title: Antitumor agents. 113. New 4 beta-arylamino derivatives of 4'-O-demethylepipodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II.
abstract: A number of 4'-O-demethylepipodophyllotoxin derivatives possessing various 4 beta-N-, 4 beta-O- or 4 beta-S-aromatic rings 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. The results indicated, that for DNA topoisomerase II, a basic unsubstituted 4 beta-anilino moiety is structurally required for the enhanced activity. Substitution on this moiety with CN, COOCH3, COOC2H5, OH and COOCH3, OCH3, COCH3, CH2OH, OCH2O, OCH2CH2O, phenoxy, morpholino, NO2, and NH2 either at the para and/or the meta position yielded compounds which are as potent or more potent than etoposide. Substitution with COOC2H5 and OH at the ortho position afforded inactive compounds. Replacement of the aryl nitrogen with oxygen or sulfur gave compounds which are much less active or inactive. However, replacement of the phenyl ring with a pyridine nucleus furnished compounds which are as active or slightly more active than etoposide. There is a lack of correlation between the ability of these compounds in inhibiting DNA topoisomerase II and in causing protein-linked DNA breaks.
authors.affiliation: Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Y H
authors.initials: YH
authors.lastname: Kuo
authors.forename: D
authors.initials: D
authors.lastname: Schnur
authors.forename: J P
authors.initials: JP
authors.lastname: Bowen
authors.forename: S Y
authors.initials: SY
authors.lastname: Liu
authors.forename: F S
authors.initials: FS
authors.lastname: Han
authors.forename: J Y
authors.initials: JY
authors.lastname: Chang
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; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D011034:Podophyllotoxin