Journal Article

Effect of Geometric Isomerism in Dinuclear Platinum Antitumour Complexes on the Rate of Formation and Structure of Intrastrand Adducts with Oligonucleotides

Kirste J. Mellish, Yun Qu, Neel Scarsdale and Nicholas Farrell

in Nucleic Acids Research

Volume 25, issue 6, pages 1265-1271
Published in print March 1997 | ISSN: 0305-1048
Published online March 1997 | e-ISSN: 1362-4962 | DOI: https://dx.doi.org/10.1093/nar/25.6.1265
Effect of Geometric Isomerism in Dinuclear Platinum Antitumour Complexes on the Rate of Formation and Structure of Intrastrand Adducts with Oligonucleotides

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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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