title: Effect of geometric isomerism in dinuclear platinum antitumour complexes on the rate of formation and structure of intrastrand adducts with oligonucleotides.
abstract: 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)] 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 degrees 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 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 1,1/c,c complexes to form 1,2 GG intrastrand adducts with sterically more demanding double-stranded DNA.
authors.affiliation: Virginia Commonwealth University, Department of Chemistry, 1001 West Main Street, Richmond, VA 23284-2006, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Mellish
authors.forename: Y
authors.initials: Y
authors.lastname: Qu
authors.forename: N
authors.initials: N
authors.lastname: Scarsdale
authors.forename: N
authors.initials: N
authors.lastname: Farrell
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D002945:Cisplatin / Q000737:chemistry*; D015226:Dinucleoside Phosphates / Q000737:chemistry*; D006157:Guanosine Monophosphate / Q000737:chemistry*; D006859:Hydrogen; D007536:Isomerism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D015226:Dinucleoside Phosphates; D009838:Oligodeoxyribonucleotides; C034697:transplatin; C034298:deoxyguanylyl-(3'-5')-guanosine; D006859:Hydrogen; D006157:Guanosine Monophosphate; D002945:Cisplatin; D000111:Acetylcysteine