A tetranuclear platinum compound designed to overcome cisplatin resistance

The synthesis and characterisation of the first generation of a poly(propyl eneimine) dendrimer DAB(PA)(4), substituted with four trans-diamminechlorop latinum moieties is reported. The compound DAB(PA-tPt-Cl)(4) was designed t o overcome two problems often associated with cisplatin resistance in cance r cells: (i) deactivation of the platinum species by intracellular thiolate s and (ii) improved repair of crosslinks with DNA, The four-armed molecule can be expected to form crosslinks with DNA that are very different from th e adducts formed by cisplatin. Also, the tetranuclear compound has four lea ving groups, while cisplatin has only two. Therefore, DAB(PA-tPt-Cl)(4) wou ld be less susceptible towards inactivation by reaction with intracellular thiolates. A reaction with an excess of the model nucleobase guanosine 5'-m onophosphate (GMP) confirmed that the tetranuclear compound is capable of b inding a maximum of four nucleobases. Therefore, the inactivation of one or two arms would still leave the molecule with enough reactivity to form cro sslinks with DNA. Cytotoxicity tests were performed on two mouse leukemia L 1210 cell lines, both sensitive and resistant towards cisplatin, and in sev en human tumor cell lines. In all cell lines, the tetranuclear compound sho wed a low cytotoxicity. It is suggested that the low activity is related to the structure of the compound, probably the high charge (+6) at physiologi cal pH and its branched structure hamper the molecule in crossing the cell membranes.