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Results for “Coordination Complexes”

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PubMed1986

Phase I clinical trial and pharmacokinetics of carboplatin (NSC 241240) by single monthly 30-minute infusion.

Carboplatin (diammine [1,1-cyclobutanedicarboxylate(2-)-O,o']platinum) is a second generation platinum coordination complex. It has a spectrum of activity that is similar to that of cisplatin and is less nephrotoxic and emetogenic in experimental animals. Fifty-two 30-minute infusions of carboplatin were given to 20 evaluable patients with a variety of solid tumors. Maximum tolerated dose was 440 mg/m2. Thrombocytopenia (less than 100,000/mm3) occurred in six of seven patients; two patients experienced a leukocyte count less than 2000/mm3. Platelet and leukocyte count nadirs occurred on day 21. No nephrotoxicity was seen. Blood urea nitrogen, serum creatine levels, and creatinine clearances remained normal, and no consistent elevation of urinary beta 2-microglobulin, leucine aminopeptidase, or N-acetyl-beta-glucosaminidase occurred. Nausea and vomiting were mild to moderate. A single patient developed mild peripheral neuropathy. No auditory toxicity was noted. The recommended dose for Phase II studies is 400 mg/m2 every 28 days for good risk patients; heavily pretreated patients should receive 320 mg/m2.

Antineoplastic Agents↗

PubMed2002

Synergism of catalysis and reaction center rehybridization in nucleophilic additions to cumulenes: the one-, two-, three-water hydrolyses of carbodiimide and methyleneimine.

The results of a theoretical study of the one-, two- and three-water hydrolyses of carbodiimide and the one- and two-water hydrolyses of methyleneimine are presented. All structures were optimized and characterized at the MP2(full)/6-31G* level of theory. Energies for the one-water hydrolysis of carbodiimide were determined at numerous higher levels of theory, up to the QCISD(T)(fc)/6-311+G(3df,2p)//MP2(full)/6-31G* level. The Delta E0(Delta G298) activation barriers for the rate-determining steps of the one-, two- and three-water hydrolyses of carbodiimide, respectively, are 44.8 (46.3), 29.3 (32.3) and 22.9 (26.2) kcal mol(-1) at the MP2(full)/6-31G* level. The consideration of a second water molecule catalyzes the hydrolysis by 15.5 kcal mol(-1) on the E0 surface and by 14.0 kcal mol(-1) on the G298 surface with respect to the one-water hydrolysis. Placement of a third water molecule opposite the site of proton transfer catalyzes the reaction by an additional 6.4 kcal mol(-1) on the E0 surface and by 6.1 kcal mol(-1) on the G298 surface. The catalytic effect of the third water molecule results from the synergistic effects of rehybridization and charge relaxation in the transition state. The charge relaxation in the transition state is illustrated through natural population analysis calculations on the pre-coordination complexes and the transition state structures. We also consider the placement of the third water molecule in the proton transfer chain and we show this to be of little catalytic relevance. The activation barriers determined for the one- and two-water hydrolyses of methyleneimine are Delta G298=51.9 and Delta G298=35.5 kcal mol(-1), respectively, and they are larger than for carbodiimide. The results are compared with the hydrolyses of carbon dioxide and formaldehyde.

Carbodiimides↗

PubMedDate not supplied

Cisplatin: chemistry, distribution and biotransformation.

A review of the use of cisplatin in cancer chemotherapy in humans is presented. The emphasis is placed on the chemistry, in vivo distribution and biotransformation of this agent. The existing literature pertinent to the physicochemical properties of cisplatin and structure activity relationships of platinum coordination complexes is reviewed. The chemistry of this drug, both in aqueous media and in biological systems is discussed as well as current analytical methodology used for monitoring 'cisplatin levels' in biological fluids. Recent advances in analytical methodology specific for cisplatin are also presented and recent findings in the area of the possible biotransformations of this important anticancer agent are discussed.

