cis-Dichloroplatinum(II) complexes tethered to 9-aminoacridine-4-carboxamides: synthesis and action in resistant cell lines in vitro.

A series of intercalator-tethered platinum(II) complexes PtLCl(2) have been prepared where L are the diamine ligands N-[2-[(aminoethyl)amino]ethyl]-9-aminoacridine-4-carboxamide, N-[3-[(2-aminoethyl)amino]propyl]-9-aminoacridine-4-carboxamide, N-[4-[(2-aminoethyl)amino]butyl]-9-aminoacridine-4-carboxamide and N-[5-[(aminoethyl)amino]pentyl]-9-aminoacridine-4-carboxamide and N-[6-[(aminoethyl)amino]hexyl]-9-aminoacridine-4-carboxamide. The activity of the complexes was assessed in the CH-1, CH-1cisR, 41M, 41McisR and SKOV-3 cell lines. The compounds with the shorter linker chain lengths are generally the most active against these cell lines and are much more toxic than Pt(en)C1(2). For example, for the n=2 compound the IC(50) values are 0.017 microM (CH-1), 1.7 microM (41M), 1.4 microM (SKOV-3) and the resistance ratios are 51 (CH-1cisR) and 1.6 (41McisR). For the untethered analogue Pt(en)C1(2) the IC(50) values are 2.5 microM (CH-1), 2.9 microM (41M), 45 microM (SKOV-3) and the resistance ratios are 2.8 (CH-1cisR) and 4.1 (41McisR). The very large differential in IC(50) values between the CH-1 and CH-1cisR pair of cell lines for the 9-aminoacridine-4-carboxamide tethered platinum complexes indicates that repair of platinum-induced DNA damage may be a major determinant of the activity of these compounds.     

Optical properties of DNA complexes with antitumor compounds of bivalent platinum

The optical properties of the DNA complexes with the compounds of bivalent platinum were studied. The compounds differed by the nature of the anionic and neutral ligands and their spatial arrangement about the platinum atom. It was shown that the same as cis-[Pt (NH3)2Cl2] the platinum compounds with the biological activity, i.e. [Pt (en) Cl2], cis-[PtNH3 (Bz) Cl2] and cis-[Pt (NH3)2NO2Cl] induced at low values of r (a ratio of the number of the platinum moles added to the number of the DNA nucleotide moles in the solution) an increase in the amplitude of the positive band in the spectrum of the circular dichroism (CD) of the linear DNA and a marked decrease in the amplitude of the negative band in the spectrum of the CD of the liquid crystalline microphase of DNA formed in the presence of polyethyleneglycol. By the character of the action on the CD spectrum of the linear and condensed DNA [Pt (tetrameen)Cl2] which had no selective antimitotic effect might be referred to the above platinum compounds. Trans-[Pt (NH3)2NO2Cl], [PtNH3PyCl2], cis-[Pt (NH3)2(NO2)2] and [Pt (NH3)3Cl]Cl having no biological activity either induced only a decrease in the amplitude of the positive band in the CD spectrum of the linear DNA or had no effect on the CD spectrum. The effect of these compounds on the CD spectrum of the liquid crystalline microphase of DNA was slightly pronounced or not observed.     

A circular dichroism study of DNA.platinum complexes. Differentiation between monofunctional, cis-bidentate and trans-bidentate platinum fixation on a series of DNAs

The circular dichroism (CD) spectra of a series of DNA . platinum complexes are presented. The following platinum compounds, [Pt(dien)Cl]Cl, cis-Pt(NH3)2Cl2, cis-Pt(en)Cl2, trans-Pt-(NH3)2Cl2, K[Pt(NH3)Cl3] and K2[PtCl4] were complexed with the DNA extracted from bacteria Micrococcus lysodeikticus (72% dG + dC), Escherichia coli (50% dG + dC), Clostridium perfringens (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. [Pt(dien)Cl]Cl, is fixed to DNA with only one bond (monofunctional complex formation) and no significant change of the CD positive band of DNA is found. The main feature of the second type is a continuous intensity decrease of the positive band as observed for trans-Pt(NH3)2Cl2 (trans-bidentate complex formation). The third type concerns the cis-bidentate platinum fixation obtained with cis-Pt(NH3)2Cl2, cis-Pt(en)Cl2, K[Pt(NH3)Cl3] and K2[PtCl4]. The CD spectra are in this case characterized by an increase in the positive Cotton effect which is dG + dC-dependent up to an rb value around 0.10 (where rb = number of platinum atoms bound per nucleotide), followed by a decrease until DNA saturation with platinum is reached. A linear decrease in the amplitude of the negative band is detected in all the complexes except in the case of the monofunctional DNA . Pt complexes. For the cis-bidentate and trans-bidentate platinum fixation, a continuous bathochromic shift occurs.     

