title: Cytotoxic sesquiterpenoids from Ratibida columnifera.
abstract: Bioassay-directed fractionation of the flowers and leaves of Ratibida columnifera using a hormone-dependent human prostate (LNCaP) cancer cell line led to the isolation of 10 cytotoxic substances, composed of five novel xanthanolide derivatives (2-4, 7, and 8), a novel nerolidol derivative (9), and three known sesquiterpene lactones, 9alpha-hydroxy-seco-ratiferolide-5alpha-O-angelate+ ++ (1), 9alpha-hydroxy-seco-ratiferolide-5alpha-O-(2-methylbut yrate) (5), 9-oxo-seco-ratiferolide-5alpha-O-(2-methylbutyrate) (6), as well as a known flavonoid, hispidulin (10). On the basis of its cytotoxicity profile, compound 5 was selected for further biological evaluation, and was found to induce G1 arrest and slow S traverse time in parental wild type p53 A2780S cells, but only G2/M arrest in p53 mutant A2780R cells, with strong apoptosis shown for both cell lines. The activity of 5 was not mediated by the multidrug resistance (MDR) pump, and it was not active against several anticancer molecular targets (i.e., tubulin polymerization/depolymerization, topoisomerases, and DNA intercalation). While these results indicate that compound 5 acts as a cytotoxic agent via a novel mechanism, this substance was inactive in in vivo evaluations using the murine lung carcinoma (M109) and human colon carcinoma (HCT116) models.
authors.affiliation: Program for Collaborative Research in the Pharmaceutical Sciences and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: B
authors.initials: B
authors.lastname: Cui
authors.forename: Y H
authors.initials: YH
authors.lastname: Lee
authors.forename: H
authors.initials: H
authors.lastname: Chai
authors.forename: J C
authors.initials: JC
authors.lastname: Tucker
authors.forename: C R
authors.initials: CR
authors.lastname: Fairchild
authors.forename: C
authors.initials: C
authors.lastname: Raventos-Suarez
authors.forename: B
authors.initials: B
authors.lastname: Long
authors.forename: K E
authors.initials: KE
authors.lastname: Lane
authors.forename: A T
authors.initials: AT
authors.lastname: Menendez
authors.forename: C W
authors.initials: CW
authors.lastname: Beecher
authors.forename: G A
authors.initials: GA
authors.lastname: Cordell
authors.forename: J M
authors.initials: JM
authors.lastname: Pezzuto
authors.forename: A D
authors.initials: AD
authors.lastname: Kinghorn
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019659:Asteraceae / Q000737:chemistry*; D002453:Cell Cycle / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D010946:Plants, Medicinal / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D012717:Sesquiterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D014404:Tubulin / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D012717:Sesquiterpenes; D059004:Topoisomerase I Inhibitors; D014404:Tubulin