Biotransformation↗

PubMed1986

Fast atom bombardment mass spectrometry of cisplatin analogs.

Cisplatin analogs of the type PtLACl2 and PtLALB are thermally unstable, non-volatile and highly insoluble. For these platinum coordination complexes, LA is a bidentate amine ligand and LB is a bidentate carboxylate ligand. Mass spectral data for structural elucidation of these compounds are absent in the literature because they are difficult to ionize. Nevertheless, a routine fast atom bombardment mass spectroscopic method has been developed utilizing the mixed solvent system of dimethyl sulfoxide:thioglycerol in a ratio of about 1:3 v/v. Using both positive and negative ionization modes, structurally significant ions were observed from representative molecules of the two named classes of compounds. [M-H]- ions were observed in both structural classes while [M + H]+ ions were observed only in the PtLALB class of compounds. Additional ions observed are rationalized in terms of the condensed-phase solution chemistry of the cisplatin analogs and the mixed solvent system when exposed to the fast atom beam. The two mechanisms causing ionization of the cisplatin analogs in the condensed phase appear to be: displacement of the ligands with dimethyl-sulfoxide and addition of chloride and the ionized solvents [dimentyl sulfoxide + H]+ and [thioglycerol - H]- to the cisplatin analogs. It is hypothesized that the addition reactions of the ionized solvents occur because of the differences in the basicity of the solvents and their reactivity in forming platinum(II)-sulfur bonds.

Cisplatin↗

PubMed2004

Synthesis and self-assembly of a rigid exotopic bisphenanthroline macrocycle: surface patterning and a supramolecular nanobasket.

The synthesis and characterisation of a rigid nanoscale macrocycle with two exotopic phenanthroline binding sites is reported. Scanning tunnelling microscopy (STM) at the solid-liquid interface reveals the formation of highly ordered monolayers of macrocycles with dimensions that are in good agreement with the calculated structure. Using the HETPHEN concept several bisheteroleptic coordination complexes with other phenanthrolines and a nanoscale basket assembly were prepared in presence of copper(I) ions. NMR spectroscopy, mass spectrometric data and elemental analysis point to three distinct isomers of the basket assembly in solution. A silver basket was prepared and readily converted to its copper analogue. Electrospray ionisation (ESI)-MS and spectrophotometric investigations provided additional mechanistic insight into the assembly process. Hence, the exotopic bisphenanthroline macrocycle in combination with HETPHEN concept proves to be very effective in controlling the compositional aspects of multicomponent self-assembly.

Journal Article↗

PubMed2006

Ionic solid-state dimers and polymers derived from imidazolium dicarboxylic acids.

A series of imidazolium dicarboxylic acids have been prepared from the reaction of the 1,3-bis(carboxymethyl)imidazolium zwitterion with the Brønsted acids HX (X = F, Br, Cl, ClO4). The structures of these acids have been established in the solid state by single-crystal X-ray diffraction, which revealed that the cations and anions form strong hydrogen bonds through O-H...X interactions, leading to the formation of dimeric and polymeric networks. These acids react with elemental zinc and cobalt to form stable polymeric coordination complexes, some of which have also been characterised by X-ray diffraction.

Journal Article↗

PubMed2007

Hydrogencyanamide-bridged one-dimensional polymers built on Mn(III)-Schiff base fragments: synthesis, structure, and magnetism.

