A strategy for tumor-selective chemotherapy by enzymatic liberation of seco-duocarmycin SA-derivatives from nontoxic prodrugs.
Immuno-conjugates obtained by linking enzymes with appropriate monoclonal antibodies, which bind to tumor-associated antigens, can be employed in a tumor-selective antibody directed enzyme prodrug therapy (ADEPT). For this strategy the glycosides 17a--c were prepared as prodrugs of CI-TMI 14 which is a structurally simplified analogue of the highly potent antitumor agent duocarmycin SA 2. Exposure of 17a--c to cultured carcinoma cells of line A549 displayed a very low toxicity; however, after addition of the corresponding enzymes and exposure for 24 h at prodrug concentrations of <0.1 microM the proliferation of the carcinoma cells was inhibited almost completely with ED(50prodrug)/ED(50drug) of up to 270 in the presence and in the absence of the enzyme. The synthesis of 17a--c was achieved by transformation of nitroanisidine 6 into 12 which was glycosidated to give 16a--c. Removal of the silyl groups, introduction of a chlorine atom and solvolysis of the acetal groups led to 17a-c, of which 17a and 17c are promising candidates for further elaboration.
Tietze
L F
LF
Institut für Organische Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, D-37077 Göttingen, Germany. ltietze@gwdg.de
Lieb
M
M
Herzig
T
T
Haunert
F
F
Schuberth
I
I
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000302:isolation & purification*; D000906:Antibodies / Q000737:chemistry; D001984:Bronchial Neoplasms / Q000473:pathology; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011355:Prodrugs / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry / Q000302:isolation & purification*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D000080890:Duocarmycins; D007211:Indoles; D011355:Prodrugs; D011758:Pyrroles; C066098:duocarmycin SA