Duocarmycin-based prodrugs for cancer prodrug monotherapy.
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.
Tietze
Lutz F
LF
Institute of Organic und Biomolecular Chemistry of the Georg-August-University Göttingen, D-37077 Göttingen, Germany. ltietze@gwdg.de
Schuster
Heiko J
HJ
Schmuck
Kianga
K
Schuberth
Ingrid
I
Alves
Frauke
F
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000080890:Duocarmycins; D005965:Glucuronates / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D020723:Glucuronic Acid / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry
C529919:(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; D000970:Antineoplastic Agents; D000080890:Duocarmycins; D005965:Glucuronates; D007211:Indoles; D011355:Prodrugs; D011758:Pyrroles; C529918: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; C066098:duocarmycin SA; D020723:Glucuronic Acid