J Med Chem 1996 Apr 12;39(8):1736-47
Design, synthesis, and evaluation of latent alkylating agents activated by
glutathione S-transferase.
Satyam A, Hocker MD, Kane-Maguire KA, Morgan AS, Villar HO, Lyttle MH
Terrapin Technologies, Inc., South San Francisco, California 94080, USA.
In search of compounds with improved specificity for targeting the important cancer-associated
P1-1 glutathione S-transferase (GST) isozyme, new analogs 4 and 5 of the previously reported
glutathione S-transferase (GST)-activated latent alkylating agent
gamma-glutamyl-alpha-amino-beta-[[[2-[[bis[bis(2-chloroethyl)amino]ph osp
horyl]oxy]ethyl]sulfonyl]propionyl]-(R)-(-)-phenylglycine (3) have been designed, synthesized,
and evaluated. One of the diastereomers of 4 exhibited good selectivity for GST P1-1. The
tetrabromo analog 5 of the tetrachloro compound 3 maintained its specificity and was found to be
more readily activated by GSTs than 3. The GST activation concept was further broadened
through design, synthesis, and evaluation of a novel latent urethane mustard 8 and its diethyl ester
9. Interestingly, 8 showed very good specificity for P1-1 GST. Cell culture studies were carried
out on 4, 5, 8, and 9 using cell lines engineered to have varying levels of GST P1-1 isozyme.
New analogs 4 and 5 exhibited increased toxicity to cell lines with overexpressed GST P1-1
isozyme. The urethane mustard 8 and its diethyl ester 9 were found to be not as toxic. However,
they too exhibited more toxicity to a cell line engineered to have elevated P1-1 levels, which was
in agreement with the observed in vitro specificity of 8 for P1-1 GST isozyme. Mechanistic
studies on alkaline as well as enzyme-catalyzed decomposition of latent mustard 3 provided
experimental proof for the hypothesis that 3 breaks down into an active phosphoramidate
mustard and a reactive vinyl sulfone. The alkylating nature of the decomposition products was
further demonstrated by trapping those transient species as relatively stable diethyldithiocarbamic
acid adducts. These results substantially extend previous efforts to develop drugs targeting GST
and provide a paradigm for development of other latent drugs. |
