Cytotoxic alpha-bromoacrylic derivatives of low molecular weight |
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Authors: | Beria Italo Caldarelli Marina Geroni Cristina Mongelli Nicola Reinach Benedetta Vignati Luisella Cozzi Paolo |
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Affiliation: | Chemistry Department, Pharmacia Discovery Research Oncology, Viale Pasteur 10, 20014 Nerviano, Milan, Italy. italo.beria@pharmacia.com |
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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. |
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