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PubMed2001

Stacking efficiency of diselenadiazolyl pi-dimers. Consequences for electronic structure and transport properties.

The preparation and crystal structure of 5-cyanofuran-2-[1,2,3,5-diselenadiazolyl], [RCN(2)Se(2)] (R = 5-cyanofuran), is reported. Crystal data for C(6)H(2)ON(3)Se(2): monoclinic, space group P2(1), a = 7.1121(7), b= 20.541(2), c =20.923(2) A, beta = 99.785(1) degrees, Z = 16. The crystal structure consists of diselenadiazolyl pi-dimer stacks running parallel to the x direction; the asymmetric unit consists of four pi-dimer units. The dimers are aligned into snakelike ribbons along the y direction, with consecutive dimers linked by head-to-tail CN-Se contacts. Each pi-dimer stack is bordered by two out-of-register stacks, but most interstack Se-Se contacts lie outside the van der Waals separation. Along the pi-dimer stacks, the intradimer Se-Se distances range from 3.183(10) to 3.294(1) A, and the interdimer Se-Se distances range from 3.826(1) to 3.945(1) A. Like other pi-dimer stacked diselenadiazolyls, [C(6)H(2)ON(3)Se(2)](2) is diamagnetic over the temperature range 4-380K. Variable temperature single-crystal conductivity measurements reveal a room-temperature conductivity near 10(-5) S cm(-1) and provide a calculated band gap of 0.72 eV. The structural results and transport properties are interpreted in the light of Extended Hückel band structure calculations.

Journal Article↗
PubMed2006

Structural evolution in polyoxometalates: a DFT study of dimerization processes in Lindqvist and Keggin cluster anions.

Density functional theory (DFT) calculations are used to investigate dimerization, by acid condensation, between Lindvist and Keggin cluster anions. When specific addendum atoms are present (notably, Ti, V, Nb, and Cr), these clusters dimerize in the presence of acid via the formation of mu-O linkages. These processes may be viewed as molecular models for the formation of metal-oxygen bonds in the active sites of metalloenzymes, or in materials chemistry, and we here provide detailed information concerning these reactions. For this, DFT calculations are used to provide insight into the mechanism(s) associated with dimerization of Lindqvist clusters, W5MO19(n-) (M = W, Mo, V, Nb, and Ti) in acidic media. In full accord with experimental data, our calculations show that dimerization of Nb and Ti derivatives is thermodynamically favored and that this is not the case for dimerization between Mo, V, and W addendum atoms. In addition, dimerization of PW11TiO40(5-) and SiW11NbO40(5-) to give the corresponding dimers was also calculated to be exothermic. Two possible mechanisms, involved in two competing pathways, are evaluated and discussed. Conclusions are presented concerning the role played by the nature of the metal atoms taking part in M-mu-O-M bond formation. A correlation is established between the relative strengths of specific terminal M=O bonds in monomeric precursors and the tendency of these to form M-mu-O-M bonds.

Journal Article↗
PubMed1996

Heme-Peptide Models for Hemoproteins. 2. N-Acetylmicroperoxidase-8: Study of the pi-pi Dimers Formed at High Ionic Strength Using a Modified Version of Molecular Exciton Theory.

AcMP8 is the Cys-14-acetylated water-soluble heme-octapeptide fragment obtained proteolytically from cytochrome c. Two successive dimerization equilibria are observed with increasing ionic strength in aqueous solution at neutral pH (part 1, preceding article). The electronic spectra of the two pi-pi dimers were extracted from the absorption envelopes at 2.01 and 4.02 M ionic strength and resolved by Gaussian analysis. The principal transitions were assigned using a tailored version of molecular exciton theory based on coupling of the main x- and y-polarized transition dipole moments of the interacting heme groups. The spectra of both pi-pi dimers indicate that the y-polarized exciton states are blue-shifted relative to the excited states of the monomer, while the x-polarized exciton states exhibit a red shift. These shifts were correctly predicted by a simple dipole-dipole coupling model. From an analysis of the resultant transition dipole moments to the exciton states with B(x)()(0,0) and B(y)()(0,0) character and the magnitudes of their red and blue exciton shifts, respectively, we have determined the dipole-dipole interaction geometries for both dimers. The principal difference between the interaction geometry in the first dimer and that in the second is a stronger interaction for the y-polarized transition dipoles and somewhat weakened interaction for the x-polarized transition dipoles. From an analysis of available crystallographic data for porphyrin and metalloporphyrin pi-pi dimers (Scheidt, W. R.; Lee, Y. J. Struct. Bonding 1987, 64, 1) and the results of our exciton model, we conclude that the origin of the coordinate system for the Soret transition dipole moments of AcMP8 is not metal-centered. Furthermore, since the true directions of the x- and y-axes of the low-symmetry heme chromophore in AcMP8 are unknown, we have not been able to determine the structures of the pi-pi dimers from a knowledge of their transition dipole-dipole interaction geometries. This study therefore highlights one of the shortfalls of molecular exciton theory.

