title: Antitumor agents. 148. Synthesis and biological evaluation of novel 4 beta-amino derivatives of etoposide with better pharmacological profiles.
abstract: A series of novel 4 beta-amino derivatives of etoposide (1), which can form water-soluble salts and demonstrate excellent activity against mdr- and topo II-resistant cell lines, have been synthesized. Compared with etoposide, compounds 5-6, 8, and 10-16 show comparable or greater inhibition of human DNA topo II. In a cellular protein-DNA complex formation assay, compounds 5-6, 8, 10-14, and 16 are more potent than 1. A dose-response study of 8 shows that it is 20 times more active in formation of protein-linked DNA breaks than etoposide. Furthermore, both 8 and its free base 7 were found to be highly active toward etoposide-resistant KB cell lines. All compounds were also evaluated in vitro against a total of 56 human tumor cell lines derived from seven cancer types. Comparison of the log10 GI50 mean graph midpoints of 5-19 (-4.89 to -7.30) with that of 1 (-4.08) shows these new analogs to be 6-1659-fold more active than 1.
authors.affiliation: Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
authors.forename: Y L
authors.initials: YL
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005047:Etoposide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D006801:Humans; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; C086159:4'-O-demethyl-4-((4''-(1''-benzylpiperidinyl))amino)-4-desoxypodophyllotoxin; C086160:4'-O-demethyl-4-((2''-(dimethylamino)ethyl)amino)-4-desoxypodophyllotoxin; C086161:4'-O-demethyl-4-((3''-(dimethylamino)propyl)amino)-4-desoxypodophyllotoxin; D005047:Etoposide