The ability of NCNH(-) to construct transition metal coordination polymers and to transmit magnetic coupling was investigated. By introduction of various tetradentate Schiff base ligands (L) and different solvents (S), nine NCNH(-)-bridged manganese(III) coordination complexes were obtained. Their structures can be divided into three types: I) NCNH-bridged chains built on mononuclear [Mn(III)(L)] units, [Mn(III)(L)(mu(1,3)-NCNH)](n) (L=5-Brsalen (1), 5-Clsalen (2)); II) NCNH-bridged chains built on dinuclear [Mn(III) (2)(L)(2)] units, complexes 3-8, [Mn(III) (2)(L)(2)(mu(1,3)-NCNH)]ClO(4)S (L=salen, 5-Fsalen, 5-Clsalen, 5-OCH(3)salen; S=CH(3)OH or C(2)H(5)OH); III) NCNH-bridged Mn(III) dimers linked by hydrogen bonds into a 1D polymer, {[Mn(III)(3-OCH(3)salen)(H(2)O)](2)(mu(1,3)-NCNH)}ClO(4) x 0.5 H(2)O (9, salen=N,N'-bis(salicylidene)-1,2-diaminoethane). In these complexes, the N[triple chemical bond]C--NH(-) resonance structure dominates the bonding mode of the NCNH(-) ligand adopting the mu(1,3)-bridging mode. Magnetic characterization shows that the asymmetric NCNH(-) bridge transmits antiferromagnetic interaction between Mn(III) ions and often favors the weak ferromagnetism caused by spin canting in these one-dimensional chains. However, these complexes exhibit different magnetic behaviors at low temperatures.

Journal Article↗

PubMed1995

Differential innervation of protruder and retractor muscles of the tongue in rat.

Protrusion and retraction of the tongue are essential components of such orofacial behaviors as mastication, respiration, and swallowing. Stimulation of the medial branch of the hypoglossal nerve yields tongue protrusion, while stimulation of the lateral branch yields tongue retraction in rat. We exploited the transsynaptic transport capabilities of pseudorabies virus to determine specific circuits that innervate protruder and retractor muscles of the rat tongue. Each group of muscles is innervated by distinct populations of hypoglossal motoneurons: caudal ventral and ventrolateral motoneurons form the largest proportion of those innervating protruders, whereas rostral dorsal motoneurons innervate retractors. Our primary finding was differential innervation of protruder and retractor motoneurons by premotoneurons in the lateral tegmental field: premotoneurons innervating protruder motoneurons were more ventral and ventromedial than those innervating retractor motoneurons. In addition, protruder motoneurons received projections from the ipsilateral lateral parabrachial nucleus but not spinal trigeminal nucleus or medial and ventral subnuclei of the solitary tract; the converse was true for retractor motoneurons. These results suggest segregation of functional networks that control hypoglossal motoneurons. The dorsal medulla, in or around the solitary tract, contains neurons specific to retractor motoneurons, and the region ventrolateral to the hypoglossal nucleus contains circuitry specific to protruder motoneurons. Common innervation of medial and lateral branch motoneurons is provided by premotoneurons in the raphe and gigantocellular reticular formation of the medial medulla. The midline medullary nuclei with diverse projections may coordinate complex behavior or modulate general motoneuron excitability, whereas the lateral reticular formation, with anatomically discrete projections, may control motoneurons that contribute to distinct orofacial behaviors.

Animals↗

PubMedDate not supplied

Phase I and II agents in cancer therapy: two cisplatin analogues and high-dose cisplatin in hypertonic saline or with thiosulfate protection.

Cisplatin is a chemotherapeutic coordination complex that has been evaluated extensively. It is particularly active against testicular cancer, but carcinomas of the ovary, bladder, cervix, and head and neck are also responsive. To increase efficacy and decrease toxicity, a number of platinum analogues have been developed and tested. One of these, carboplatin, is of particular interest. In clinical trials, it has demonstrated antitumor activity comparable to that of cisplatin, without evidence of significant renal toxicity or neurotoxicity. A second interesting platinum analogue is iproplatin. Preliminary phase I studies suggest reduced adverse renal and neurologic effects similar to those seen with carboplatin, with efficacy comparable to cisplatin. Attempts to overcome the dose-limiting toxicity of cisplatin by administering high-dose cisplatin (40 mg/m2/d for five days) in hypertonic saline or with thiosulfate protection are also reviewed. These techniques have eliminated nephrotoxicity as the dose-limiting toxicity of cisplatin. However, nonrenal toxicity, especially neurotoxicity, remains substantial. The extent to which high-dose cisplatin-based chemotherapy should be used in routine clinical practice has not been determined.

