Highly selective glycosylated prodrugs of cytostatic CC-1065 analogues for antibody-directed enzyme tumor therapy.
Novel prodrugs of the cytotoxic antibiotic CC-1065 for an antibody-directed enzyme prodrug therapy (ADEPT) were prepared that show an excellent selectivity with a high toxicity of the corresponding drug. In particular, the seco-CBI analogue of CC-1065, 1-chloromethyl-5-hydroxy-1,2-dihydro-3H-benz[e]indole, as well as the novel methyl-seco-CBI analogue 1-(1'-chloroethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole, were synthesized and transformed into their galactosides 10 a and 10 b, respectively. These galactosides can be cleaved with beta-D-galactosidase to give the free cytotoxic compounds. They were tested in in vitro cytotoxicity assays by using human bronchial carcinoma cells of line A549 in the presence and in the absence of beta-D-galactosidase. While the seco-CBI prodrugs revealed only modest selectivity, prodrugs of the methyl-seco-CBI analogue bearing an anti orientation of the substituents at the two stereogenic centers of the N-heterocycle displayed an excellent selectivity with an ED(50) quotient of about 750. The cytotoxicity of the corresponding phenol was rather high, with an ED(50) of 1.3 nM. The diastereomer with a syn orientation at the stereogenic centers was much less toxic.
Tietze
L F
LF
Institut für Organische Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany. ltietze@gwdg.de
Herzig
T
T
Fecher
A
A
Haunert
F
F
Schuberth
I
I
D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism; D000906:Antibodies / Q000276:immunology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D000080890:Duocarmycins; D057487:Enzyme Therapy; D006031:Glycosylation; D006801:Humans; D007211:Indoles; D007933:Leucomycins / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D000970:Antineoplastic Agents; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D011355:Prodrugs; C018782:CC 1065; D004247:DNA