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PubMed2006

Complexes of Ag(I), Hg(I) and Hg(II) with multidentate pyrazolyl-pyridine ligands: From mononuclear complexes to coordination polymers via helicates, a mesocate, a cage and a catenate.

The coordination chemistry of a series of di- and tri-nucleating ligands with Ag(I), Hg(I) and Hg(II) has been investigated. Most of the ligands contain two or three N,N'-bidentate chelating pyrazolyl-pyridine units pendant from a central aromatic spacer; one contains three binding sites (2 + 3 + 2-dentate) in a linear sequence. A series of thirteen complexes has been structurally characterised displaying a wide range of structural types. Bis-bidentate bridging ligands react with Ag(I) to give complexes in which Ag(I) is four-coordinate from two bidentate donors, but the complexes can take the form of one-dimensional coordination polymers, or dinuclear complexes (mesocate or helicate). A tris-bidentate triangular ligand forms a complicated two-dimensional coordination network with Ag(I) in which Ag...Ag contacts, as well as metal-ligand coordination bonds, play a significant role. Three dinuclear Hg(I) complexes were isolated which contain an {Hg2}2+ metal-metal bonded core bound to a single bis-bidentate ligand which can span both metal ions. Also characterised were a series of Hg(II) complexes comprising a simple mononuclear four-coordinate Hg(II) complex, a tetrahedral Hg(II)4 cage which incorporates a counter-ion in its central cavity, a trinuclear double helicate, and a trinuclear catenated structure in which two long ligands have spontaneously formed interlocked metallomacrocyclic rings thanks to cyclometallation of two of the Hg(II) centres.

Journal Article↗
PubMed1990

Superoxide dismutase and Fenton chemistry. Reaction of ferric-EDTA complex and ferric-bipyridyl complex with hydrogen peroxide without the apparent formation of iron(II).

A ferric-EDTA complex, prepared directly from FeCl3 or from an oxidized ferrous salt, reacts with H2O2 to form hydroxyl radicals (.OH), which degrade deoxyribose and benzoate with the release of thiobarbituric acid-reactive material, hydroxylate benzoate to form fluorescent dihydroxy products and react with 5,5-dimethylpyrrolidine N-oxide (DMPO) to form a DMPO-OH adduct. Degradation of deoxyribose and benzoate and the hydroxylation of benzoate are substantially inhibited by superoxide dismutase and .OH-radical scavengers such as formate, thiourea and mannitol. Inhibition by the enzyme superoxide dismutase implies that the reduction of the ferric-EDTA complex for participation in the Fenton reaction is superoxide-(O2.-)-dependent, and not H2O2-dependent as frequently implied. When ferric-bipyridyl complex at a molar ratio of 1:4 is substituted for ferric-EDTA complex (molar ratio 1:1) and the same experiments are conducted, oxidant damage is low and deoxyribose and benzoate degradation were poorly if at all inhibited by superoxide dismutase and .OH-radical scavengers. Benzoate hydroxylation, although weak, was, however, more effectively inhibited by superoxide dismutase and .OH-radical scavengers, implicating some role for .OH. The iron-bipyridyl complex had available iron-binding capacity and therefore would not allow iron to remain bound to buffer or detector molecules. Most .OH radicals produced by the iron-bipyridyl complex and H2O2 are likely to damage the bipyridyl molecules first, with few reacting in free solution with the detector molecules. Deoxyribose and benzoate degradation appeared to be mediated by an oxidant species not typical of .OH, and species such as the ferryl ion-bipyridyl complex may have contributed to the damage observed.

2,2'-Dipyridyl↗
PubMed1971

Strand-specific supercoiled DNA-protein relaxation complexes: comparison of the complexes of bacterial plasmids ColE1 and ColE2.

Certain bacterial plasmids can be isolated as unique complexes of supercoiled circular DNA and protein. These complexes are distinguished by the conversion of the supercoiled DNA to the relaxed or open-circular DNA form upon treatment with ionic detergents, proteases, or alkali. This report demonstrates that the open-circular DNA resulting from the pronase-induced relaxation of the complexes of colicinogenic factors E(1) (ColE(1)) and E(2) (ColE(2)) possesses a strand-specific break. In each case this break is found in the heavy strand of the DNA as defined by CsCl centrifugation in the presence of poly(U,G). In addition, the ColE(1) and ColE(2) complexes exhibit certain properties that are plasmid specific. Heat treatment, and to a lesser extent pronase treatment, inactivates the ColE(2) complex, making it insensitive to agents that formerly were capable of inducing relaxation (conversion of the DNA to the open-circular form). In contrast, the ColE(1) complex is not inactivated by these treatments. The potential role of these strand-specific relaxation complexes in DNA replication is discussed.

