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J Pept Sci. 2009 Mar;15(3):235-41. doi: 10.1002/psc.1108.

Inverse-electron-demand Diels-Alder reaction as a highly efficient chemoselective ligation procedure: synthesis and function of a BioShuttle for temozolomide transport into prostate cancer cells.

Author information

1
German Cancer Research Center, Peptide Synthesis Unit, INF 580, 69120 Heidelberg, Germany. r.pipkorn@dkfz.de

Abstract

Hormone-refractory prostate cancer (HRPC), insensitive to most cytostatic interventions, features low response rates and bad prognosis. Studies with HRPC treated with temozolomide (TMZ) showed a poor response and the results were discouraging. Therefore, TMZ has been considered to be ineffective for the treatment of patients with symptomatic and progressive HRPC. A solution to this problem is demonstrated in this study by combining proper solid-phase peptide synthesis and a chemoselective new 'click' chemistry based on the Diels-Alder reaction with 'inverse-electron-demand' (DAR(inv)) for the construction of a highly efficient TMZ-BioShuttle in which TMZ is ligated to transporter and subcellular address molecules. The transport to the targeted nuclei resulted in much higher efficiency and better pharmacological effects. The reformulation of TMZ to TMZ-BioShuttle achieved higher in vitro killing of prostate cancer cells. Accordingly, the potential of TMZ for the treatment of prostate tumors was dramatically enhanced even in a tenfold lower concentration than applied normally. This TMZ-BioShuttle may be well suited for combining chemotherapy with other cytostatic agents or radiation therapy.

PMID:
19177421
DOI:
10.1002/psc.1108
[Indexed for MEDLINE]

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