Toxins 2009, 1(2), 134-150; doi:10.3390/toxins1020134
Article

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

Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
* Author to whom correspondence should be addressed.
Received: 3 November 2009; in revised form: 28 November 2009 / Accepted: 1 December 2009 / Published: 2 December 2009
(This article belongs to the Special Issue Feature Papers)
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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.
Keywords: ADEPT; anticancer agents; cancer therapy; CC-1065; cytotoxicity; DNA alkylation; duocarmycins; electrospray mass spectrometry; HPLC; oligonucleotides; structure activity relationship

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MDPI and ACS Style

Tietze, L.F.; Krewer, B.; Von Hof, J.M.; Frauendorf, H.; Schuberth, I. Determination of the Biological Activity and Structure Activity Relationships of Drugs Based on the Highly Cytotoxic Duocarmycins and CC-1065. Toxins 2009, 1, 134-150.

AMA Style

Tietze LF, Krewer B, Von Hof JM, Frauendorf H, Schuberth I. Determination of the Biological Activity and Structure Activity Relationships of Drugs Based on the Highly Cytotoxic Duocarmycins and CC-1065. Toxins. 2009; 1(2):134-150.

Chicago/Turabian Style

Tietze, Lutz F.; Krewer, Birgit; Von Hof, J. Marian; Frauendorf, Holm; Schuberth, Ingrid. 2009. "Determination of the Biological Activity and Structure Activity Relationships of Drugs Based on the Highly Cytotoxic Duocarmycins and CC-1065." Toxins 1, no. 2: 134-150.

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