Journal Article↗
PubMed2001

Dimeric phenalenyl-based neutral radical molecular conductors.

We report the preparation, crystallization, and solid-state characterization of ethyl (3)- and butyl (4)-substituted spiro-biphenalenyl radicals. Both of these compounds are found to be conducting face-to-face pi-dimers in the solid state but with different room-temperature magnetic ground states. At room temperature, 4 exists as a diamagnetic pi-dimer (interplanar separation of approximately 3.1 A), whereas 3 is a paramagnetic pi-dimer (interplanar separation of approximately 3.3 A), and both compounds show phase transitions between the paramagnetic and diamagnetic forms. Electrical resistivity measurements of single crystals of 3 and 4 show that the transition from the high-temperature paramagnetic pi-dimer form to the low-temperature diamagnetic pi-dimer structure is accompanied by an increase in conductivity by about 2 orders of magnitude. This behavior is unprecedented and is very difficult to reconcile with the usual understanding of a Peierls dimerization, which inevitably leads to an insulating ground state. We tentatively assign the enhancement in the conductivity to a decrease in the on-site Coulombic correlation energy (U), as the dimers form a super-molecule with twice the amount of conjugation.

Journal Article↗
PubMed2003

Stable (long-bonded) dimers via the quantitative self-association of different cationic, anionic, and uncharged pi-radicals: structures, energetics, and optical transitions.

Unusual dimers with wide interplanar separations, that is, very long bonds with d(D) approximately 3.05 A, are common to the spontaneous self-association of various organic pi-radicals in solution and in the crystalline solid state, independent of whether they are derived from negatively charged anion radicals of planar electron acceptors (TCNE-*, TCNQ-*, DDQ-*, CA-*), positively charged biphenylene cation-radical (OMB+*), or neutral phenalene radical (PHEN*). All dimeric species are characterized by intense absorption bands in the near-IR region that are diagnostic of the charge-transfer transitions previously identified with intermolecular associations of various electron-donor/acceptor dyads. The extensive delocalizations of a pair of pi-electrons accord with the sizable values of (i) the enthalpies (-Delta H(D)) and entropies (-Delta S(D)) of pi-dimerization measured by quantitative UV-vis/EPR spectroscopies and (ii) the electronic coupling element H(ab) evaluated from the strongly allowed optical transitions, irrespective of whether the diamagnetic dimeric species bear a double-negative charge as in (TCNE)(2)(2-), (TCNQ)(2)(2-), (DDQ)(2)(2-), (CA)(2)(2-) or a double-positive charge as in (OMB)(2)(2+) or are uncharged as in (PHEN)(2). These long-bonded dimers persist in solution as well as in the solid state and suffer only minor perturbations with Delta d(D) < 10% from extra-dimer forces that may be imposed by counterion electrostatics, crystal packing, and so forth. The characteristic optical transitions in such diamagnetic two-electron dimers are shown to be related to those in the corresponding paramagnetic one-electron pimers of the same pi-radicals with their parent acceptor, both in general accord with Mulliken theory.

Journal Article↗
PubMed2006

Aromaticity on the pancake-bonded dimer of neutral phenalenyl radical as studied by MS and NMR spectroscopies and NICS analysis.

We have demonstrated the first MS and NMR observation of a face-to-face pi-bonded dimer of an organic radical (pancake-bonded dimer coined by R. S. Mulliken) in solution, using tri-tert-butylated phenalenyl radical 1, a 3-fold symmetric neutral hydrocarbon. In addition to the direct detection of the dimer signal by cold-spray ionization mass spectrometry (CSI-MS), 1H and 13C NMR spectra in solution gave definitive evidence of a well-defined D3d dimer structure with a 12-center-2-electron-long C-C bond formation, which is the same symmetry as seen in the crystalline state. On the basis of the NMR peaks of the dimer in the aromatic region (6.47 ppm for 1H NMR and 120-143 ppm for 13C NMR), we carried out nucleus-independent chemical shift (NICS) analysis, which showed that the ring center of the dimer became more aromatic (-7.1 ppm) than that of the monomer (-3.8 ppm). The trend of aromaticity generation was more pronounced in the interior of the dimer, which has been interpreted by the negative electron density induced in the bonding region as seen in the electrostatic potential surface.

