Antitumor agents. 124. New 4 beta-substituted aniline derivatives of 6,7-O,O-demethylene-4'-O-demethylpodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II.
A series of 6,7-O,O-demethylene-4'-O-demethyl-4 beta-(substituted anilino)-4-desoxypodophyllotoxins (18-23), 6,7-O,O-demethylene-6,7-O,O-dimethyl-4'-O-demethyl-4 beta-(substituted anilino)-4-desoxypodophyllotoxins (28-31), and their corresponding 4'-O-methyl analogues (12-17 and 24-27) have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. Compounds 18-23 are 2-fold more potent than etoposide and compounds 12, 16, 17, 30, and 31 are as active as etoposide in their inhibition of the human DNA topoisomerase II. Compounds 19 and 20 and 29-31 are as active or more active than etoposide in causing protein-linked DNA breakage. These results indicate that a free C-4' hydroxy group is essential for the DNA breakage activity, and that the hydroxyl groups at C-6 and -7 positions may be involved in an interaction which is responsible for the inhibitory activity of DNA topoisomerase II. The maintenance of an intact methylene dioxy-type ring-A system would contribute to enhanced activity. In addition, the sterically less hindered substitution at C-6 and C-7 positions may be important for optimal interactions with DNA topoisomerase II. There is no correlation between the ability of these compounds to inhibit DNA topoisomerase II and their ability to cause protein-linked DNA breaks in cells. This may relate to the difference in uptake of these compounds. The better correlation was observed between the protein-linked DNA breaks and the cytotoxicity in KB cells of these compounds.
Wang
Z Q
ZQ
Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
Hu
H
H
Chen
H X
HX
Cheng
Y C
YC
Lee
K H
KH
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007624:KB Cells / Q000187:drug effects; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D011034:Podophyllotoxin