Ethidium bromide (EtdBr) was used to differentiate perturbations induced in salmon sperm DNA complexed with a series of platinum compounds. The DNA -Pt complexes were classified into two groups. First, those which show a DNA . Pt . EtdBr fluorescence almost identical to that of the D N A . EtdBr complex and second, those which decrease linearly the fluorescence of the EtdBr molecules upon platinum fixation.In the first group, the platinum compounds are fixed to DNA at only one site, [PtCL] were found to be of the second group. These platinum compounds react with DNA through chelation; the fluorescence decrease was found to be 70% for rb = 0.20. trans-Pt-(NH3)2C12 can fit into either the first group, when one chlorine atom is still covalently fixed on platinum (one DNA . Pt bond), or into the second one, when the chlorine atoms are displaced (transbidentate fixation). Scatchard plots indicated that when one Pt compound is fixed to DNA by chelation it inhibited the intercalation of one EtdBr molecule, this relationship being verified for r b I 0.10. The binding constant of EtdBr to the different DNA . Pt complexes was not altered. Since no fluorescence quenching was detected in the DNA . Pt . EtdBr complexes, the fluorescence decrease was attributed to the so-called 'chelation effect' and interpreted in terms of local denaturations of the DNA molecule. The perturbations could be due to the rupture of the hydrogen bonds in dG . dC pairs since chelation should modify the deoxyguanosine residues in DNA.Rosenberg's discovery [l] of the antimitotic and antitumour [2] properties of the cis-platinum compounds gave a new interest to cancer chemotherapy. The uncharged cis-dichlorodiammine platinum(II), cis-Pt(NH3)2C12 is currently being tested against a wide variety of tumours [3]. The activity of this compound in vivo [4] and in vitro [5] has been shown to be due to its interaction with DNA.For several years, we have been involved in the study of the interaction in vitro between DNA and This paper was presented in part at the Third International Symposium on Platinum Coordination Complexes in Cancer Chemotherapy, Dallas, Texas, U.S. A., October 18-20, 1976.Abbreviations. EtdBr, ethidium bromide or 3,8-diamino-6-phenyl-5-ethylphenanthridinium bromide; en = ethylenediamine, H~N-CHZ-CHI-NH~ ; dien = bis(2-aminoethyl)amine, HlN-CHz-CH2-NH-CH2-CH2-NH2 ; guanine N-7, nitrogen atom on position 7 of the guanine molecule in DNA; guanine 0 -6 , oxygen atom on carbon 6 of the guanine molecule in DNA; adenine N-7, nitrogen atom on position 7 of the adenine molecule; adenine NH2-6, NH2 group on carbon 6 of the adenine molecule. platinum [6 -81. We were first concerned exclusively with the mode of fixation of a series of platinum compounds to DNA. Platinum fixation was quantified [6] and found to be in complete agreement with the results obtained by Horacek and Drobnik [9], Howle et al. [lo] and Gale et al. [ll], but disagreed with the results of Munchausen and Rahn [12]. Platinum specificity for DNA was demonstrated [6,7] and diff...
The circular dichroism (CD) spectra of a series of DNA . platinum complexes are presented.The following platinum compounds, [Pt(dien)Cl]Cl, ci.~-Pt(NH3)2C12, cis-Pt(en)C12, trans-Pt-(NH3)zC1z, K [Pt(NH3)CI3] and Kz [PtCL] were complexed with the DNA extracted from bacteria Micrococcus lysodeikticus (72 dG + dC), Escherichia coli (50 dG + dC), Clo.str~idiiim p rfiingens (32 dG + dC) and salmon sperm (41 "/, dG + dC). Strong differences were found between the different DNA . Pt complexes. Three types of spectra clearly demonstrate the different platinum binding modes on DNA. In the first type, the platinum compound, i.e. For the cis-bidentate and trans-bidentate platinum fixation, a continuous bathochromic shift occurs.Rosenberg's discovery [I, 21 of the surprising antitumoral properties of certain platinum compounds led us to investigate the interaction of a series of these compounds with DNA which has been shown to be a target in vivo [3] and in vitro [4]. Recently [5], we have confirmed the role of DNA as a target in bacteria by testing the mutagenic activity of a series of platinum compounds on Salmonella typhimurium. Moreover we have carried out a series of experiments in vitro which clearly demonstrate the reactivity of platinum compounds towards DNA and also pointed out the different platinum binding modes. All the platinum compounds we have used react covalently with DNA, Abbreviations. EtdBr, ethidium bromide = 3,X-diamino-6-phenyl-5-ethylphenanthridinium bromide ; en, ethylenediamine = H2N-CHz-CH2-NH2 ; dim, bis(2-aminoethy1)amine = H~N-CHZ-CHZ-NH-CH2-CH2-NH2: guanine N-7, nitrogen atom on position 7 of the guanine molecule in DNA; guanine 0-6, oxygen atom on carbon 6 of the guanine molecule in DNA; adenine N-7, nitrogen atom on position 7 of the adenine molecule; adenine N-3, nitrogen atom on position 3 of the adenine molecule; cytosine N-3, nitrogen atom on position 3 of the cytosine molecule; MezSO, dimethyl sulfoxide. rb, number of Pt atoms bound per nucleotide.i.e. contain at least one labile site. This point is worthy of attention since it was shown that aromatic platinum compounds [6-81 which do not contain any labile site, intercalate between two base pairs in DNA, like certain aromatic organic molecules.The DNA . platinum interaction was quantified
The nitrogen Is binding energies of a series of porphyrins and several platinohematoporphyrin complexes obtained by x-ray photoelectron spectroscopy (XPS) are presented and discussed. The influence of different substituents at the periphery of the porphyrins has been studied; however, no significant change could be detected between the Njs binding energies of the porphyrins studied. A value of 2 eV has been found between aza and pyrrole type nitrogen binding energies. The nature of the sitting-atop (SAT) complex reported in the literature is discussed. XPS gives strong evidence for the existence of the SAT complex, cA-PtCl2H2(Hemato-IX). Two types of nitrogens located at 399.9 eV for N-H and at 398.6 eV for N-*Pt have been found in the SAT complex. Furthermore, the N]s region for the platinohematoporphyrin Pt(Hemato-IX) shows that the four nitrogens are equivalent. A value of 399.4 eV is found for the Njs binding energy of N-Pt where platinum is covalently bound to hematoporphyrin. The difference between the two types of nitrogen binding energies tends to zero in the series, H2(Hemato-IX) ( £ = 2.3 eV) -* ris-PtCl2H2(Hemato-IX) ( = 1.3 eV) -* Pt(Hemato-lX) ( £ = 0 eV), indicating a tendency toward equivalency upon platinum insertion.
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