%0 Journal Article
%T Determination of the Biological Activity and Structure Activity Relationships of Drugs Based on the Highly Cytotoxic Duocarmycins and CC-1065
%A Lutz F. Tietze
%A Birgit Krewer
%A J. Marian Von Hof
%A Holm Frauendorf
%A Ingrid Schuberth
%J Toxins
%D 2009
%I MDPI AG
%R 10.3390/toxins1020134
%X 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.
%K ADEPT
%K anticancer agents
%K cancer therapy
%K CC-1065
%K cytotoxicity
%K DNA alkylation
%K duocarmycins
%K electrospray mass spectrometry
%K HPLC
%K oligonucleotides
%K structure activity relationship
%U http://www.mdpi.com/2072-6651/1/2/134