New mustard prodrugs for antibody-directed enzyme prodrug therapy: alternatives to the amide link.
Antibody-directed enzyme prodrug therapy (ADEPT) is a two-step approach for the treatment of cancer which seeks to generate a potent cytotoxic agent selectively at a tumor site. In this work described the cytotoxic agent is generated by the action of an enzyme CPG2 on a relatively nontoxic prodrug. The prodrug 1 currently on clinical trial is a benzamide and is cleaved by CPG2 to a benzoic acid mustard drug 1a. We have synthesized a series of new prodrugs 3-8 where the benzamide link has been replaced by, for example, carbamate or ureido. Some of these alternative links have been shown to be good substrates for CPG2 and therefore new candidates for ADEPT. The active drugs 3a and 4a derived from the best of these prodrugs are potent cytotoxic agents (1-2 microM) some 100 times more than 1a. The prodrugs 3 and 4 are some 100-200-fold less cytotoxic, in a proliferating cell assay, than their corresponding active drugs 3a and 4a.
Dowell
R I
RI
Cancer Research Department, Zeneca Pharmaceutical, Cheshire, U.K.
Springer
C J
CJ
Davies
D H
DH
Hadley
E M
EM
Burke
P J
PJ
Boyle
F T
FT
Melton
R G
RG
Connors
T A
TA
Blakey
D C
DC
Mauger
A B
AB
D000816:Aniline Mustard / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology; D006801:Humans; D000922:Immunotoxins; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis*; D014407:Tumor Cells, Cultured; D011623:gamma-Glutamyl Hydrolase / Q000378:metabolism*
C096843:(4-(N,N-bis(2-chloroethyl)amino)phenoxycarbonyl)glutamic acid; D000970:Antineoplastic Agents; D000922:Immunotoxins; C098659:N-((4-(N,N-bis(chloroethyl)amino)phenyl)carbamoyl)glutamic acid; D011355:Prodrugs; D000816:Aniline Mustard; D011623:gamma-Glutamyl Hydrolase