Abstract
New prodrugs of daunorubicin, 1c, 1e and 2c, including a galactopyranosyl residue linked to the N-3' of the daunosaminyl moiety through substituted o- or p-benzyloxycarbonyl groups were synthesized. Their low cytotoxicity and high stability in plasma fulfil the conditions for antibody-directed enzyme prodrug therapy (ADEPT). Enzymatic hydrolysis using alpha-D-galactosidase gives rise to daunorubicin by subsequent self-elimination of the spacers. However, elimination clearly depends on the aromatic substitution pattern, as demonstrated especially by comparison with non-substituted analogues.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antibodies, Monoclonal / chemistry
-
Antibodies, Monoclonal / therapeutic use
-
Antibodies, Monoclonal / toxicity
-
Daunorubicin / administration & dosage
-
Daunorubicin / analogs & derivatives*
-
Daunorubicin / therapeutic use*
-
Drug Stability
-
Enzyme Therapy*
-
Humans
-
Immunotoxins / blood
-
Immunotoxins / chemistry*
-
Immunotoxins / toxicity
-
Mice
-
Phenols / blood
-
Phenols / chemical synthesis
-
Phenols / toxicity
-
Prodrugs / chemical synthesis
-
Prodrugs / therapeutic use*
-
Structure-Activity Relationship
-
alpha-Galactosidase / metabolism
Substances
-
Antibodies, Monoclonal
-
Immunotoxins
-
Phenols
-
Prodrugs
-
alpha-Galactosidase
-
Daunorubicin