Bacterial Proteins↗
PubMed1983

Protein complexes of intermediate-sized filaments: melting of cytokeratin complexes in urea reveals different polypeptide separation characteristics.

Subunit complexes of cytokeratin polypeptides from intermediate-sized filaments (IF) of various tissues and cultured cells from rat, cow, and man were solubilized in low-salt buffer containing 4 M urea and exposed to increasing concentrations of urea, followed by urea gradient electrophoresis or two-dimensional gel electrophoresis at different urea concentrations. Correspondingly, cytokeratin polypeptides dissociated in 9.5 or 10 M urea were dialyzed into lower concentrations of urea and allowed to reassociate into specific complexes. It was found that the polypeptide constituents of a given cytokeratin complex dissociate in the form of a rather sharp "melting curve" and that dissociated polypeptides reassociate in the same mode of dependence on urea concentration. The midpoint of melting in urea (Um) is a characteristic property of a given complex of cytokeratin polypeptides. Um values differ markedly between different cytokeratin complexes, ranging from 5.9 to 9.0 M urea. The results also show that cytokeratins do not form complexes with vimentin, another type of IF protein. The data suggest that certain cytokeratin polypeptides are complementary and contain sequences that direct their association into specific complexes forming IF subunits.

Animals↗
PubMed1990

The invariant chain forms complexes with class II major histocompatibility complex molecules and antigenic peptides "in vivo".

The binding of a chicken ovalbumin peptide (residues 323-339), Ova-(323-339), to I-Ad molecules was investigated in vitro and in vivo. By using antigenic peptides labeled either with a hapten or with fluorescein, complexes formed in vitro between I-Ad and antigenic peptides were detected by Western blot analysis with an antibody recognizing the hapten 7-nitrobenzo-2-oxa-1,3-diazole and by scanning gels for fluorescence emitted by fluoresceinated peptide. Both techniques reveal that Ova-(323-339) binds not only to I-Ad alpha/beta heterodimers and separated alpha and beta chains but also to complexes of higher molecular mass. Additional analysis shows that one of these additional complexes contains I-Ad heterodimers, antigenic peptides, and also invariant chain. To explore the physiological role of these complexes, cells were incubated with haptenated peptide and the I-Ad-peptide complexes formed in vivo were purified by affinity chromatography using hapten-specific antibody. The complexes formed migrate with a significantly higher apparent molecular mass than the alpha/beta heterodimers. A band at 180 kDa contained the alpha/beta heterodimer, the antigenic peptide, and the invariant chain. These results show that in vivo high molecular mass complexes formed by the I-Ad heterodimer and the invariant chain bind antigenic peptides.

Animals↗
PubMed2003

Disruption of the zinc finger motifs in the Leishmania tarentolae LC-4 (=TbMP63) L-complex editing protein affects the stability of the L-complex.

The uridine insertion/deletion editing complex, which we have termed the L-complex, is composed of at least 16 polypeptides stabilized entirely by protein-protein interactions. Three L-complex proteins contain zinc finger motifs that could be involved in these interactions. In Leishmania these proteins are labeled LC-1, LC-4, and LC-7b, and the orthologs in Trypanosoma brucei are labeled MP81, MP63, and MP42. Overexpression of TAP-tagged LC-4 in Leishmania tarentolae led to a partial localization of the protein in the L-complex together with the endogenous LC-4 protein, suggesting at least a dimeric organization. Disruption of zinc fingers 1 or 2 (ZnF-1 and ZnF-2) in the tagged LC-4 protein was performed by mutation of the two zinc-binding cysteines to glycines. Disruption of ZnF-1 led to a partial growth defect and a substantive breakdown of the L-complex, whereas disruption of ZnF-2 had no effect on cell growth and caused a partial breakdown of the L-complex. A close interaction of LC-4 with 2-4 proteins, including REL1 (RNA ligase) and LC-3, was suggested by chemical crosslinking and co-immunoprecipitation experiments. Our results suggest that both ZnF-1 and ZnF-2 in LC-4 play a role in protein-protein interactions and indicate that the LC-4 subcomplex may be required for formation or stability of the entire L-complex.

