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.