A study of interactions of platinum (II) compounds with DNA by means of CD spectra of solutions and liquid crystalline microphases of DNA

The optical properties of the DNA complexes with divalent platinum compounds of the cis-diamine type differing both in the nature of anionic and neutral ligands and in the spatial arrangement about the platinum atom were studied. The platinum compounds cis-[Pt(NH3)2Cl2], [Pt(en)Cl2], [Pt(tetrameen)Cl2], cis-[Pt(NH3)2NO2Cl], and cis-[PtNH3(Bz)Cl2] at small values of r (r is the molar ratio of a platinum compound to DNA nucleotides in the reaction mixture) were found to induce an increase in the amplitude of the positive band in the circular dichroic (CD) spectrum of linear DNA. All the compounds listed except cis-[Pt(NH3)2NO2Cl] caused a sharp decrease of the amplitude of the negative band in the CD spectrum of a liquid crystalline microphase of DNA formed in solution in the presence of poly(ethylene glycol). All these platinum compounds (except [Pt(tetrameen)Cl2]) exhibit biological (antimitotic, antitumour, etc.) activity. The platinum compounds trans-[Pt(NH3)Cl2], trans-[Pt(NH3)2NO2Cl], cis-[PtNH3PyCl2], cis-[Pt(NH3)2(NO2)2], and [Pt(NH3)3Cl]Cl exhibiting a low (if any) biological activity, either induced a decrease of the amplitude of the positive band in the CD spectrum of linear DNA, or did not affect the CD spectrum at all. The effect of these platinum compounds on the CD spectrum of the liquid crystalline microphase of DNA was either weak or absent. It is assumed that the specific biological action of platinum compounds of the cis-diamine type is determined by the polydentate binding to DNA: in addition to the cis-bidentate covalent binding of platinum to DNA nitrogen bases, a hydrogen bond formation between the DNA and cis-amino ligands occurs by means of protons at nitrogen atoms.     

The interaction of cisplatin and analogues with DNA in reconstituted chromatin

The influence of chromatin structure on cis-diamminedichloroplatinum(II) (cisplatin) DNA damage was investigated in a reconstituted nucleosome system. Nucleosomes were reconstituted on the somatic 5S rRNA gene from Xenopus borealis using the octamer transfer method of reconstitution. Footprinting techniques, utilising bleomycin and DNase I as the damaging agents, were employed to establish the precise location of positioned nucleosomes with respect to the DNA sequence. Reconstituted nucleosomal DNA was treated with cisplatin and drug-induced DNA adduct formation was quantitatively analysed with a polymerase stop assay using Taq DNA polymerase. A densitometric comparison of the relative damage band intensities between purified and reconstituted DNA revealed regions of relative protection corresponding to the sites of the positioned nucleosome cores. This indicated that the preferred site of cisplatin DNA binding was in the linker region of the nucleosome. Statistical analysis showed significant protection from cisplatin DNA damage in the core region of the nucleosome. Three cisplatin analogues were also investigated in this reconstituted nucleosome system. These analogues, cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (carboplatin), cis-dichlorobis(cyclohexylamine)platinum(II) (cis-[PtCl(2)(C(6)H(11)NH(2))(2)]) and dichloro(N-[3-[(2-aminoethyl)-amino]propyl]acridine-4-carboxamide)platinum(II) (ac-PtenCl(2)(n3)), were also found to target the linker region of the nucleosome. The latter DNA-targeted acridine-platinum complex gave rise to the most predominant footprints of all the Pt compounds tested.     