Amino Acid Sequence↗
PubMed2004

Efficient incorporation of eukaryotic initiation factor 1 into the multifactor complex is critical for formation of functional ribosomal preinitiation complexes in vivo.

Eukaryotic initiation factor 1 (eIF1) is a low molecular weight factor critical for stringent AUG selection in eukaryotic translation. It is recruited to the 43 S complex in the multifactor complex (MFC) with eIF2, eIF3, and eIF5 via multiple interactions with the MFC constituents. Here we show that FLAG epitope tagging of eIF1 at either terminus abolishes its in vitro interactions with eIF5 and eIF2beta but not that with eIF3c. Nevertheless, both forms of FLAG-eIF1 fail to bind eIF3 and are incorporated into the 43 S complex inefficiently in vivo. C-terminal FLAG tagging of eIF1 is lethal; overexpression of C-terminal FLAG-eIF1 severely impedes 43 S complex formation and derepresses GCN4 translation due to limiting of eIF2.GTP.Met-tRNA(i)(Met) ternary complex binding to the ribosome. Furthermore, N-terminal FLAG-eIF1 overexpression reduces eIF2 binding to the ribosome and moderately derepresses GCN4 translation. Our results provide the first in vivo evidence that eIF1 plays an important role in promoting 43 S complex formation as a core of factor interactions. We propose that the coordinated recruitment of eIF1 to the 40 S ribosome in the MFC is critical for the production of functional 40 S preinitiation complex.

Base Sequence↗
PubMed2005

Caspase-7 is directly activated by the approximately 700-kDa apoptosome complex and is released as a stable XIAP-caspase-7 approximately 200-kDa complex.

MCF-7 cells lack caspase-3 but undergo mitochondrial-dependent apoptosis via caspase-7 activation. It is assumed that the Apaf-1-caspase-9 apoptosome processes caspase-7 in an analogous manner to that described for caspase-3. However, this has not been validated experimentally, and we have now characterized the caspase-7 activating apoptosome complex in MCF-7 cell lysates activated with dATP/cytochrome c. Apaf-1 oligomerizes to produce approximately 1.4-MDa and approximately 700-kDa apoptosome complexes, and the latter complex directly cleaves/activates procaspase-7. This approximately 700-kDa apoptosome complex, which is also formed in apoptotic MCF-7 cells, is assembled by rapid oligomerization of Apaf-1 and followed by a slower process of procaspase-9 recruitment and cleavage to form the p35/34 forms. However, procaspase-9 recruitment and processing are accelerated in lysates supplemented with caspase-3. In lysates containing very low levels of Smac and Omi/HtrA2, XIAP (X-linked inhibitor of apoptosis) binds tightly to caspase-9 in the apoptosome complex, and as a result caspase-7 processing is abrogated. In contrast, in MCF-7 lysates containing Smac and Omi/HtrA2, active caspase-7 is released from the apoptosome and forms a stable approximately 200-kDa XIAP-caspase-7 complex, which apparently does not contain cIAP1 or cIAP2. Thus, in comparison to caspase-3-containing cells, XIAP appears to have a more significant antiapoptotic role in MCF-7 cells because it directly inhibits caspase-7 activation by the apoptosome and also forms a stable approximately 200-kDa complex with active caspase-7.

Apoptosis↗
PubMed2005

CpG-binding protein (CXXC finger protein 1) is a component of the mammalian Set1 histone H3-Lys4 methyltransferase complex, the analogue of the yeast Set1/COMPASS complex.

CpG-binding protein (CXXC finger protein 1 (CFP1)) binds to DNA containing unmethylated CpG motifs and is required for mammalian embryogenesis, normal cytosine methylation, and cellular differentiation. Studies were performed to identify proteins that interact with CFP1 to gain insight into the molecular function of this protein. Immunoprecipitation and mass spectrometry reveal that human CFP1 associates with a approximately 450-kDa complex that contains the mammalian homologues of six of the seven components of the Set1/COMPASS complex, the sole histone H3-Lys4 methyltransferase in yeast. In vitro assays demonstrate that the human Set1/CFP1 complex is a histone methyltransferase that produces mono-, di-, and trimethylated histone H3 at Lys4. Confocal microscopy reveals that CFP1 and Set1 co-localize to nuclear speckles associated with euchromatin. A Set1 complex of reduced mass persists in murine embryonic stem cells lacking CFP1. These cells carry elevated levels of methylated histone H3-Lys4 and reduced levels of methylated histone H3-Lys9. Together with the previous finding of reduced levels of cytosine methylation, these data indicate that cells lacking CFP1 contain reduced levels of heterochromatin. Furthermore, ES cells lacking CFP1 exhibit a 4-fold excess of histone H3-Lys4 methylation following induction of differentiation, indicating that CFP1 restricts the activity of the Set1 histone methyltransferase complex. These results reveal a mammalian counterpart to the yeast Set1/COMPASS complex. The presence of CFP1 in this complex implicates this protein as a critical epigenetic regulator of histone modification in addition to cytosine methylation and reveals one mechanism by which this protein intersects with the epigenetic machinery.

