgit; von Hof, J. Marian; Frauendorf, Holm; Schuberth, Ingrid
Issue Date
2009
Type
Journal Article
Abstract
The natural antibiotics CC-1065 and the duocarmycins are highly cytotoxic compounds which however are not suitable for cancer therapy due to their general toxicity. We have developed glycosidic prodrugs of seco-analogues of these antibiotics for a selective cancer therapy using conjugates of glycohydrolases and tumour-selective monoclonal antibodies for the liberation of the drugs from the prodrugs predominantly at the tumour site. For the determination of structure activity relationships of the different seco-drugs, experiments addressing their interaction with synthetic DNA were performed. Using electrospray mass spectrometry and high performance liquid chromatography, the experiments revealed a correlation of the stability of these drugs with their cytotoxicity in cell culture investigations. Furthermore, it was shown that the drugs bind to AT-rich regions of double-stranded DNA and the more cytotoxic drugs induce DNA fragmentation at room temperature in several of the selected DNA double-strands. Finally, an explanation for the very high cytotoxicity of CC-1065, the duocarmycins and analogous drugs is given.
Publisher
Mdpi Ag
Journal
Toxins 
ISSN
2072-6651
Publication of Göttingen University
Yes
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