Journal Article↗
PubMed1998

The DFRC Method for Lignin Analysis. 4. Lignin Dimers Isolated from DFRC-Degraded Loblolly Pine Wood.

Sixteen lignin dimers were directly isolated by gel permeation and reversed-phase TLC and HPLC from loblolly pine (Pinus taeda L.) sapwood following large-scale application of the new derivatization followed by reductive cleavage (DFRC) procedure. Their structures were elucidated by GC/MS and NMR. These dimers included representatives from all of the common interunit linkages in softwood lignins (beta-1, beta-beta, 5-5, beta-5, and 5-O-4). The DFRC procedure efficiently cleaves beta-aryl ethers, the major structural unit, so beta-ethers were not found among the dimeric products. All but two of the isolated dimers were guaiacyl-guaiacyl (from coniferyl alcohol-derived units in lignin); small amounts of p-hydroxyphenyl/guaiacyl beta-5 and beta-1 dimers were characterized. Several dimers have benzaldehydes as one unit-since aldehydes are not created by the procedure, they are either present in the native lignin or are formed during the minimal preparation of the wood. The dimers isolated and identified here will eventually allow their quantitation to aid in the structural analyses of wide-ranging plant materials.

Journal Article↗
PubMed1995

Synthesis and anti-HIV activity of [AZT]-[TSAO-T] and [AZT]-[HEPT] dimers as potential multifunctional inhibitors of HIV-1 reverse transcriptase.

In an attempt to combine the HIV-inhibitory capacity of 2',3'-dideoxynucleoside (ddN) analogues and non-nucleoside reverse transcriptase (RT) inhibitors (NNRTI), we have designed, synthesized, and evaluated for their anti-HIV activity several dimers of the general formula [ddN]-(CH2)n-[NNRTI]. These dimers combine in their structure a ddN such as AZT and a NNRTI such as TSAO-T and HEPT linked through an appropriate spacer between the N-3 of the thymine base of both compounds. The [TSAO-T]-(CH2)n-[AZT] dimers proved markedly inhibitory to HIV-1. Also, if AZT was replaced by thymidine in the dimer molecules, potent anti-HIV-1 activity was observed. However, although the compounds proved inhibitory to HIV-1, they were less potent inhibitors than the parent compounds from which they were derived. None of the dimers were endowed with anti-HIV-2 activity. In contrast with the TSAO-T monomers, none of the TSAO-T-containing dimers proved markedly cytotoxic to the cells. There was a clear trend toward decreased antiviral potency with lengthening the methylene spacer in the [TSAO-T]-(CH2)n-[AZT] dimers.

Antiviral Agents↗
PubMed1992

Synthesis and biological activity of new dimers in the 7H-pyrido[4,3-c] carbazole antitumor series.

Ditercalinium (NSC 366241) is a 7H-pyrido[4,3-c]carbazole dimer with a diethylbipiperidine rigid chain linking the two heterocyclic rings. Ditercalinium is characterized by a high DNA affinity and bisintercalating ability, associated with potent antitumor properties, involving an original mechanism of action. Unfortunately as ditercalinium is hepatotoxic, its clinical evaluation has been interrupted. In order to eliminate or at least minimize the serious drawbacks related to its toxic effects, several chemical modifications have been made to the structure of ditercalinium, and their influence has been evaluated by measuring the DNA affinities, intercalation properties, and toxicity toward leukemia cells of the newly synthesized dimers. Reduction of the pyridinic moieties of ditercalinium, in order to suppress the permanent charges provided by the quaternizing chain, led to an almost complete loss of activity, although the DNA bisintercalating property of the dimer was preserved. Dimerization of the 7H-pyrido[4,3-c]carbazole rings by introduction of the rigid spacer on the N7- or C6-positions corresponding to the convex face of the pyridocarbazole, instead of the N2-position in ditercalinium, led to DNA bisintercalating dimers practically devoid of antitumor properties. However after quaternarization of the N2 atoms, the dimer linked by the N7 atoms exhibited a very high DNA affinity (greater than 10(9) M-1) and recovered antitumor activity, supporting the requirement of positive charges for the emergence of antitumor activity in these dimers. Introduction on the C6 of the 7H-pyridocarbazole ring of an aminomethyl or carboxyl group, a sugar residue, or C or N free amino acids such as Lys or Glu has also been carried out, in order to increase the hydrophilic properties of the molecules or to enable them to use amino acid transport systems. Although some of these compounds were active, none of them exhibited the pharmacological potency of ditercalinium.

