Issue 8, 2010
From the journal:

Organic & Biomolecular Chemistry

Synthesis of the first spacer containing prodrug of a duocarmycin analogue and determination of its biological activity†‡

Heiko J. Schuster,a   Birgit Krewer,a   J. Marian von Hof,a   Kianga Schmuck,a   Ingrid Schuberth,a   Frauke Alvesb  and  Lutz F. Tietze*a  

* Corresponding authors

a Institut for Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstrasse 2, Göttingen, Germany
E-mail: ltietze@gwdg.de
Fax: +49(0)551-399476

b Centre of Internal Medicine, Department of Haematology and Oncology of the Georg-August-University of Göttingen, Robert-Koch-Straße 40, Göttingen, Germany

Abstract

The synthesis of the first spacer containing, duocarmycin analogue prodrug 11 was realised, its biological properties evaluated and compared to its counterpart prodrug 2 without a spacer unit. The synthesis comprises the manufacture of the new acetylated derivatives 19 and 20b of two double spacer systems, their activation and coupling to the pharmacophoric seco-drug (+)-3. Unprecedented biological results were found as the new prodrug 11 showed a fairly low QIC50 value of 20, but on the other hand a high stability and very low DNA alkylation efficiency. These findings indicate a changed cytostatic mode of action induced by the self-immolative spacer moiety which was employed.

Graphical abstract: Synthesis of the first spacer containing prodrug of a duocarmycin analogue and determination of its biological activity

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Article information

DOI
https://doi.org/10.1039/B925070K
Article type
Paper
Submitted
30 Nov 2009
Accepted
26 Jan 2010
First published
17 Feb 2010

Org. Biomol. Chem., 2010,8, 1833-1842

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Synthesis of the first spacer containing prodrug of a duocarmycin analogue and determination of its biological activity

H. J. Schuster, B. Krewer, J. M. von Hof, K. Schmuck, I. Schuberth, F. Alves and L. F. Tietze, Org. Biomol. Chem., 2010, 8, 1833 DOI: 10.1039/B925070K

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