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Conformational differences between GXG chelates of cis- and trans-platinum.
Abstracts
428
J009
CONFORMATIONAL DIFFERENCES BETWEEN GXG CHELATES OF CIS- AND TRANS.PLATINUM.
Nelleke Boogaard and Jan Reedijk, Department of Chemistry, Gorlaeus Laboratories Leiden Ut~iversizy. 1'.(). Box 9502, 2300 RA L2iden, THE NETHERLANDS Part of the research on the interaction of platintun antitumor drugs with DNA, focusses on the differences between the GXG-adducts of the active compound cis-Pt(NH3)2Clz (cisPt) and the inactive isomer transPt. As model compounds for these adducts small DNA fragments have been chosen, lhal preferentia!y R>rm GXG-chelales. Results will be presented about the conformational differences b c ~ e c n complexes of both platinum isomers with the trinucleotide d(GpTpG). The invc~lip, ations have been carried out using several advanced NMR techniques. General characteristics of the formed GXG-chelates are similar for both plalinum compounds. Most striking difference between the chelales and the unplatmalcd trinucleotide is the behaviour (5t the intervening nucleotide unit. in both adducts /' this thymidine is deshielded. This implies a kind of 'bulged out' structure and a complete lack of slacking between the nucleotides. Such a l%amre was also observed m earlier studies [1,2]. A detailed conformational analysis of / i k the chelates, however, reveaIs several 1 / "}_ /' differences. The biggest dissimilarities from j ,; ....... ~ ..... \ 'normal' B-DNA, and from the unplatinated trmucleotide, are found in the 5"-part of the d(GpTpG)qransPt adduct. The dihydrals of / \ :\ the sugar ring of the 5' guauosine and the dihydrals around the 5' ptlosphorus atom in _//' / this transPt adduct have changed / considerably, due ~o chelate formation. For / the cisPt adduct the changes in these dihydrals are much less pronounced, and FIGURE t. Confornmlion of both fall partly within the normal ranges for guanosines around the tr~z~zxPl. B-DNA. The discrepancies with 'normal' B-DNA in the transPt adduct originate from the square planar confomlation around the platinurn atom+ resulting in a big gap between both ends of tile t.rmucleolide (Figure 1t.
Acknowledgements: We want to thank Johnson & Matthey Ltd. for their generous loan of KzPtCl~. EEC support (grant ST2J-0462-C) made it possiblc to have regular scientific discusskms with the group (5t" prof.dr, J.C. Chottard in Pari>. 1. 2.
J.tt.J. den Hartog et al., Eur. J. Biochem., 134, 485 (1983). D. Gibson and S.J.Lippard, lnorg Chem., 26, 2275 (1987L
428
J009
CONFORMATIONAL DIFFERENCES BETWEEN GXG CHELATES OF CIS- AND TRANS.PLATINUM.
Nelleke Boogaard and Jan Reedijk, Department of Chemistry, Gorlaeus Laboratories Leiden Ut~iversizy. 1'.(). Box 9502, 2300 RA L2iden, THE NETHERLANDS Part of the research on the interaction of platintun antitumor drugs with DNA, focusses on the differences between the GXG-adducts of the active compound cis-Pt(NH3)2Clz (cisPt) and the inactive isomer transPt. As model compounds for these adducts small DNA fragments have been chosen, lhal preferentia!y R>rm GXG-chelales. Results will be presented about the conformational differences b c ~ e c n complexes of both platinum isomers with the trinucleotide d(GpTpG). The invc~lip, ations have been carried out using several advanced NMR techniques. General characteristics of the formed GXG-chelates are similar for both plalinum compounds. Most striking difference between the chelales and the unplatmalcd trinucleotide is the behaviour (5t the intervening nucleotide unit. in both adducts /' this thymidine is deshielded. This implies a kind of 'bulged out' structure and a complete lack of slacking between the nucleotides. Such a l%amre was also observed m earlier studies [1,2]. A detailed conformational analysis of / i k the chelates, however, reveaIs several 1 / "}_ /' differences. The biggest dissimilarities from j ,; ....... ~ ..... \ 'normal' B-DNA, and from the unplatinated trmucleotide, are found in the 5"-part of the d(GpTpG)qransPt adduct. The dihydrals of / \ :\ the sugar ring of the 5' guauosine and the dihydrals around the 5' ptlosphorus atom in _//' / this transPt adduct have changed / considerably, due ~o chelate formation. For / the cisPt adduct the changes in these dihydrals are much less pronounced, and FIGURE t. Confornmlion of both fall partly within the normal ranges for guanosines around the tr~z~zxPl. B-DNA. The discrepancies with 'normal' B-DNA in the transPt adduct originate from the square planar confomlation around the platinurn atom+ resulting in a big gap between both ends of tile t.rmucleolide (Figure 1t.
Acknowledgements: We want to thank Johnson & Matthey Ltd. for their generous loan of KzPtCl~. EEC support (grant ST2J-0462-C) made it possiblc to have regular scientific discusskms with the group (5t" prof.dr, J.C. Chottard in Pari>. 1. 2.
J.tt.J. den Hartog et al., Eur. J. Biochem., 134, 485 (1983). D. Gibson and S.J.Lippard, lnorg Chem., 26, 2275 (1987L