Modulation of platinum antitumor drug binding to DNA by linked and free intercalators

We report the DNA binding site preferences of the novel molecule AO-Pt, in which the anticancer drug dichloro(ethylenediamine)platinum(II) is linked by a hexamethylene chain to acridine orange. The sequence specificity of platinum binding was mapped by exonuclease III digestion of 165 and 335 base pair restriction fragments from pBR322 DNA. Parallel studies were carried out with the unmodified anticancer drugs cis-diamminedichloroplatinum(II) (cis-DDP) and dichloro(ethylenediamine)platinum(II), [Pt(en)Cl2]. Oligo(dG) sequences are the most prevalent binding sites for AO-Pt, with secondary binding occurring mainly at d(AG) sites. cis-DDP and [Pt(en)Cl2] bind less readily to the secondary sequences, with cis-DDP showing greater binding site selectivity than [Pt(en)Cl2]. The DNA intercalator ethidium bromide promotes binding of [Pt(en)Cl2] and cis-DDP to many sites containing d(CGG) and, to a lesser extent, d(AG) sequences. AO-Pt exhibits enhanced binding to these sequences without the need for an external intercalator. Unlinked acridine orange, however, does not promote binding of [Pt(en)Cl2] and cis-DDP to d(CGG) and d(AG) sequences. These results are discussed in terms of the sequence preferences, stereochemistry, and relative residence times of the intercalators at their DNA binding sites. By modulating local structure in a sequence-dependent manner, both linked and, in the case of ethidium, free intercalators can influence the regioselectivity of covalent modification of DNA by platinum antitumor drugs.     

Preparation, 195Pt NMR spectra and biological activity of platinum (IV) complexes with dipeptides

Three dipeptide complexes of the form K[Pt(IV) (dipep) Cl(OH)2] and four dipeptide complexes of the form K[Pt(IV)-(Hdipep)Cl2(OH)2] were newly prepared. The 195 Pt NMR peak of the K[Pt(IV) (dipep)Cl(OH)2] complexes appeared at about 1200 ppm and these chemical shifts were about 3150 ppm downfield compared with those of the K[Pt(II) (dipep) Cl] complexes. The chemical shifts of the K[Pt(IV) (Hdipep) Cl2 (OH)2] complexes were at about 900 ppm, i.e., about 3050 ppm downfield compared with those of the K[Pt(II) (Hdipep)Cl] complexes. The H[Pt(IV) (Hdigly) Cl2(OH)2] and K[Pt(IV) (Hdigly) Cl2(OH)2] complexes inhibited the growth of C. albicans at a more diluted concentration than cisplatin at 1 microgram/ml, but the platinum complexes only weakly inhibited the growth of these cells compared with the cisplatin-inhibited growth of Meth-A and Hep-2 cells at 10 micrograms/ml. These results suggested that the platinum complexes selectively inhibited the growth of fungal cells.     

Intercalation into the DNA double helix and in vivo biological activity of water-soluble planar [Pt(diimine)(N,N-dihydroxyethyl-N'-benzoylthioureato)]+Cl- complexes: a study of their thermal stability, their CD spectra and their gel mobility

The interaction of newly synthesised water-soluble planar complexes of general structure [Pt(diimine)(N,N-dihydroxyethyl-N'-benzoylthioureato)]+Cl- with DNA was investigated by means of DNA melting studies, CD spectroscopy, and DNA gel mobility studies. Addition of stoichometric amounts of [Pt(diimine)H2L-S,O]Cl complexes to polynucleotides caused a significant increase in the melting temperature of poly(dA-dT) and calf-thymus DNA, respectively, indicating that these complexes interacted with DNA and stabilised the double helical structure. The CD spectra confirmed the relatively strong binding of three related Pt(II) complexes ([Pt(2,2'-bipyridine)H2L-S,O]Cl, [Pt(4,4'-dimethyl-2,2'-bipyridine)H2L-S,O]Cl, and [Pt(1,10-phenanthroline)H2L-S,O]Cl), to DNA. Comparison with the published CD spectra of ethidium bromide/DNA complex suggests a similar intercalation mode of binding. cis-[(4,4'-di-tert-butyl-2,2'-bipyridyl)N,N-di(2-hydroxyethyl)-N'-benzoylthioureatoplatinum(II)] chloride, with its very bulky tert-butyl groups, did not intercalate into the polynucleotide double helix. In DNA mobility studies in the presence of the four [Pt(diimine)H2L-S,O]Cl complexes, only [Pt(2,2'-bipyridine)H2L-S,O]Cl affected the DNA mobility to any detectable extent. Finally, in vivo studies on the biological activity of the complexes, using an Escherichia coli DNA excision repair deficient uvrA mutant strain, indicated that only the [Pt(2,2'-bipyridine)H2L-S,O]Cl complex showed significant cellular toxicity and that this was, in part, linked to DNA damage.     

