Highly selective glycosylated prodrugs of cytostatic CC-1065 analogues forantibody-directed enzyme tumor therapy

Citation
Lf. Tietze et al., Highly selective glycosylated prodrugs of cytostatic CC-1065 analogues forantibody-directed enzyme tumor therapy, CHEMBIOCHEM, 2(10), 2001, pp. 758-765
Citations number
17
Categorie Soggetti
Chemistry & Analysis
Journal title
CHEMBIOCHEM
ISSN journal
14394227 → ACNP
Volume
2
Issue
10
Year of publication
2001
Pages
758 - 765
Database
ISI
SICI code
1439-4227(20011001)2:10<758:HSGPOC>2.0.ZU;2-Q
Abstract
Novel prodrugs of the cytotoxic antibiotic CC-1065 for an antibody directed enzyme prodrug therapy (ADEPT) were prepared that show an excellent select ivity with a high toxicity of the corresponding drug. In particular,a the s eco-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 10a and 10b, respectively. These galactosides can be cl eaved with beta -D-galactosidase to give the free cytoxic compounds. They w ere tested in in vitro cytotoxicity assays by using human bronchial carcino ma cells of line A549 in the presence and in the absence of beta -D-galacto sidase. While the seco-CBI prodrugs revealed only modest selectivity, prodr ugs of the methyl-seco-CBI analogue bearing an anti orientation of the subs tituents at the two stereogenic centers of the N-heterocycle displayed an e xcellent selectivity with an ED50 quotient of about 750. The cytotoxicity o f the corresponding phenol was rather high, with an ED50 of 1.3 nM. The dia stereomer with a syn orientation at the stereogenic centers was much less t oxic.