Effect of geometric isomerism in dinuclear platinum antitumour complexes on the rate of formation and structure of intrastrand adducts with oligonucleotides

The dinuclear platinum complexes [(trans-PtCl (NH3)(2)}(2) mu-{NH2(CH2)(n)NH2}](NO3)(2) [1,1/t,t (n = 4,6)] and [{cis-PtCl(NH3)(2)}(2) mu-(NH2(CH2)(n)NH2}](NO3)(2) [1,1/C,C (n = 4,6)1 exhibit antitumour activity comparable with cisplatin. 1,1/c,c complexes do not form 1,2 GG intrastrand adducts, the major adduct of cisplatin, with double-stranded DNA. This H-1 NMR spectroscopy study shows that, in the absence of a complementary strand, 1,1/c,c (n = 4,6) form a 1,2 GG (N7, N7) intrastrand adduct with r(GpG), d(GpG) and d(TGGT). Initial binding to r(GpG) (and also reaction with GMP) at 37 degrees C was slower for 1,1/c,c compared with l,lit,t, whereas the second binding step (adduct closure) was faster for 1,1/c,c. However, the H-1 NMR spectra of the 1,1/c,c adducts at 37 degrees C show two H8 signals, one of which is broad and becomes sharper on increasing the temperature, indicating restricted rotation around the Pt-N7 bond. For the d(GpG)-1,1/c,c (n = 4) adduct, 2D NMR spectroscopy assigned the broad H8 signal to the 3' G, which has syn base orientation and 60% S-type/40% N-type sugar conformation. The 5' G has anti base orientation and S-type sugar conformation. Apart from the restricted rotation around the 3' G, the structure is similar to that of 1,2 GG intrastrand adducts of 1,1/t,t. This steric hindrance may explain the inability of l,1/c,c complexes to form 1,2 GG intrastrand adducts with sterically more demanding double-stranded DNA.