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

• 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
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200400419

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.