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Synthesis and Biological Evaluation of Novel Analogues and Prodrugs of the Cytotoxic Antibiotic CC‐1065 for Selective Cancer Therapy
Author(s) -
Tietze Lutz F.,
Herzig Tobias,
Feuerstein Tim,
Schuberth Ingrid
Publication year - 2002
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/1099-0690(200205)2002:10<1634::aid-ejoc1634>3.0.co;2-y
Subject(s) - prodrug , chemistry , moiety , adept , cytotoxicity , alkylation , stereochemistry , chemical synthesis , carboxylic acid , combinatorial chemistry , selectivity , in vitro , biochemistry , catalysis
This paper describes novel seco ‐analogues 25−27 of the cytotoxic antibiotic CC‐1065 ( 1 ) and their prodrugs 5 , 6a , and 6b , for antibody‐directed enzyme prodrug therapy (ADEPT). The partially hydrogenated seco ‐CCI‐analogue 7 and the corresponding methyl‐CCI analogues 8a and 8b were synthesized by alkylation of 9 with 15 and 16 , respectively, followed by radical cyclization and deprotection. Treatment of 7 , 8a , and 8b with the galactose trichloroacetimidate 21 and the bisindolyl‐carboxylic acid 20 in the presence of EDC followed by solvolysis gave the desired prodrugs 5 , 6a , and 6b , respectively. Compounds 25−27 were prepared by treatment of 7 , 8a , and 8b with 20 after deprotection. In vitro tests showed a strong cytotoxicity for 25 and a fairly low toxicities for 26 and 27 . However, the selectivity of the prodrugs 5 , 6a , and 6b was not sufficient for ADEPT. Interestingly, 8a and 8b did not undergo Winstein cyclization to produce the spirocyclopropylcyclohexadienone moiety. (© Wiley‐VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)