title: Molecular editing and assessment of the cytotoxic properties of iejimalide and progeny.
abstract: Systematic variation of all substructures embedded into the framework of iejimalide B (2) led to a panel of synthetic analogues of this polyunsaturated macrolide, featuring structural modifications that are not accessible by derivatization of the natural lead compound itself. The assessment of the cytotoxicity of these compounds with the aid of a monolayer proliferation assay (12 human tumor cell lines in vitro) as well as a colony formation assay (24 human tumor xenografts ex vivo) revealed the exceptional potency of 2 and several of its synthetic congeners, with IC(50) values in the picomolar range for the most sensitive cell lines. Whereas structural modifications of the macrocycle or of the side chain generally lead to a decrease in activity, changes of the peptidic terminus are not only well accommodated but engender increased tumor selectivity as well. 2 and two of the most promising analogues were selected for in vivo studies in mice, in which their activity against human tumor xenografts of breast cancer (MAXF 401) and prostate cancer (PRXF PC-3M) was tested. In contrast to a previous report in the literature however, which had claimed in vivo activity for the parent iejimalides, these tests did not show a significant therapeutic effect against the chosen solid tumors upon intraperitoneal administration.
authors.affiliation: Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany.
authors.forename: Julien
authors.initials: J
authors.lastname: Gagnepain
authors.forename: Emilie
authors.initials: E
authors.lastname: Moulin
authors.forename: Cristina
authors.initials: C
authors.lastname: Nevado
authors.forename: Mario
authors.initials: M
authors.lastname: Waser
authors.forename: Armin
authors.initials: A
authors.lastname: Maier
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kelter
authors.forename: Heinz-Herbert
authors.initials: HH
authors.lastname: Fiebig
authors.forename: Alois
authors.initials: A
authors.lastname: Fürstner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D001688:Biological Products / Q000737:chemistry*; D002219:Carbamates / Q000737:chemistry* / Q000633:toxicity*; D002384:Catalysis; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D002219:Carbamates; D018942:Macrolides; C520301:iejimalide B