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The dinuclear platinum complexes [{trans-PtCl (NH3)2}2µ-{HNH2(CH2)nNH2}](NO3)2 [1,1/t,t (n = 4,6)] and [{cis-PtCl(NH3)2}2µ-{NH2(CH2)nNH2}](NO3)2 [1,1/c,c (n = 4,6)] 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 1H 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°C was slower for 1,1/c,c compared with 1,1/t,t, whereas the second binding step (adduct closure) was faster for 1,1/c,c. However, the 1H NMR spectra of the 1,1/c,c adducts at 37°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 1,1/c,c complexes to form 1,2 GG intrastrand adducts with sterically more demanding double-stranded DNA.
Journal Article. 3858 words. Illustrated.
Subjects: Chemistry ; Biochemistry ; Bioinformatics and Computational Biology ; Genetics and Genomics ; Molecular and Cell Biology
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