Carboplatin↗

PubMed1976

Structure of neuronal assemblies in cerebral cortex.

Interrelations in the apical dendrite bundles of a single neuronal column were revealed by means of light and electron microscopy in the cat motor cortex. Such column presents an integrated structural module. There were also found wider joinings of several columns, among which complex coordination may exist.

Animals↗

PubMed2006

Affinity monolith chromatography.

The combined use of monolithic supports with selective affinity ligands as stationary phases has recently given rise to a new method known as affinity monolith chromatography (AMC). This review will discuss the basic principles behind AMC and examine the types of supports and ligands that have been employed in this method. Approaches for placing affinity ligands in monoliths will be considered, including methods based on covalent immobilization, biospecific adsorption, entrapment, and the formation of coordination complexes. Several reported applications will then be presented, such as the use of AMC for bioaffinity chromatography, immunoaffinity chromatography, immobilized metal-ion affinity chromatography, dye-ligand affinity chromatography, and biomimetic chromatography. Other applications that will be discussed are chiral separations and studies of biological interactions based on AMC.

Chromatography, Affinity↗

PubMed2005

Changes induced by levodopa and subthalamic nucleus stimulation on parkinsonian speech.

Levodopa (L-dopa) and subthalamic nucleus (STN) stimulation treatments have been associated with both improvement and exacerbation of dysarthria in Parkinson's disease (PD). We report four cases illustrating variant responses of dysarthria to dopaminergic and STN stimulation therapies. Patients' motor disability and dysarthria were perceptually rated by the Unified Parkinson's Disease Rating Scale (UPDRS) in four conditions according to medication and STN stimulation. Dedicated software packages allowed acquisition and analysis of acoustic recordings. Case 1, who had a severe off period aphonia, experienced improvement of speech induced by both levodopa and STN stimulation. In Case 2, both treatments worsened speech due to the appearance of dyskinesias. Case 3 had a dysarthria exacerbation induced by STN stimulation with parameters above optimal levels, interpreted as current diffusion from the STN to corticobulbar fibers. In Case 4, dysarthria exacerbation occurred with stimulation at an electrode contact located caudally to the target, also arguing for current diffusion as a potential mechanism of speech worsening. The presented cases demonstrated variant effects in relation to L-dopa and STN stimulation on speech. It seems that motor speech subcomponents can be improved like other limb motor aspect, but that complex coordination of all speech anatomical substrates is not responsive to STN stimulation. These hypotheses may be helpful for better understanding and management of STN stimulation effects on motor speech and skeleton-motor subsystems.

Adult↗

PubMed2001

Three-dimensional model of the cyclin-dependent kinase 1 (CDK1): Ab initio active site parameters for molecular dynamics studies of CDKS.

Cyclin-dependent kinase 1 (CDK1) is an interesting target for potential anticancer drugs, and its three-dimensional (3D) structure is presently unknown. The purpose of this work was to build a 3D model of CDK1, which could be used in drug design studies. The protein 3D structure was homology modeled, based on the known crystal structure of CDK2, and new nonbonded parameters for the Mg(2+) coordination complex were developed by means of ab initio quantum chemical calculations. These parameters were both obtained and validated using the CDK2 structure as reference, and then they were used for the refinement of the CDK1 model. The resulting CDK1 structure was satisfactory and stable at room temperature, as shown by the molecular dynamics simulations carried out over a 1-ns time interval on the entire protein. A number of representative kinases in the active and inactive form, including the inactive CDK1 modeled in this work, were compared. The results illustrate the conformational variability of the activation loop of the inactive form of the kinases and suggest a way for selectively targeting the single CDKs.

