Aldolase Antibody Activation of Prodrugs of Potent Aldehyde-Containing Cytotoxics for Selective Chemotherapy

Prodrugs of potent aldehyde analogues of the anticancer drug doxorubicin (Dox) were synthesized. These prodrugs were efficiently activated by antibody 93F3 and no drug formation was observed in the absence of 93F3 in either phosphate buffered saline or cell culture media. In the presence of antibody...

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Bibliographic Details
Published in:Chemistry : a European journal 2004-10, Vol.10 (21), p.5467-5472
Main Authors: Sinha, Subhash C., Li, Lian-Sheng, Watanabe, Shin-ichi, Kaltgrad, Eiton, Tanaka, Fujie, Rader, Christoph, Lerner, Richard A., Barbas III, Carlos F.
Format: Article
Language:English
Subjects:
Aldehydes - chemistry
aldolase
Antibiotics, Antineoplastic - chemical synthesis
Antibiotics, Antineoplastic - chemistry
Antibiotics, Antineoplastic - pharmacology
antibodies
Antibodies, Catalytic - chemistry
Cell Line, Tumor
Cell Proliferation - drug effects
chemotherapy
doxorubicin
Doxorubicin - analogs & derivatives
Doxorubicin - chemistry
Doxorubicin - pharmacology
Fructose-Bisphosphate Aldolase - chemistry
Humans
Immunoglobulin Fab Fragments - chemistry
Neoplasms - drug therapy
Neoplasms - pathology
prodrugs
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacology
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Summary:Prodrugs of potent aldehyde analogues of the anticancer drug doxorubicin (Dox) were synthesized. These prodrugs were efficiently activated by antibody 93F3 and no drug formation was observed in the absence of 93F3 in either phosphate buffered saline or cell culture media. In the presence of antibody 93F3, these prodrugs were activated and decreased the proliferation of human cancer cells in in vitro proliferation assays. Selective activation of the prodrugs by using antibody 93F3 (see scheme) affords the active iminium drugs via the corresponding aldehyde intermediates. The iminium drugs inhibit the cell proliferation of various cancer cell lines, including Kaposi's sarcoma (SLK) and breast cancer (MDA‐MB‐435) cell lines.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.200400419