Blotting, Western↗
PubMed1993

The reference range for complexed alpha 2-macroglobulin human plasma: development of a new enzyme linked in immunosorbent assay (ELISA) for quantitation of complexed alpha 2-macroglobulin.

Purified alpha 2-macroglobulin was complexed by reaction with methylamine and used to raise monoclonal murine antibodies. A four-step enzyme linked immunosorbent assay (ELISA) was developed to determine the antibody-specificity of the produced monoclonal murine antibodies towards human native and complexed alpha 2-macroglobulin. Two monoclonal antibodies were selected, H11A11 (specific towards complexed alpha 2-macroglobulin) and 1CG4 (recognizes both forms of the molecule), and purified by affinity chromatography on protein G. The purified antibodies were used to develop a fast three-step ELISA for exact quantitation of complexed and total alpha 2-macroglobulin in human plasma. The intra-assay coefficient of variation (CV) for measurement of complexed alpha 2-macroglobulin is 2.2-9.9%, whereas the inter-assay CV was determined to be 3.7-10.5% and the recovery of the assay is 93-108%. The assay for total alpha 2-macroglobulin has an intra-assay CV of 3.0-15.5%, an interassay CV of 5.1-21.2% and a recovery of 91-116%. Citrated plasma samples from 139 healthy blood donors were examined, resulting in a reference range for complexed alpha 2-macroglobulin of 13.5-31.1 mg 1(-1) with a median value of 21.7 mg 1(-1). The concentration of total alpha 2-macroglobulin was measured by the same assay using the monoclonal antibodies 1CG4. For total alpha 2-macroglobulin we determined the reference range to be 1.12-3.54 g 1(-1) with a median value of 2.14 g 1(-1). Based on these results the reference range for complexed alpha 2-macroglobulin as a percentage of total alpha 2-macroglobulin was calculated to be 0.8-1.9% with a median value of 1.0%.

Adult↗
PubMed1998

X-ray studies on crystalline complexes involving amino acids and peptides XXXIV. Novel mode of aggregation, interaction patterns and chiral effects in the maleic acid complexes of DL- and L- arginine.

Amino acid - carboxylic acid complexes provide useful information in relation to molecular interactions in present day biological systems and to prebiotic self-organisation. The crystal structures of the complexes of maleic acid with DL- arginine (orthorhombic; Pca2(1); a=15.9829, b=5.4127, c=16.1885; R=0.0522 for 956 reflections) and L- arginine (triclinic; P1; a=5.2641, b=8.0388, c=9.7860, alpha=106.197, beta=97.275, gamma=101.64; R=0.039 for 1749 reflections) have been determined. The complexes are made up of positively charged zwitterionic arginine molecules and negatively charged semi-maleate ions which contain an intramolecular symmetric O-H-O hydrogen bond. In both the structures, the amino acid molecules aggregate into layers. In each layer, S2 head-to-tail sequences are interconnected through specific intermolecular interactions between alpha-carboxylate and guanidyl groups, an arrangement observed for the first time in crystal structures involving arginine. The carboxylate-guanidyl interactions are of different types in the two complexes and consequently aggregation patterns in them exhibit substantial differences. Interactions between the amino acid layers involve the semi-maleate ions in both the complexes. In addition, water-bridges also exist in the L complex. The full potential of the guanidyl group for specific interactions is realized in both the structures. The L complex contains an array of water-mediated salt bridges. The structures demonstrate that the effect of chirality on molecular aggregation can span a wide range.

Amino Acids↗
PubMed1990

Loss of a DNA-protein complex correlates with extinguished major histocompatibility complex class II expression in a human B cell.

