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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(s) -
Pipkorn Rüdiger,
Waldeck Waldemar,
Didinger Bernd,
Koch Mario,
Mueller Gabriele,
Wiessler Manfred,
Braun Klaus
Publication year - 2009
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.1108
Subject(s) - temozolomide , prostate cancer , cancer research , chemotherapy , chemistry , medicine , pharmacology , oncology , cancer
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. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.