The interaction of an anti-tumour platinum complex with DNA.

The interaction of the anti-tumour active cis platinum (II) complexes with DNA has been investigated using dichloro(ethylenediamine)platinum(II) and E. coli DNA. Equilibrium dialysis studies indicate that Pt(en)Cl2 binds reversibly to DNA to a saturation value of 0.57 Pt: P, which is consistent with the platinum being bound both monofunctionally and bifunctionally. Pt(en)Cl2 inhibits the intercalation of 9-aminoacridine (9AA) by cross-linking the bases of the double helix, but at no stage does all the bound platinum cross-link. It is suggested that this inhibition of intercalation is due to intrastrand cross-linking.     

Platinum complexes of p- and m-aminobenzamidine. Synthesis, characterization, and cytotoxic activity.

Four platinum(II) aminobenzamidine complexes have been prepared and characterized by IR and 1H and 13C NMR spectroscopy, and tested for their ability to interact with the nicked and closed circular forms of the pUC8 plasmid DNA. The results show that the complexes of formula [Pt(LH)2Cl2]2X have a cis- geometry with an amino-Pt bonding, where L is either p- or m-aminobenzamidine and where 2X is 2Cl- or PtCl4(2-). It was observed that these complexes significantly alter the electrophoretic mobility of nicked and closed circular forms of DNA and that the alteration in electrophoretic mobility due to Pt(II)-p-aminobenzamidine binding is higher than that due to Pt(II)-m-aminobenzamidine. No difference in mobility was observed whether the DNA interacted with complexes having as counteranion Cl- or PtCl4(2-). The synthesized compounds were, in addition, assayed for antitumor activity in vitro against colon (CX-1), lung (LX-1), and mammary (MX-1) human tumor cells. The results show that these complexes inhibited the multiplication of the tumor cells and that they show higher specificity for lung cells.     

Mono- and polynuclear complexes of Pt(II) with polypyridyl ligands. Synthesis, spectroscopic and structural characterization and cytotoxic activity

An array of poly- and mononuclear complexes of Pt(II) with polypyridyl ligands is reported. The framework complexes [(PtCl(2))(2)(bpp)(2)(micro-PtCl(2))](H(2)O)(2) [bpp=2,3-bis(2-pyridyl)pyrazine], [PtCl(2)(micro-tptz)PtClNCPh]Cl [tptz=2,4,6-tris(2-pyridyl)-1,3,5-triazine], and mononuclear PtCl(2)(NH(2)dpt) [NH(2)dpt=4-amino-3,5-bis(2-pyridyl)-1,2,4-triazole] have been prepared and structurally characterized. Both neutral and ionic complexes are present, with bifunctional and monofunctional Pt(II) moieties, whose size and shape enable them to behave as novel scaffolds for DNA binding. Pt(II) complexes were tested for their biological activity. Cell viability assay and flow cytometric analysis demonstrated that these complexes, particularly [PtCl(2)(micro-tptz)PtClNCPh]Cl, were effective death inducers in human colon rectal carcinoma HT29 cells and their cytotoxic activity was higher than that exerted by cisplatin. Morphological analysis of treated HT29 cells, performed by fluorescence microscopy after Hoechst 33258 staining, showed the appearance of the typical features of apoptosis. Moreover, our results suggested that mitochondria are involved in apoptosis induced by Pt(II) complexes in HT29 cells as demonstrated by dissipation of mitochondrial transmembrane potential.     

Synthesis, spectroscopic, cytotoxic, and DNA binding studies of binuclear 2,2'-bipyridine-platinum(II) and -palladium(II) complexes of meso-alpha,alpha'-diaminoadipic and meso-alpha,alpha'-diaminosuberic acids.