An E beta DNA protein complex termed complex A, whose binding activity has recently been shown to correlate with both constitutive and regulated class II expression in murine cell lines, is also present in a human B cell, Raji. The DNA involved in complex A, which includes three previously defined transcriptional motifs, W, X, and Y, is a cis-acting transcription element in Raji cells. Both complex A binding activity and transcriptional activity of its target sequence are absent in an Ia- mutant subclone of Raji, RJ 2.2.5. This cell line, whose defect is complemented by a locus on mouse chromosome 16, reexpresses both class II and complex A upon transfection with mouse genomic DNA. We suggest that factors that form complex A or that regulate complex A formation account for the molecular lesion in this cell line.

Animals↗
PubMed1995

T cell recognition of major histocompatibility complex class II complexes with invariant chain processing intermediates.

Peptides from the lumenal portion of invariant chain (Ii) spanning residues 80-106 (class II-associated Ii peptide [CLIP]) are found in association with several mouse and human major histocompatibility complex (MHC) class II allelic variants in wild-type and presentation-deficient mutant cells. The ready detection of these complexes suggests that such an intermediate is essential to the MHC class II processing pathway. In this study, we demonstrate that T cells recognize CLIP/MHC class II complexes on the surface of normal and mutant cells in a manner indistinguishable from that of nominal antigenic peptides. Surprisingly, T cell hybrids specific for human CLIP bound to murine MHC class II molecule I-Ab and a new monoclonal antibody 30-2 with the same specificity, recognize two independent epitopes expressed on this peptide/class II complex. T cell recognition is dependent on a Gln residue (position 100) in CLIP, whereas the 30-2 antibody recognizes a Lys residue-at position 90. These two residues flank the 91-99 sequence that is conserved among human, mouse, and rat Ii, potentially representing an MHC class II-binding site. Our results suggest that the COOH-terminal portion of CLIP that includes TCR contact residue Gln 100 binds in the groove of I-Ab molecule. Moreover, both T cells and the antibody recognize I-Ab complexed with larger Ii processing intermediates such as the approximately 12-kD small leupeptin-induced protein (SLIP) fragments. Thus, SLIP fragments contain a CLIP region bound to MHC class II molecule in a conformation identical to that of a free CLIP peptide. Finally, our data suggest that SLIP/MHC class II complexes are precursors of CLIP/MHC class II complexes.

Alleles↗
PubMed2004

Complexity: an internet resource for analysis of DNA sequence complexity.

The search for DNA regions with low complexity is one of the pivotal tasks of modern structural analysis of complete genomes. The low complexity may be preconditioned by strong inequality in nucleotide content (biased composition), by tandem or dispersed repeats or by palindrome-hairpin structures, as well as by a combination of all these factors. Several numerical measures of textual complexity, including combinatorial and linguistic ones, together with complexity estimation using a modified Lempel-Ziv algorithm, have been implemented in a software tool called 'Complexity' (http://wwwmgs.bionet.nsc.ru/mgs/programs/low_complexity/). The software enables a user to search for low-complexity regions in long sequences, e.g. complete bacterial genomes or eukaryotic chromosomes. In addition, it estimates the complexity of groups of aligned sequences.

Algorithms↗
PubMed1997

Structural and mechanistic studies on D-amino acid oxidase x substrate complex: implications of the crystal structure of enzyme x substrate analog complex.

As an extension of our recent X-ray crystallographic determination of the tertiary structure of D-amino acid oxidase (DAO) [Mizutani, H. et al. (1996) J. Biochem. 120, 14-17], we solved the crystal structure of the complex of DAO with a substrate analog, o-aminobenzoate (OAB). The alignment between flavin and OAB in the crystal structure of the complex is consistent with charge-transfer interaction through the overlap between the highest occupied molecular orbital of OAB and the lowest unoccupied molecular orbital of flavin. Starting with the atomic coordinates of this complex as the initial model, we carried out molecular mechanics simulation for the DAO-D-leucine complex and thus obtained a model for the enzyme-substrate complex. According to the enzyme-substrate complex model, the alpha-proton is pointed toward N(5) of flavin while the lone-pair of the substrate amino group can approach C(4a) of flavin within an interacting distance. This model as well as DAO-OAB complex enables the evaluation of the substrate-flavin interaction prior to electron transfer from the substrate to flavin and provides two possible mechanisms for the reductive-half reaction of DAO, i.e., the electron-proton-electron transfer mechanism and the ionic mechanism.

