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Highly Selective Glycosylated Prodrugs of Cytostatic CC‐1065 Analogues for Antibody‐Directed Enzyme Tumor Therapy
Author(s) -
Tietze Lutz F.,
Herzig Tobias,
Fecher Anja,
Haunert Frank,
Schuberth Ingrid
Publication year - 2001
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/1439-7633(20011001)2:10<758::aid-cbic758>3.0.co;2-g
Subject(s) - prodrug , stereocenter , stereochemistry , chemistry , cytotoxicity , selectivity , enzyme , indole test , in vitro , biochemistry , enantioselective synthesis , catalysis
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‐3 H ‐benz[ e ]indole, as well as the novel methyl‐seco‐CBI analogue 1‐(1′‐chloroethyl)‐5‐hydroxy‐1,2‐dihydro‐3 H ‐benz[ e ]indole, were synthesized and transformed into their galactosides 10 a and 10 b , respectively. These galactosides can be cleaved with β ‐ 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 β ‐ 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 n M . The diastereomer with a syn orientation at the stereogenic centers was much less toxic.