Four new binuclear complexes of formula [M2(bipy)2(BAA)]Cl2 (where M is Pt(II) or Pd(II), bipy is 2,2'-bipyridine, and BAA is a dianion of meso-alpha-alpha'-diaminoadipic acid (DAA) or meso-alpha,alpha'-diaminosuberic acid (DSA) have been synthesized. These complexes have been characterized by chemical analysis and ultraviolet-visible, infrared, and 1H NMR spectroscopy. The mode of binding of ligands in these complexes has been ascertained by infrared and detailed 1H NMR spectroscopy. These complexes are 1:2 electrolyte in conductivity water. They have also been tested against P388 lymphocytic leukemia cells and their target is DNA molecules. [Pt2(bipy)2(DSA)]Cl2, [Pd2(bipy)2(DSA)Cl2, and [Pd2(bipy)2(DAA)]Cl2 show I.D.50 values comparable or lower than cis-diamminedichloroplatinum(II) and [Pt(bipy)(Ala)]Cl. In addition, binding studies of [Pt2(bipy)2(DSA)]Cl2 and [Pd2(bipy)2(DAA)]Cl2 to calf thymus DNA have been carried out and the mode of binding seems to be hydrogen bonding, as suggested earlier for analogous mononuclear amino acid-DNA complexes.     

Mixed ligand complexes of platinum(II) and palladium(II) with cytokinin-derived compounds Bohemine and Olomoucine: X-ray structure of [Pt(BohH+-N7)Cl(3)].9/5H2O [Boh=6-(benzylamino)-2-[(3-(hydroxypropyl)-amino]-9-isopropylpurine,Bohemine

The new square-planar Pt(II) and Pd(II) complexes with cytokinin-derived compounds Bohemine and Olomoucine, having the formulae [Pt(BohH(+))Cl(3)].H(2)O (1), [Pt(Boh)(2)Cl(2)].3H(2)O (2), [Pt(Boh-H)Cl(H(2)O)(2)].H(2)O (3), [Pt(OloH(+))Cl(3)].H(2)O (4), [Pd(BohH(+))Cl(3)].H(2)O (5), [Pd(Boh)Cl(2)(H(2)O)] (6), [Pd(Boh-H)Cl(H(2)O)].EtOH (7) and [Pd(OloH(+))Cl(3)].H(2)O (8), where Boh=6-(benzylamino)-2-[(3-(hydroxypropyl)amino]-9-isopropylpurine and Olo=6-(benzylamino)-2-[(2-(hydroxyethyl)amino]-9-methylpurine, have been synthesized. The complexes have been characterized by elemental analyses, IR, FAB+ mass, 1H, 13C and 195Pt NMR spectra, and conductivity data. The molecular structure of the complex [Pt(BohH(+)-N7)Cl(3)].9/5H(2)O has been determined by an X-ray diffraction study. Results from physical studies show that both Bohemine and Olomoucine are coordinated to transition metals through the N(7) atom of purine ring in all the complexes. The prepared compounds have been tested in vitro for their possible cytotoxic activity against G-361 (human malignant melanoma), HOS (human osteogenic sarcoma), K-562 (human chronic myelogenous leukemia) and MCF-7 (human breast adenocarcinoma) cell lines and IC(50) values have been also determined for all the complexes. IC(50) values estimated for the Pt(II)-Bohemine complexes (2.1-16 microM) allow us to conclude that they could find utilization in antineoplastic therapy. Thus, from a pharmacological point of view, Pt(II) complexes of Bohemine may represent compounds for a new class of antitumor drugs.     

Synthesis, characterization, and cytotoxic activity of copper(II) and platinum(II) complexes of 2-benzoylpyrrole and X-ray structure of bis[2-benzoylpyrrolato(N,O)]copper(II)

Copper(II) and platinum(II) complexes of 2-benzoylpyrrole (2-BZPH) were synthesized and characterized with IR, 1H and 13C NMR spectroscopies and coordination geometry with ligands arranged in transoid fashion. The crystal structure of [Cu(II)(2-BZP)2] was determined by X-ray diffraction. Death of complex treated Jurkat cells was measured by flow cytometry. The bis-chelate complexes [Cu(II)(2-BZP)2] and [Pt(II)(2-BZP)2] adopt square-planar coordination geometry with ligands, arranged in transoid fashion. Concentrations of 1-10 microM Platinum(II) complexes reduced cell survival from 100% to 20%, in contrast to the copper(II) complex which caused no cell death at a concentration of 10 microM. While the Pt(II) complexes may have damaged DNA to induce cell death, treatment with the Cu(II) complex did not induce Jurkat cell death.     

