title: Structure-activity relationship analysis of novel derivatives of narciclasine (an Amaryllidaceae isocarbostyril derivative) as potential anticancer agents.
abstract: Narciclasine (1) is a plant growth regulator that has been previously demonstrated to be proapoptotic to cancer cells at high concentrations (> or = 1 microM). Data generated in the present study show that narciclasine displays potent antitumor effects in apoptosis-resistant as well as in apoptosis-sensitive cancer cells by impairing the organization of the actin cytoskeleton in cancer cells at concentrations that are not cytotoxic (IC(50) values of 30-90 nM). The current study further revealed that any chemical modification to the narciclasine backbone generally led to compounds of variable stability, weaker activity, or even the complete loss of antiproliferative effects in vitro. However, one hemisynthetic derivative of narciclasine, compound 7k, demonstrated by both the intravenous and oral routes higher in vivo antitumor activity in human orthotopic glioma models in mice when compared to narciclasine at nontoxic doses. Narciclasine and compound 7k may therefore be of potential use to combat brain tumors.
authors.affiliation: Unibioscreen SA, 40 Avenue Joseph Wybran, 1070 Brussels, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: Ingrassia
authors.forename: Florence
authors.initials: F
authors.lastname: Lefranc
authors.forename: Janique
authors.initials: J
authors.lastname: Dewelle
authors.forename: Laurent
authors.initials: L
authors.lastname: Pottier
authors.forename: Véronique
authors.initials: V
authors.lastname: Mathieu
authors.forename: Sabine
authors.initials: S
authors.lastname: Spiegl-Kreinecker
authors.forename: Sébastien
authors.initials: S
authors.lastname: Sauvage
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Yazidi
authors.forename: Mischaël
authors.initials: M
authors.lastname: Dehoux
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Eric
authors.initials: E
authors.lastname: Van Quaquebeke
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
mesh_terms: D047151:Amaryllidaceae Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D049109:Cell Proliferation; D004333:Drug Administration Routes; D004355:Drug Stability; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D010617:Phenanthridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D047151:Amaryllidaceae Alkaloids; D000970:Antineoplastic Agents; D010617:Phenanthridines; C010753:narciclasine