Amino Acid Sequence↗

PubMed1994

Comprehension and imitation of syntax following early hemisphere damage.

Twenty-five children with early left (LL = 16) or right (RL = 9) hemisphere damage and 25 age-matched controls were tested on their comprehension and imitation of complex coordinate, passive, and relative clause structures using a matched experimental design. The predominant deficit exhibited by left-injured children was one of significantly impaired imitation coupled with relatively preserved comprehension. For RL subjects the deficit was less pronounced in either comprehension or imitation. Manipulation of surface and configurational features of sentence structure revealed task differences in the pattern of correct performance; however, error strategies observed across the two methodologies were shown to converge in a number of critical ways, as well as to replicate those previously obtained with adult aphasics. The results are interpreted as consistent with an early and continuous left hemisphere specialization for expressive syntax.

Adolescent↗

PubMed2001

Overexpression of camello, a member of a novel protein family, reduces blastomere adhesion and inhibits gastrulation in Xenopus laevis.

Vertebrate gastrulation involves complex coordinated movements of cells and cell layers to establish the axial structures and the general body plan. Adhesion molecules and the components of extracellular matrix were shown to be involved in this process. However, other participating molecules and detailed mechanisms of the control of gastrulation movements remain largely unknown. Here, we describe a novel Xenopus gene camello (Xcml) which is expressed in the suprablastoporal zone of gastrulating embryos. Injection of Xcml RNA into dorsovegetal blastomeres retards or inhibits gastrulation movements. Database searches revealed a family of mammalian mRNAs encoding polypeptides highly similar to Xcml protein. Characteristic features of the camello family include the presence of the central hydrophobic domain and the N-acetyltransferase consensus motifs in the C-terminal part, as well as functional similarity to Xcml revealed by overexpression studies in Xenopus embryos. Xcml expression results in the decrease of cell adhesion as demonstrated by the microscopic analysis and the blastomere aggregation assay. Cell fractionation and confocal microscopy data suggest that Xcml protein is localized in the secretory pathway. We propose that Xcml may fine tune the gastrulation movements by modifying the cell surface and possibly extracellular matrix proteins passing through the secretory pathway.

Acetyltransferases↗

PubMed2001

Determination of the pK(a) of the four Zn2+-coordinating residues of the distal finger motif of the HIV-1 nucleocapsid protein: consequences on the binding of Zn2+.

The nucleocapsid protein NCp7 of human immunodeficiency virus type 1 is characterized by two highly conserved CCHC motifs that bind Zn2+ strongly. To elucidate the striking pH-dependence of the apparent Zn2+-binding constants of these motifs further, we investigated, using 1H NMR, potentiometry and fluorescence spectroscopy, the acid-base properties of the four Zn2+-coordinating residues of (35-50)NCp7, a peptide corresponding to the distal finger motif of NCp7. With the exception of the H(beta2) proton of Cys39, the pH-dependence of the H(beta) proton resonances of the three Cys residues and, the H(delta) and H(epsilon) resonances of His44 in the apopeptide could be fitted adequately with a single pK(a). This suggests that the protonating groups are non-interacting, a feature that was confirmed by a potentiometric titration. The pK(a) of His44, Cys36, Cys39, and Cys49 in the apopeptide were found to be 6.4, 8.0, 8.8 and 9.3, respectively. Accordingly, the deprotonation is almost sequential and may thus induce a sequential binding of Zn2+ to the four coordinating residues. The high pK(a) of Cys49 is probably related to the negative charge of the neighboring Asp48. Such a high pK(a) may be a general feature in nucleocapsid proteins (NCs), since an acidic residue generally occupies the (i-1) position of the C-terminal Cys residue of single-finger NCs and distal finger motifs in two-finger NCs. Molecular dynamics simulation suggested the formation of a hydrogen bonded network that weakly structured the Cys36-Cys39 segment in the apopeptide. This network depends on the protonation state of Cys36 and may thus explain the biphasic behavior of the pH-dependence of the Cys39 H(beta2) resonance. Finally, the pK(a) values were used to build up a model describing the coordination of Zn2+ to (35-50)NCp7 at equilibrium. It appears that each protonation step of the coordination complex decreases the Zn2+-binding constant by about four orders of magnitude and that a significant dissociation of Zn2+ from the holopeptide can be achieved in acidic cell compartments.

