Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy.
A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with beta-glucuronidase. As expected, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by a fusion protein which has been obtained from human beta-glucuronidase and humanized CEA-specific binding region. The six prodrugs are highly stable and are more than 100-fold less cytotoxic than doxorubicin against murine L1210 cell lines. The ortho-substituted phenyl carbamates 25a,b,c are better substrates for beta-glucuronidase than the corresponding para-substituted analogues. After taking into account additional factors such as stability in plasma and kinetics of enzymatic cleavage, we selected the o-nitro prodrug 25c for clinical trials.
Florent
J C
JC
UMR 176 CNRS/Institut Curie, Section Recherche, 26 rue d'Ulm, F-75248 Paris Cedex 05, France.
Dong
X
X
Gaudel
G
G
Mitaku
S
S
Monneret
C
C
Gesson
J P
JP
Jacquesy
J C
JC
Mondon
M
M
Renoux
B
B
Andrianomenjanahary
S
S
Michel
S
S
Koch
M
M
Tillequin
F
F
Gerken
M
M
Czech
J
J
Straub
R
R
Bosslet
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D003630:Daunorubicin / Q000737:chemistry* / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D004926:Escherichia coli / Q000201:enzymology; D005965:Glucuronates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005966:Glucuronidase / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000276:immunology; D007700:Kinetics; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D005965:Glucuronates; D007140:Immunoglobulin Fab Fragments; C114198:N-(4-glucuronyl-3-nitrobenzyloxycarbonyl)doxorubicin; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D004317:Doxorubicin; D005966:Glucuronidase; D003630:Daunorubicin