The reaction of 14C-labelled platinum ethylenediamine dichloride with nucleic acid constituents

Robins, A. B.

doi:10.1016/0009-2797(73)90084-7

Cited by 75 publications

(8 citation statements)

References 14 publications

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“…) In aqueous solution the chlorides exchange for aquo or hydroxide ligands and it is most likely that, in the cell, the drugs are predominantly in the form of monoaquo, monohydroxy electrophilic reagents (X), (XI). Although the mode, or rather modes, of interaction of these drugs with the nucleic acids, polynucleotides and their constituents are not yet completely elucidated and may involve many aspects (monofunctional or bifunctional attack, chelation, intra or interstrand linkings) it is nevertheless interesting to observe, in relation with the proposals developed in this paper, that quite generally the polymeric units are more reactive than the monomers (Robins 1973 a, b;Scovell & Reaoch, 1979).…”

Section: Ch 3 N=nmentioning

confidence: 84%

Molecular electrostatic potential of the nucleic acids

Pullman

1981

Quart. Rev. Biophys.

422

269

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It is generally acknowledged that geometrical and conformational properties of biopolymers have an important effect on their biochemical behaviour. It is less easily recognized that these properties depend also on their macromolecular electronic characteristics.The aim of this review is to demonstrate the significance of such macromolecular electronic effects. Particularly useful for this sake is the recently much developed concept of ‘molecular electrostatic potential’ (MEP) (Scrocco & Tomasi, 1973, 1978) by which is defined the electrostatic (Coulomb) potential created in the neighbouring space by the nuclear charges and the eletronic distribution of a molecule.

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Section: Ch 3 N=nmentioning

confidence: 84%

Molecular electrostatic potential of the nucleic acids

Pullman

1981

Quart. Rev. Biophys.

422

269

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“…Raman-pH Profile for the 1:1 System at 25 °C. Raman difference spectra (RADS) were recorded for solutions 25 mM in cytidine and 25 mM in (H3N)2PtH (i.e" r = (H3N)2Ptn:nucleoside = 1) in H20 vs. 25 mM cytidine at pH values of 1.5, 3, 5, 7, 9, and 11 to establish the effect of pH on the reaction. Since the pK for the N(3) proton of CydH+ is 4.22 at 25 °C,3 the cytidine reference is protonated at pH 1.5 and 3 but not appreciably at pH 5.…”

Section: Data and Resultsmentioning

confidence: 99%

Heavy metal-nucleoside interactions. 10. Binding of cis-diammineplatinum(II) to cytidine and uridine in aqueous solution: necessary conditions for formation of platinum-uridine "blues"

Chu¹,

Duncan²,

Tobias³

1977

Inorg. Chem.

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Both cytidine and uridine react with (H3N)2Ptn and enPt11 in aqueous solution over a wide pH range. The reactions with cytidine are complete within a few hours, while those with uridine are considerably slower. In both cases mono and bis complexes are formed. In acidic solution, (H3N)2Ptn behaves as a bifunctional electrophile toward cytidine, while at pH 7 it acts as a unifunctional electrophile. The equilibrium constant for [(H3N)2Pt(OH2)2]2+ + Cyd <=± [(H3N)2PtCyd(OH2)]2+ + H20 was estimated from Raman spectra to have the value log K = ca. 2.9 (0.1 M C104~). The hydroxo ligand produced by hydrolysis of [(H3N)2Pt(OH2)2]2+ is an effective blocking group. Raman and and l3C NMR spectra all identify N(3) as the sole binding site. In particular, no interaction occurs at high pH with a deprotonated amine group. With uridine, the Raman and *H and l3C NMR experiments all show that binding occurs at N(3) of the conjugate base UrdH_f.No reaction takes place under comparable conditions with 3-methyluridine. The equilibrium constant for [(H3N)2Pt(OH2)2]2+ + UrdH-f [(H3N)2PtUrdH-1OH2]+ has a value log K > 9.6 (0.1 M C104~), comparable to H3CHgOH2+. The selectivity of the bases in a native polynucleotide for binding the substitutionally inert (H3N)2Ptn and related species is kinetic not thermodynamic in origin as also is the case with alkylating agents. Binding will occur preferentially at nonprotonated sites rather than N(3) of uridine or thymidine or N(l) of guanosine, the principal binding sites for labile heavy metal species.Kinetic and thermodynamic effects governing heavy metal binding are discussed. The binding behavior of labile species such as H+ or CH3Hg+ is of little use in predicting the reactions of the inert platinum(II) complexes. At pH 6-7, the monouridine complex undergoes a change which causes small shifts in the NMR spectrum. Exposure of solutions containing equimolar (H3N)2Ptn and uridine with pH <8 to the atmosphere results in the characteristic platinum-uracil "blue". The Raman spectra suggest that the principal species in these solutions is the colorless [(H3N)2PtUrdH_!OH2]+.

