Steric constraints inside the metal-coordination sphere as revealed by diastereotopic splitting of methylene protons

Giannini, Giuseppe; Natile, Giovanni

doi:10.1021/ic00014a007

Cited by 12 publications

(4 citation statements)

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“…This was revealed by the 1 H nuclear magnetic resonance showing a remarkable diastereotopic splitting of the methylene protons of the CH 2 Me groups adjacent to the asymmetric carbons. Therefore, the average orientation of the 1-butanol-2-yl radicals is such that the ethyl residues are hindered in their rotation around the carbon-ethyl bond (28).…”

Section: Platinum Complexes With Chiral N-substituted Ethylenediaminesmentioning

confidence: 99%

Chiral discrimination in platinum anticancer drugs.

Benedetti

Malina

Kašpárková

et al. 2002

Environ Health Perspect

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In this article we review the biological activity of analogs of the antitumor drug cisplatin that contain chiral amine ligands. Interaction with DNA and formation of cross-links with adjacent purine bases are considered to be the crucial steps in the antitumor activity of this class of complexes. Because double-helical DNA has a chiral structure, interaction with enantiomeric complexes of platinum should lead to diastereomeric adducts. It has been demonstrated that DNA cross-links of platinum complexes with enantiomeric amine ligands not only can exhibit different conformational features but also can be processed differently by the cellular machinery as a consequence of these conformational differences. These results expand the general knowledge of how the stereochemistry of the platinum-DNA adduct can influence the cell response and contribute to understanding the processes that are crucial for antitumor activity. The steric requirements of the chiral ligands, in terms of configuration and flexibility, are also elucidated.

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Section: Platinum Complexes With Chiral N-substituted Ethylenediaminesmentioning

confidence: 99%

Chiral discrimination in platinum anticancer drugs.

Benedetti

Malina

Kašpárková

et al. 2002

Environ Health Perspect

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“…The biological activity of platinum complexes with enantiomeric amine ligands such as cis-[PtCl 2 (RR-DACH)] and cis-[PtCl 2 (SS-DACH)] (DACH ϭ 1,2-diaminocyclohexane) and other enantiomeric pairs has been intensively investigated (Kidani et al, 1978;Noji et al, 1981Noji et al, , 1983Coluccia et al, 1986Coluccia et al, , 1991Fanizzi et al, 1987;Pasini and Zunino, 1987;Giannini and Natile, 1991;Vickery et al, 1993;Fenton et al, 1997). For instance, the DACH carrier ligand has been shown to significantly affect the ability of platinum-DNA adducts to block essential processes such as replication and transcription (Page et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

DNA Interactions of Antitumor Cisplatin Analogs Containing Enantiomeric Amine Ligands

Malina

Hofr

Maresca

et al. 2000

Biophysical Journal

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Modifications of natural DNA and synthetic oligodeoxyribonucleotide duplexes in a cell-free medium by analogs of antitumor cisplatin containing enantiomeric amine ligands, such as cis-[PtCl(2)(RR-DAB)] and cis-[PtCl(2)(SS-DAB)] (DAB = 2,3-diaminobutane), were studied by various methods of molecular biophysics and biophysical chemistry. These methods include DNA binding studies by pulse polarography and atomic absorption spectrophotometry, mapping of DNA adducts using transcription assay, interstrand cross-linking assay using gel electrophoresis under denaturing conditions, differential scanning calorimetry, chemical probing, and bending and unwinding studies of the duplexes containing single, site-specific cross-link. The major differences resulting from the modification of DNA by the two enantiomers are the thermodynamical destabilization and conformational distortions induced in DNA by the 1,2-d(GpG) intrastrand cross-link. It has been suggested that these differences are associated with a different biological activity of the two enantiomers observed previously. In addition, the results of the present work are also consistent with the view that formation of hydrogen bonds between the carbonyl oxygen of the guanine residues and the "quasi equatorial" hydrogen of the cis amine in the 1, 2-d(GpG) intrastrand cross-link plays an important role in determining the character of the distortion induced in DNA by this lesion.

