Antitumor agents, 107. New cytotoxic 4-alkylamino analogues of 4'-demethyl-epipodophyllotoxin as inhibitors of human DNA topoisomerase II.
A series of analogues of etoposide, the C-4 amino- and alkylamino-substituted 4'-demethyl-epipodophyllotoxins, have been synthesized and studied for their activity to inhibit type II human DNA topoisomerase as well as their activity in causing cellular protein-linked DNA breakage. Substitution of the glycosidic moiety of 1 by a 2"-hydroxyethylamino or 2"-methoxyethylamino chain at the C-4 beta position resulted in potent inhibitors of the human DNA topoisomerase II. This inhibitory activity correlates reasonably well with their activity in causing protein-linked DNA breakage in KB cells. The in vitro cytotoxicity (KB) appears to have no correlation with the inhibitory activity of the human DNA topoisomerase II.
Lee
K H
KH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
Imakura
Y
Y
Haruna
M
M
Beers
S A
SA
Thurston
L S
LS
Dai
H J
HJ
Chen
C H
CH
Liu
S Y
SY
Cheng
Y C
YC
D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D004247:DNA; D011034:Podophyllotoxin