Cytotoxicity and inhibition of DNA topoisomerase I of polyhydroxylated triterpenoids and triterpenoid glycosides.
Cytotoxicity and inhibition on human DNA topoisomerase I (TOP1) and II (TOP2) of 74 plant-originated triterpenoids and triterpenoid glycosides were investigated. The cytotoxic compounds are primarily polyhydroxylated oleananes (GI(50) of A549: 1.0-10.19 microM). Sixteen cytotoxic aesculiosides isolated from Aesculus pavia inhibited TOP1 catalytic activity by interacting directly with the free enzyme and preventing the formation of the DNA-TOP1 complex. Interestingly, hydrolysis of six active aesculiosides (1, 4, 6, 8, 10, and 23) lost their TOP1 activities but enhanced their cytotoxicities. None of the test compounds showed any activity against TOP2. Structure-activity relationship (SAR) investigations indicated that cytotoxic oleananes required at least one angeloyl moiety at either C-21 or C-22 but the sugar moiety at C-3 may decrease their cytotoxicities. An angeloyl or tigeloyl group at C-21 is required for oleananes to bind the free TOP1 enzyme although the type and length of acyl moiety at C-22 also affects their activity. However, sugar moiety at C-3 is necessary for their TOP1 activities.
Wang
Ping
P
National Center for Pharmaceutical Crops, Arthur Temple College of Forestry and Agriculture, Stephen F. Austin State University, Nacogdoches, TX 75962, USA.
Ownby
Stacy
S
Zhang
Zhizhen
Z
Yuan
Wei
W
Li
Shiyou
S
D031319:Aesculus / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D006027:Glycosides / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D006801:Humans; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014315:Triterpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D006027:Glycosides; D059004:Topoisomerase I Inhibitors; D014315:Triterpenes; D004264:DNA Topoisomerases, Type I