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.
Institute of Organic und Biomolecular Chemistry of the Georg-August-University Göttingen, D-37077 Göttingen, Germany. ltietze@gwdg.de
Lutz F
LF
Tietze
Heiko J
HJ
Schuster
Kianga
K
Schmuck
Ingrid
I
Schuberth
Frauke
F
Alves
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