title: Cytotoxic alpha-bromoacrylic derivatives of low molecular weight.
abstract: In vitro and in vivo activities of a small series of alpha-bromoacrylic derivatives of low molecular weight (MW) are described and compared with those of alpha-bromoacrylic derivatives of distamycin-like frames. Low MW compounds, when lacking of a strong basic moiety, are potent cytotoxics, while analogues bearing a strong basic moiety are not. This suggests the existence of an active transport mechanism for distamycin-derived cytotoxics characterized by strong basic amidino or guanidino moieties. Low MW compounds are inactive in vivo, possibly because of the metabolic lability of alpha-bromoacrylic moiety. The same moiety is however present in a series of potent anticancer distamycin-like minor groove binders, for example, PNU-166196 (brostallicin), a fact that underlines the features of the latter.
authors.affiliation: Chemistry Department, Pharmacia Discovery Research Oncology, Viale Pasteur 10, 20014 Nerviano, Milan, Italy. italo.beria@pharmacia.com
authors.forename: Italo
authors.initials: I
authors.lastname: Beria
authors.forename: Marina
authors.initials: M
authors.lastname: Caldarelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Geroni
authors.forename: Nicola
authors.initials: N
authors.lastname: Mongelli
authors.forename: Benedetta
authors.initials: B
authors.lastname: Reinach
authors.forename: Luisella
authors.initials: L
authors.lastname: Vignati
authors.forename: Paolo
authors.initials: P
authors.lastname: Cozzi
mesh_terms: D000179:Acrylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004214:Distamycins / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008970:Molecular Weight; D013329:Structure-Activity Relationship
chemical_list: D000179:Acrylates; D000970:Antineoplastic Agents; D004214:Distamycins; D006842:Hydrocarbons, Brominated; C030000:stallimycin; D004247:DNA