title: Synthesis, cytotoxicity, and apoptosis induction in human tumor cells by geiparvarin analogues.
abstract: A series of geiparvarin analogues modified on the unsaturated alkenyloxy bridge, where a H-atom replaced the 3'-Me group, were synthesized and evaluated against a panel of human tumor cell lines in vitro. These compounds demonstrated a stronger increase in growth inhibitory activity when compared to the parent compound geiparvarin (8). In particular, the activity increased even further in the series of demethylated compounds when a Me substituent in the coumarin moiety is introduced. On the contrary, the same modifications exerted on the parent compound led to an activity reduction. Interestingly, the new derivatives proved to be fully inhibitory to drug-resistant cell lines, thus suggesting that they are not subject to the pump-mediating efflux of antitumor drugs. On the basis of their cytotoxic profiles, the most-active compounds were selected for further biological evaluation. The extracellular acidification rate by the new geiparvarin analogues was measured with the Cytosensor microphysiometer. The new derivatives significantly increased the acidification rate during the 24-48 h of incubation in a concentration-dependent manner. Cell-cycle analysis, evaluated by flow cytometry, revealed a strong apoptotic induction by these compounds confirmed by DNA laddering and observation by electron microscopy. Interestingly, the apoptotic pathway did not appear to be mediated by the activation of caspase-3.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Via Marzolo 5, I-35131 Padova. giampietro.viola.1@unipd.it
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
authors.forename: Daniela
authors.initials: D
authors.lastname: Vedaldi
authors.forename: Francesco
authors.initials: F
authors.lastname: dall'Acqua
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Silvia
authors.initials: S
authors.lastname: Disarò
authors.forename: Monica
authors.initials: M
authors.lastname: Spinelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: Marco
authors.initials: M
authors.lastname: Boccalini
authors.forename: Stefano
authors.initials: S
authors.lastname: Chimichi
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003374:Coumarins / Q000138:chemical synthesis* / Q000633:toxicity*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D018922:HL-60 Cells; D006801:Humans
chemical_list: D003374:Coumarins; C058446:geiparvarin