ANTITUMOR AGENTS .113. NEW 4BETA-ARYLAMINO DERIVATIVES OF 4'-O-DEMETHYLEPIPODOPHYLLOTOXIN AND RELATED-COMPOUNDS AS POTENT INHIBITORS OF HUMAN DNA TOPOISOMERASE-II

被引:123
作者
WANG, ZQ
KUO, YH
SCHNUR, D
BOWEN, JP
LIU, SY
HAN, FS
CHANG, JY
CHENG, YC
LEE, KH
机构
[1] UNIV N CAROLINA,SCH PHARM,NAT PROD LAB,CHAPEL HILL,NC 27599
[2] UNIV N CAROLINA,SCH PHARM,DIV MED CHEM & NAT PROD,MOLEC MODELING LAB,CHAPEL HILL,NC 27599
[3] YALE UNIV,SCH MED,DEPT PHARMACOL,NEW HAVEN,CT 06510
关键词
D O I
10.1021/jm00171a050
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A number of 4'-O-demethylepipodophyllotoxin derivatives possessing various 4β-N-, 4β-O- or 4β-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 toposoimerase II, a basic unsubstituted 4/3-anilino moiety is structurally required for the enhanced activity. Substitution on this moiety with CN, COOCH3, COOC2H6, OH and COOCH3,OCH3, COCH3, CH2OH, 0CH2O, 0CH2CH2O, 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. © 1990, American Chemical Society. All rights reserved.
引用
收藏
页码:2660 / 2666
页数:7
相关论文
共 16 条
[1]   ANTITUMOR AGENTS .99. SYNTHETIC RING C AROMATIZED PODOPHYLLOTOXIN ANALOGS AS POTENTIAL INHIBITORS OF HUMAN DNA TOPOISOMERASE-II [J].
BEERS, SA ;
IMAKURA, Y ;
DAI, HJ ;
LI, DH ;
CHENG, YC ;
LEE, KH .
JOURNAL OF NATURAL PRODUCTS, 1988, 51 (05) :901-905
[2]  
Issell BF., 1984, ETOPOSIDE VP 16 CURR
[3]  
Jardine I., 1980, ANTICANCER AGENTS BA, P319
[4]   MITOSIS INHIBITING NATURAL PRODUCTS .24. SYNTHESIS AND ANTIMITOTIC ACTIVITY OF GLYCOSIDIC LIGNAN DERIVATIVES RELATED TO PODOPHYLLOTOXIN [J].
KELLERJU.C ;
KUHN, M ;
WARTBURG, AV ;
STAHELIN, H .
JOURNAL OF MEDICINAL CHEMISTRY, 1971, 14 (10) :936-&
[5]  
KLINGSBER E, 1962, HETEROCYCLIC COMPO 3, P1
[6]   MITOSIS INHIBITING NATURAL SUBSTANCES .23. A NEW METHOD OF GLYCOSIDATION .2. GLYCOSIDES OF 4'-DEMETHYLEPIPODOPHYLLOTOXIN [J].
KUHN, M ;
VONWARTB.A .
HELVETICA CHIMICA ACTA, 1969, 52 (04) :948-&
[7]   ANTITUMOR AGENTS .111. NEW 4-HYDROXYLATED AND 4-HALOGENATED ANILINO DERIVATIVES OF 4'-DEMETHYLEPIPODOPHYLLOTOXIN AS POTENT INHIBITORS OF HUMAN DNA TOPOISOMERASE-II [J].
LEE, KH ;
BEERS, SA ;
MORI, M ;
WANG, ZQ ;
KUO, YH ;
LI, L ;
LIU, SY ;
CHANG, JY ;
HAN, FS ;
CHENG, YC .
JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (05) :1364-1368
[8]   ANTITUMOR AGENTS .107. NEW CYTO-TOXIC 4-ALKYLAMINO ANALOGS OF 4'-DEMETHYL-EPIPODOPHYLLOTOXIN AS INHIBITORS OF HUMAN DNA TOPOISOMERASE-II [J].
LEE, KH ;
IMAKURA, Y ;
HARUNA, M ;
BEERS, SA ;
THURSTON, LS ;
DAI, HJ ;
CHEN, CH ;
LIU, SY ;
CHENG, YC .
JOURNAL OF NATURAL PRODUCTS, 1989, 52 (03) :606-613
[9]   ANTI-TUMOR AGENTS .62. SYNTHESIS AND BIOLOGICAL EVALUATION OF PODOPHYLLOTOXIN ESTERS AND RELATED DERIVATIVES [J].
LEVY, RK ;
HALL, IH ;
LEE, KH .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1983, 72 (10) :1158-1161
[10]  
LIU SY, 1989, MOL PHARMACOL, V36, P78