Amino Acid Sequence↗

PubMed1985

Comparative cytotoxicity between cisplatin and second generation platinum analogs.

The cytotoxic activity of cis-DDP and four second generation platinum coordination complexes (TNO-6; JM-82; JM-8; and JM-9) was compared on six established human colon carcinoma cell lines with different degrees of differentiation. Cytotoxicity was evaluated by the inhibition of colony formation technique. Cis-DDP was uniformily active against all lines. JM-8 and JM-9 were virtually ineffective for all cell lines, even at concentrations as high as 50 micrograms/ml. JM-82 was slightly more active although (with the exception of LoVo cells) still about 10-fold less efficacious than cis-DDP. TNO-6 was the only derivative with appreciable cytotoxic activity although about 2 to 5-fold less than cis-DDP for lines SW48, 620, 480, and 1116. For LoVo and SW403, TNO-6 was slightly more active than cis-DDP. In both such instances, increased efficacy resulted from abrogation of the shoulder region of the survival curve while the slope remained essentially intact. Thus any enhancement in therapeutic efficacy with these second generation analogues can only be expected from possible decreases in toxic effects but not from superior tumor cell kill activity.

Antineoplastic Agents↗

PubMed1976

Tissue fixation and osmium black formation with nonvolatile octavalent osmium compounds.

Several compounds of osmiumVIII, including potassium osmiamate and coordination complexes of OsO4 with ammonia and various heterocyclic nitrogen compounds, have been synthesized and characterized. They have also been evaluated as substitutes for OsO4 in postfixation of biological specimens and in light and electron microscopic cytochemical methods resulting in osmium black formation. The most useful of these osmic compounds, a molecular addition complex of hexamethylenetetramine (methenamine) with OsO4, has a negligible vapor pressure of OsO4. It has the molecular formula C6H12N4.2OsO4 and has been designated osmeth. Although it has only limited solubility, aqueous solutions of the compound (or of OsO4) can be rapidly prepared by dissolution in a minimal amount of dimethylformamide and subsequent dilution with distilled water or buffer. Although stable in the solid state, the complex in solution undergoes partial dissociation releasing OsO4, and the odor of OsO4 becomes apparent. Such solutions of osmeth are (approximately 0.25%) considerably less concentrated with respect to OsO4 than solutions (1-2%) ordinarily employed for ultrastructural preservation or in cytochemical studies. Osmeth has limited value for postosmication after glutaraldehyde fixation because the generation (release) of OsO4 appears to be slow. Adequate osmication of tissue blocks exists only at the surface, but effective osmication can be achieved throughout tissue sections. In cytochemical reactions resulting in the formation of osmium blacks, the osmeth solutions are as effective as OsO4 solutions of equivalent concentrations. Our findings indicate that OsO4 solutions of less than 1% may be satisfactorily utilized in many cytochemical studies. Osmeth is safer and more convenient to handle than OsO4 because small amounts may be solubilized as needed. It should be considered as a substitute for OsO4 in ultrastructural cytochemistry. These results suggest that the effectiveness of OsO4 as a fixative may, in part, be related to its nonpolarity. The infrared spectra indicate that the OsO4 molecule is tetrahedral, perfectly symmetrical and, therefore, as a whole nonpolar. As a consequence, it could be expected to readily penetrate charged surfaces of tissues, cells, and organelles. The spectral studies show that osmeth is much less symmetrical and, to that extent, polar; thus, it penetrates biomembranes less readily.

Animals↗