Amino Acid Oxidoreductases↗
PubMed1984

Partially purified "activated" receptor-glucocorticoid complex from rat liver: regulation of nuclear, chromatin, and DNA-cellulose binding of "activated" complex by pyrophosphate and ATP.

The effects of PP1 and ATP on nuclear binding of the "activated" receptor-[3H]-triamcinolone acetonide (TA) complex purified about 3,000-fold from adrenalectomized rat liver were investigated. ATP at up to 5 mM did not affect nuclear binding of the "activated" complex, but PP1 at 2-7 mM greatly enhanced it. However, ATP in the presence of PP1 decreased nuclear binding dose-dependently. Similar results were obtained in the case of chromatin binding, but PP1 alone did not alter DNA-cellulose binding of the "activated" complex, suggesting that the binding sites for chromatin and DNA on the "activated" complex are different. Furthermore, PP1 enhanced ATP-agarose binding of the "activated" complex, indicating that the PP1 binding site(s) on the receptor is different from the ATP binding site(s). The physicochemical properties of the "activated" receptor-glucocorticoid complex bound with ATP and/or PP1 were examined by sucrose density gradient centrifugation and Sephadex G-150 gel filtration. There was no detectable change in the sedimentation coefficient or molecular weight (about 4.2S; Mr approximately equal to 98,000) on binding with ATP and/or PP1. These results suggest that the binding of PP1 and PP1 plus ATP to the "activated" complex caused some allosteric change of the acceptor binding sites of the receptor, resulting in increase or decrease in its binding to nuclei, chromatin, or DNA.

Adenosine Triphosphate↗
PubMed2002

Social cognitive complexity and depression: cognitive complexity moderates the correlation between depression self-ratings and global self-evaluation.

The authors studied the psychometric characteristics of a standardized data-collection method for assessing the complexity of an individual's cognitions about self and other people (social cognitive complexity). A total of 437 college undergraduates were assessed using this method and concurrently assessed for depression, self-deception, impression management, self-esteem, and positive/negative affectivity. It was found that a measure of overall social cognitive complexity was internally consistent and demonstrated concurrent and discriminant validity. In particular, a composite measure of the complexity of both positive and negative cognitions of self and other was associated with greater self-reported depression, after controlling for the other variables studied (, impression management). It was also found that social cognitive complexity moderated the degree of global self-evaluation in self-reported depression, such that global self-evaluation accounted for a considerably higher amount of the variance of depression in low-complex individuals than it did in high-complex individuals.

Cognition↗
PubMed2004

New platinum(IV) complex with adamantylamine ligand as a promising anti-cancer drug: comparison of in vitro cytotoxic potential towards A2780/cisR cisplatin-resistant cell line within homologous series of platinum(IV) complexes.

The aim of this study was to compare anti-tumor potency of platinum(IV) complexes with increasing hydrophobicity of their ligands. Cytotoxic potential of the new platinum(IV) complex, coded as LA-12 [(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)], was compared within the series of complexes of the general formula (OC-6-43)-bis(acetato)(alkylamine)amminedichloroplatinum(IV). Alkylamine ligands with increasing hydrophobicity were: isopropylamine, cyclohexylamine, 1-adamantylamine and 3,5-dimethyl-1-adamantylamine. Particular platinum(IV) complexes were coded as LA-4, LA-2 (known as JM-216), LA-12 and LA-15, respectively. Cytotoxicity was tested with the microplate tetrazolium (MTT) assay on the panel of cancer cell lines and the results were verified by microscopy. HPLC was used to measure hydrophobicity, stability of complexes in various buffers and velocity constants for their reactivity with glutathione. Platinum(IV) complexes with bulky hydrophobic ligands (LA-12 and LA-15) demonstrated about one order higher velocity constant for pseudo-first-order reaction with glutathione in comparison to cisplatin, LA-4 and LA-2, whose velocity constants were close to those measured for cisplatin and related platinum(II) complexes. Cytotoxicities of LA-12 and LA-15 towards cisplatin-resistant epithelial carcinoma A2780/cisR were superior to cisplatin, LA-4 and LA-2 in both 24- and 72-h continuous exposure MTT tests. Rapid induction of apoptosis in the treated cancer cell lines and no cisplatin cross-resistance were found for LA-12, which is a candidate for clinical testing.

Amantadine↗