NMR Studies of Models Having the Pt(d(GpG)) 17-Membered Macrocyclic Ring Formed in DNA by Platinum Anticancer Drugs: Pt Complexes with Bulky Chiral Diamine Ligands
- 21 April 2011
- journal article
- Published by American Chemical Society (ACS) in Inorganic Chemistry
- Vol. 50 (10), 4559-4571
- https://doi.org/10.1021/ic200259s
Abstract
The highly distorted Pt(d(G*pG*)) (G* = N7-platinated G) 17-membered macrocyclic ring formed by cisplatin anticancer drug binding to DNA alters the structure of the G*G* base pair steps, canting one base, and increases dynamic motion, complicating solution structural studies. However, the ring appears to favor the HH1 conformation (HH1 denotes head-to-head guanine bases, 1 denotes the normal direction of backbone propagation). Compared to cisplatin, analogues with NH groups in the carrier ligand replaced by bulky N-alkyl groups are more toxic and less active and form less dynamic adducts. To examine the molecular origins for the biological effects of steric bulk, we evaluate Me4DABPt(d(G*pG*)) models; the bulk and chirality of Me4DAB (N,N,N′,N′-tetramethyl-2,3-diaminobutane with S,S or R,R configurations at the chelate ring carbons) impede dynamic motion and enhance the utility of NMR methods for identifying and characterizing conformers. Unlike past studies of adducts with such bulky carrier ligands, in which no HH conformer was found, the Me4DABPt(d(G*pG*)) adducts did form the HH1 conformer, providing compelling evidence that the sugar–phosphate backbone can impose constraints sufficient to overcome the alkyl-group steric effects. The HH1 conformer exhibits no significant canting. The (S,S)-Me4DABPt(d(G*pG*)) adduct has the least amount of the “normal” HH1 conformer and the greatest amount of the ΔHT1 conformer (ΔHT1 = head-to-tail G* bases with Δ chirality) ever observed (88% under some conditions). Thus, our results lead us to hypothesize that the low activity and high toxicity of analogues of cisplatin having carrier ligands with N-alkyl groups arise from the low abundance and minimal canting of the HH1 conformer and possibly from the adverse effects of an abundant ΔHT1 conformer. The new findings advance our understanding of the chemistry of the Pt(d(G*pG*)) macrocyclic ring and of the effects of carrier-ligand steric bulk on the properties of the ring.Keywords
This publication has 74 references indexed in Scilit:
- cis -Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospectsProceedings of the National Academy of Sciences of the United States of America, 2008
- A 1,2-d(GpG) Cisplatin Intrastrand Cross-Link Influences the Rotational and Translational Setting of DNA in NucleosomesJournal of the American Chemical Society, 2008
- Conformation of DNA GG Intrastrand Cross-Link of Antitumor Oxaliplatin and Its Enantiomeric AnalogBiophysical Journal, 2007
- The resurgence of platinum-based cancer chemotherapyNature Reviews Cancer, 2007
- Cellular processing of platinum anticancer drugsNature Reviews Drug Discovery, 2005
- X-ray Structure and Circular Dichroism of Pure Rotamers of Bis[guanosine-5′-monophosphate(−1)](N,N,N′,N′-tetramethylcyclohexyl-1,2-diamine)platinum(II) Complexes That HaveR,R andS,S Configurations at the Asymmetric DiamineChemistry – A European Journal, 2003
- Chiral discrimination in the formation reaction and at equilibrium for N,N,N′,N′-tetramethyl-1,2-diaminocyclohexane–PtG2 complexesDalton Transactions, 2003
- NMRPipe: A multidimensional spectral processing system based on UNIX pipesJournal of Biomolecular NMR, 1995
- Stereochemically controlled ligands influence atropisomerization of platinum(II) nucleotide complexes. Evidence for head-to-head and stable .LAMBDA. head-to-tail atropisomersJournal of the American Chemical Society, 1990
- Cytotoxicity of asymmetric platinum complexes against L-1210 cells. Effect of bulky substituents.CHEMICAL & PHARMACEUTICAL BULLETIN, 1990