Bis[platinum(II)] and bis[platinum(IV)] complexes with optically active bis(vicinal-1,2-diamines) and their interaction with DNA.

Bis[platinum(II)] [Cl2Pt(LL)PtCl2] complexes 2,5 and 8 with chiral non-racemic ligands: 1a-c (LL = (R,R), (S,S) and (R,S) N,N'-bis(3,4-diaminobutyl)hexanediamide); 4a,b (LL = (R,R) and (S,S) N,N'-bis[3,4-bis(diaminobutyl)] urea); 7a-d (LL' = (R,R), (S,S), (R,S) and (S,R) 4,5-diamino-N-(3,4-diaminobutyl) pentanamide) and bis[platinum(IV)] complex 10-13 with ligands 1a,b and 4a,b have been prepared and characterized by IR, 1H, 13C and 195Pt NMR spectra. The interactions of 2a-c, 5a, 5b, 8a-d and 10a with dsDNA were investigated with the goal of examining whether the chirality, the nature of the spacer and the oxidation state have an influence on platinum-DNA binding properties. All the bis[platinum(II)] complexes form with dsDNA intra- and interstrand crosslinks and crosslinks over sticky ends, whereas the bis[platinum(IV)] complex 10a only forms intra- and interstrand crosslinks. The platinum-DNA coordination sites were determined by the T4 DNA polymerase footprinting method. The results show that all investigated bis(platinum) complexes have high preference towards distinct purines. All isomeric bis(amide) 2a-c and mono(amide) 8a-d complexes exhibit nearly the same binding pattern, whereas the ureide complexes 5a and 5b have other coordination sites with higher sequence preference. Interestingly, the ureides 5a and 5b differ in their coordination sites not only in comparison to the bis(amides) 2a-c and mono(amides) 8a-d, but also between each other. The bis[platinum(IV)] complex 10a also differs in coordination sites in comparison to all the bis[platinum(II)] compounds.     

The effect of ancillary ligand chirality and phenanthroline functional group substitution on the cytotoxicity of platinum(II)-based metallointercalators

Fifteen platinum(II)-based metallointercalators have been synthesised that utilise substituted 1,10-phenanthroline (phen) ligands, including 5-chloro-1,10-phenanthroline (5-Cl-phen), 5-methyl-1,10-phenanthroline (5-CH3-phen), 5-amino-1,10-phenanthroline (5-NH2-phen), 5-nitro-1,10-phenanthroline (5-NO2-phen) and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), and achiral ethylenediamine (en) and the chiral ancillary ligands 1S,2S-diaminocyclohexane (S,S-dach) and 1R,2R-diaminocyclohexane (R,R-dach). Their cytotoxicity in the L1210 murine leukaemia cell line was determined using growth inhibition assays. The most cytotoxic metal complexes are those that contain S,S-dach ancillary ligands and 5-CH3-phen intercalating ligands. One metallointercalator [Pt(5-CH3-phen)(S,S-dach)]Cl2 (5MESS), displays a 5-10-fold increase in cytotoxicity compared to the clinical agent cisplatin. From DNA binding experiments there appears to be no significant difference between any of the metal complexes, indicating that neither DNA binding affinity nor the mode of binding/DNA adduct formed is the sole determinant of the cytotoxicity of this family of platinum(II)-based metallointercalators.     

Synthesis and antitumour activity of platinum(II) and platinum(IV) complexes containing ethylenediamine-derived ligands having alcohol, carboxylic acid and acetate substituents. Crystal and molecular structure of [PtL4CL2].H20 where L4 is ethylenediamine-N,N'-diacetate

Several cisplatin analogues of ethylenediamine-derived ligands containing alcohol, carboxylic acid and acetate substituents have been prepared and characterised. Oxidation of some of these square planar platinum(II) complexes using aqueous hydrogen peroxide gave octahedral platinum(IV) complexes, containing trans hydroxo ligands. Acetylation of the hydroxo ligands was achieved by reaction with acetic anhydride, giving complexes which are analogues of the antitumour drug, JM-216. Oxidation of the complex [Pt(H2L4)Cl2], where H2L4 is ethylenediamine-N,N'-diacetic acid, with H2O2 gave the platinum(IV) complex [PtL4Cl2].H2O in which L4 is tetradentate as shown by a crystal and molecular structure. This complex was previously reported to be [Pt(HL4)(OH)Cl2] in which HL4 is tridentate. Several of the complexes were tested for antitumour activity against five human ovarian carcinoma cell lines. IC50 values range from 4.0 microM for cis,trans-PtCl2(OH)2(NH2CH2CH2NHCH2CH2OH) against the CH1 cell line to >25 microM indicating moderate to low activity relative to other platinum complexes.     