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“…The carrier ligand may also affect biodistribution, rates and type of DNA adduct formation, recognition of damaged DNA by repair enzymes or regulatory/binding proteins, etc. The biological activities of platinum drugs depend on the absolute configuration of the carrier diamine, but the differences are not dramatic in those cases in which the resolved forms were tested. ,− …”

Section: Introductionmentioning

confidence: 99%

New Steric Hindrance Approach Employing the Hybrid Ligand 2-Aminomethylpiperidine for Diminishing Dynamic Motion Problems of Platinum Anticancer Drug Adducts Containing Guanine Derivatives

et al. 1999

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A fundamental problem obscuring the role of the ammine and primary amine groups in the activity of clinically used Pt anticancer drugs is the dynamic character of the adducts with DNA and DNA constituents. Dynamic motion is slower in analogues containing only secondary or tertiary amines, but such agents are not used clinically. Recently we found that enclosing the N center within a piperidine (pip) ring greatly reduces dynamic motion. In this work, we test the hypothesis that a diamine with only one pip ring, 2-aminomethylpiperidine (pipen), would slow dynamic motion enough for insightful study of adducts with one site (cis to the primary amine) closely reflecting the coordination environment of clinically used drugs. Racemic pipen was prepared and resolved by improved methods. PtCl(2)(pipen) synthesized with the pipen enantiomer having an R configuration of the asymmetric carbon (determined on the basis of the [alpha](D) sign) has the S stereochemistry at the N asymmetric center. In the adduct (S,R)-pipenPt(5'-GMP)(2), restricted rotation of the two nonequivalent N7-coordinated 5'-GMP's about the Pt-N7 bonds potentially could lead to two head-to-tail (LambdaHT and DeltaHT) and two head-to-head (HH(1) and HH(2)) atropisomers. However, 1D and 2D NOESY NMR data at pH approximately 3 indicated the dominance of the two HT atropisomers in a LambdaHT:DeltaHT ratio of 2:1. Deprotonation of the phosphate group (pH 7) further stabilized the LambdaHT form, and the CD signal had the shape characteristic of a LambdaHT form with a positive peak at approximately 280 nm. However, at pH 9.5, where the 5'-GMP N1H was largely deprotonated, the NMR spectrum and the approximately 280 nm CD peak both revealed that the LambdaHT form had decreased. When the pH was jumped down to 6.9, the NMR signals of the LambdaHT form and the approximately 280 nm CD peak increased with a half-time of approximately 3 min. Thus, the pip ring lengthens the atropisomerization time from seconds for ethylenediaminePt(5'-GMP)(2) to minutes for (S,R)-pipenPt(5'-GMP)(2). This pH jump experiment indicates that the signs of the CD signal are opposite for the LambdaHT and DeltaHT forms. Changes with pH in both the relative abundance and shifts of the H8 signals of the LambdaHT and DeltaHT forms correlated with an increase in hydrogen bonding by the phosphate group of the 5'-GMP cis to the primary amine. The hydrogen bonding changes the 5'-GMP base tilt and hence the H8 chemical shift. Such information is not obtainable on 5'-GMP adducts of clinically used anticancer drugs.

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Steric constraints inside the metal-coordination sphere as revealed by diastereotopic splitting of methylene protons

Cited by 12 publications

References 1 publication

Chiral discrimination in platinum anticancer drugs.

Chiral discrimination in platinum anticancer drugs.

DNA Interactions of Antitumor Cisplatin Analogs Containing Enantiomeric Amine Ligands

New Steric Hindrance Approach Employing the Hybrid Ligand 2-Aminomethylpiperidine for Diminishing Dynamic Motion Problems of Platinum Anticancer Drug Adducts Containing Guanine Derivatives

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