Prodrugs of anthracyclines for chemotherapy via enzyme-monoclonal antibody conjugates.
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.
Gesson
J P
JP
Laboratoire de Chimie XII, Poitiers, France.
Jacquesy
J C
JC
Mondon
M
M
Petit
P
P
Renoux
B
B
Andrianomenjanahary
S
S
Dufat-Trinh Van
H
H
Koch
M
M
Michel
S
S
Tillequin
F
F
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D003630:Daunorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004355:Drug Stability; D057487:Enzyme Therapy; D006801:Humans; D000922:Immunotoxins / Q000097:blood / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D010636:Phenols / Q000097:blood / Q000138:chemical synthesis / Q000633:toxicity; D011355:Prodrugs / Q000138:chemical synthesis / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D000519:alpha-Galactosidase / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D010636:Phenols; D011355:Prodrugs; D000519:alpha-Galactosidase; D003630:Daunorubicin