Syntheses, Characterization, and Antitumor Activities of Platinum(II) and Palladium(II) Complexes with Sugar-Conjugated Triazole Ligands

Four platinum(II) and palladium(II) complexes with sugar-conjugated bipyridine-type triazole ligands, [Pt(II) Cl(2) (AcGlc-pyta)] (3), [Pd(II) Cl(2) (AcGlc-pyta)] (4), [Pt(II) Cl(2) (Glc-pyta)] (5), and [Pd(II) Cl(2) (Glc-pyta)] (6), were prepared and characterized by mass spectrometry, elemental analysis, (1) H- and (13) C-NMR, IR as well as UV/VIS spectroscopy, where AcGlc-pyta and Glc-pyta denote 2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (1) and 2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethyl β-D-glucopyranoside (2), respectively. The solid-state structure of complex 6 was determined by single-crystal X-ray-diffraction analysis. These complexes exhibited in vitro cytotoxicity against human cervix tumor cells (HeLa) though weaker than that of cisplatin.     

Effects of amine ligand bulk and hydrogen bonding on the rate of reaction of platinum(II) diamine complexes with key nucleotide and amino acid residues

NMR spectroscopy has been used to observe the effects of the amine ligand on the rate of reaction of platinum diamine and triamine complexes with DNA and protein residues. Whereas [Pt(dien)Cl]Cl and [Pt(dien)(D(2)O)](2+) have been known to react faster with thioether residues such as N-AcMet than with 5'-GMP, we found that [Pt(Me(4)en)(D(2)O)(2)](2+) appeared to react faster with 5'-GMP. To quantitatively assess the factors influencing the rates of reaction, rate constants at pH 4 were determined for the reactions of [Pt(en)(D(2)O)(2)](2+) [en = ethylenediamine] and [Pt(Me(4)en)(D(2)O)(2)](2+) with N-AcMet, N-AcHis, 5'-GMP, and Guo (guanosine). In each case the less bulky complex ([Pt(en)(D(2)O)(2)](2+)) reacts more quickly than does the bulkier [Pt(Me(4)en)(D(2)O)(2)](2+), as expected. Both complexes reacted faster with 5'-GMP; however, analysis of the rate constants suggests that the [Pt(en)(D(2)O)(2)](2+) complex favors reaction with 5'-GMP due to hydrogen bonding with the 5'-phosphate, whereas [Pt(Me(4)en)(D(2)O)(2)](2+) disfavors reaction with N-AcMet due to steric clashes. Bulk had relatively little effect on the rate constant with N-AcHis, suggesting that peptides or proteins that coordinate via His residues would not have their reactivity affected by bulky diamine ligands.     

The binding of binuclear platinum(II)-terpyridine complexes to DNA.

The binding of platinum (II)-terpyridine complexes to DNA was studied by using equilibrium dialysis. Optical absorption methods were used to measure the ability of the ligands to aggregate in aqueous buffer. Scatchard plots for the binding of the monomeric [Pt(terpy)SC4H9]+ cation to DNA at I0.01 are curvilinear, concave upwards, suggesting two modes of binding. The association constant decreases at higher ionic strengths, consistent with polyelectrolyte theory, and 1.1 cations are released per bound ligand molecule. The association constants of the binuclear ligands [Pt(terpy)S[CH2]4S(terpy)Pt]2+ and [Pt(terpy)S[CH2]6S(terpy)Pt]2+ are 8 and 23 times larger respectively than the affinity of the monomer. For the latter binuclear derivative the increase may be ascribed to bifunctional reaction. Differential dialysis experiments with DNAs of differing base composition show that [Pt(terpy)SC4H9]+ has a requirement for a single G X C base-pair at the highest-affinity site. However, in the binuclear ligands chromophore specificity is severely compromised. Similar experiments indicate that 9-aminoacridine and selected methylene-linked diacridines show no significant sequence selectivity.