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“…Conformational considerations and pH data first suggested the two 6-NH2 groups of ApA and adenine N(l) and cytosine-4-NH2 of ApC as the chelating sites.39 However, the Ado amino groups being poor ligands of heavy metals, it has been later postulated that the cross-linking should involve the N (7) and/or N(l) positions of two adjacent stacked bases. 25 We have recently shown that Ipl reacts with c/y-[Pt(NH3)2(H20)2]2+ to give a single product which is the N(7)-N(7) cross-linked dinucleotide complex [Pt(NH3)2(IpI)]+.40 We now report the results of our study of the reaction between cw-[Pt(NH3)2- ( 20)2]2+ and three homodinucleotides with purine bases, Ipl, GpG, and ApA, and two heterodinucleotides with a purine and a pyrimidine base, GpC and ApC.…”

mentioning

confidence: 85%

“…19 Kinetic studies reveal a higher reaction rate for Guo than for Ado and Cyd. 20 The order of nucleophilicity toward the diaquo or the dichloro complex has been recently reported to be GMP > AMP » CMP. 16 However, it has been shown, in the case of CpG reacting with Pt(en)Cl2, that platinum is bound to cytosine first and then to guanine.…”

mentioning

confidence: 98%

Interaction of cis-diaquodiammineplatinum dinitrate with ribose dinucleoside monophosphates

Chottard¹,

Girault²,

Chottard³

et al. 1980

J. Am. Chem. Soc.

100

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The reactions of five dinucleoside monophosphates (Ipl, GpG, ApA, GpC, and ApC) with cA-[Pt(NH3)2(H20)2](N03)2, with both reactants ca. 4 X 10™4 M in water (pH 5.5), have been studied. Sephadex chromatography and LC, NMR, and CD analyses have been used to characterize the complexes formed. The three homodinucleotides have a geometry leading to N(7)-N(7) chelation of the metal. Ipl and GpG give a single N(7)-N(7) chelated complex while ApA also gives other products due to competitive N(l) binding to the metal. GpC and ApC lead to mixtures of several complexes and in both cases cytosine appears to have more affinity for the platinum than do guanine and adenine. In the case of GpC one of the complexes appears as an N(7)G-N(3)C platinum chelate, the CD of which supports a left-handed helical arrangement of the bases. As far as the perturbation of the DNA structure upon binding of the m-(NH3)2Ptn moiety is concerned, these results bring further support to the hypothesis of intrastrand cross-linking of adjacent guanines occurring after a local denaturation or premelting of the DNA. They also suggest that cross-linking of adjacent guanine and cytosine could occur for a left-handed sequence of the polynucleotide.The mechanism of action of the antitumor m-dichlorodiammineplatinum(II) complex3 is still the subject of active in-vestigations.4,5 There is much evidence which suggests that DNA is the primary target of the platinum(II) drug.6™9 Several studies

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The reaction of 14C-labelled platinum ethylenediamine dichloride with nucleic acid constituents

Cited by 75 publications

References 14 publications

Molecular electrostatic potential of the nucleic acids

Molecular electrostatic potential of the nucleic acids

Heavy metal-nucleoside interactions. 10. Binding of cis-diammineplatinum(II) to cytidine and uridine in aqueous solution: necessary conditions for formation of platinum-uridine "blues"

Interaction of cis-diaquodiammineplatinum dinitrate with ribose dinucleoside monophosphates

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