A comparison of DNA binding profiles of dinuclear platinum compounds with polyamine linkers and the trinuclear platinum phase II clinical agent BBR3464

Abstract

The DNA binding profiles of three bis Pt(II) polyamine-linked compounds, [{trans-PtCl(NH3)(2)}(2) {mu-spermine-N-1,N-12}](4+), [{trans-PtCl(NH3)(2)}(2){mu-spermidine-N-1,N-8}](3+) and [{trans-PtCl(NH3)(2)}(2){mu-BOC-spermidine}](2+), were compared with that of a novel trinuclear phase II clinical agent, [{trans-PtCl(NH3)(2)}(2){mu-trans-Pt(NH3)(2)(H2N(CH2)(6)NH2)(2)}](4+). All of the compounds bind preferentially in a bifunctional manner, according to unwinding of supercoiled DNA circles. The kinetics of binding of these compounds corresponds to their relative charge (2 + to 4 +). The preference for the formation of interstrand crosslinks, however, does not follow a charge-based pattern. By studying the results of DNA polymerase extension products on a DNA template modified by the compounds, and by incorporating the complementary method of RNA transcription mapping, it was possible to determine the nucleotide bases that are preferred sites of binding. The stop sites due to platinum adducts were determined, and some preliminary observations concerning the range and type of crosslinks were established. It can be concluded that dinuclear Pt compounds are similar to their trinuclear counterpart, and that charge differences do not contribute solely to the variances between the compounds.