Abstract
The synthesis and biological evaluation of novel prodrugs based on the cytotoxic antibiotic duocarmycin SA (1) for a selective treatment of cancer using a prodrug monotherapy (PMT) are described. Transformation of the phenol 8 with the glucuronic acid benzyl ester trichloroacetimidate 9b followed by reaction with DMAI x HCl (10) gives the glucuronide 11b, which is deprotected to afford the desired prodrug 4a containing a glucuronic acid moiety. In addition, the prodrug 4b with a glucuronic methyl ester unit is prepared. The cytotoxicity of the glucuronides is determined using a HTCFA-assay with IC(50) values of 610 nM for 4a and 3300 nM for 4b. In the presence of beta-glucuronidase, 4a expresses an IC(50) value of 0.9 nM and 4b of 2.1 nM resulting in QIC(50) values of about 700 for 4a and 1600 for 4b.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents / chemistry*
-
Antineoplastic Agents / pharmacology*
-
Antineoplastic Agents / therapeutic use
-
Cell Line, Tumor
-
Duocarmycins
-
Glucuronates / chemistry*
-
Glucuronates / pharmacology*
-
Glucuronates / therapeutic use
-
Glucuronic Acid / chemistry*
-
Humans
-
Indoles / chemistry*
-
Indoles / pharmacology*
-
Indoles / therapeutic use
-
Inhibitory Concentration 50
-
Neoplasms / drug therapy*
-
Prodrugs / chemistry*
-
Prodrugs / pharmacology*
-
Prodrugs / therapeutic use
-
Pyrroles / chemistry
Substances
-
(1-(10-chloroethyl)-3-((5-(2-(N,N-dimethylamino)ethoxy)indol-2-yl)carbonyl)-1,2-dihydro-3H-benz(e)indol-5-yl)-beta-D-glucopyranuronate
-
Antineoplastic Agents
-
Duocarmycins
-
Glucuronates
-
Indoles
-
Prodrugs
-
Pyrroles
-
methyl(1-(10-chloroethyl)-3-((5-(2-(N,N-dimethylamino)ethoxy)indol-2-yl)carbonyl)-1,2-dihydro-3H-benz(e)indol-5-yl)-beta-D-glucopyranuronate
-
duocarmycin SA
-
Glucuronic Acid