Animals↗
PubMed2002

Design, synthesis, and evaluation of new noncross-linking pyrrolobenzodiazepine dimers with efficient DNA binding ability and potent antitumor activity.

New sequence selective mixed imine-amide pyrrolobenzodiazepine (PBD) dimers have been developed that are comprised of DC-81 and dilactam of DC-81 subunits tethered to their C8 positions through alkanedioxy linkers (comprised of three to five and eight carbons). Thermal denaturation studies show that after 18 h of incubation with calf thymus DNA at a 5:1 DNA/ligand ratio, one of them (5c) increases the DeltaT(m) value by 17.0 degrees C. Therefore, these unsymmetrical molecules exhibit significant DNA minor groove binding affinity and 5c linked through the pentanedioxy chain exhibits efficient DNA binding ability that compares with the cross-linking DSB-120 PBD dimer (DeltaT(m) = 15.4 degrees C). Interestingly, this imine-amide PBD dimer has been linked with a five carbon chain linker unlike DSB-120, which has two DC-81 subunits with a three carbon chain linker, illustrating the effect of the noncross-linking aspect by introducing the noncovalent subunit. The binding affinity of the compounds has been measured by restriction endonuclease digestion assay based on inhibition of the restriction endonuclease BamHI. This study reveals the significance of noncovalent interactions in combination with covalent bonding aspects when two moieties of structural similarities are joined together. This allows the mixed imine-amide PBD dimer with a five carbon chain linker to achieve an isohelical fit within the DNA minor groove taking in to account both the covalent bonding and the noncovalent binding components. This has been supported by molecular modeling studies, which indicate that the PBD dimer with a five carbon chain linker gives rise to maximum stabilization of the complex with DNA at the minor groove as compared to the other PBD dimers with three, four, and eight carbon chain linkers. The energy of interaction in all of the complexes studied is correlated to the DeltaT(m) values. Furthermore, this dimer 5c has significant cytotoxicity in a number of human cancer cell lines.

Antineoplastic Agents↗
PubMed2002

Structure and thermodynamics of alpha-, beta-, and gamma-cyclodextrin dimers. Molecular dynamics studies of the solvent effect and free binding energies.

The alpha-, beta-, and gamma-cyclodextrin (CyDs) dimers were studied by molecular dynamics (MD) simulations in water as an explicit solvent. The relative stability of dimers and the involved molecular interactions were determined. Three possible starting orientations were considered for the dimers: head-to-head, head-to-tail, and tail-to-tail. MD simulations were performed over a period of 5 ns to ensure the stability of the system for both the CyD dimers and monomers. The MM-PBSA methodology was used to obtain the free binding energy of the dimers and to determine the most stable arrangement for each solvated CyD. In a vacuum, MD simulations provided the head-to-head orientation as the most stable orientation for the three CyDs, while in aqueous solution the, the head-to-tail orientation was found to be the most stable for the alpha-CyD dimer and the tail-to-tail orientation the most stable for the beta- and gamma-CyD dimers.

Journal Article↗
PubMed2004

Experimental and theoretical studies of the dimerizations of imidoylketenes.

Reaction conditions are presented that, for the first time, allow the generation and dimerization of N-alkylimidoylketenes, e.g.,1d, while avoiding the intramolecular rearrangements observed under conventional conditions. The dimer of 1d (22a) is the result of [4 + 2] cycloaddition across the C=C bond of one ketene. In contrast, the N-H imidoylketene 1c dimerizes across the C=O bond to form 24b. Furthermore, N-methylbenzoimidoylketene (5b), in equilibrium with the more stable benzoazetidinone 14b, gives the formal [4 + 4] dimer 8b. B3LYP/6-31G(d) transition structure calculations on these three modes of dimerization reproduce and offer explanations for these divergent regiochemistries. Both [4 + 2] dimerizations have planar, pseudopericyclic transition structures (25a and 29b). Five transition structures were found for the formation of 8b. A unique pseudopericyclic dimerization of 5b with an orthogonal [4 + 4] geometry (31) has a barrier of only 0.7 kcal/mol. However, the overall lowest energy pathway involves concerted addition of 5b across a sigma bond in 14b via 35.

Journal Article↗
PubMed2006

Steric modulations in the reversible dimerizations of phenalenyl radicals via unusually weak carbon-centered pi- and sigma-bonds.

[reaction: see text] Spontaneous self-associations of various tricyclic phenalenyl radicals lead reversibly to either pi- or sigma-dimers, depending on alkyl-substitution patterns at the alpha- and beta-positions. Thus, the sterically encumbered all-beta-substituted tri-tert-butylphenalenyl radical (2*) affords only the long-bonded pi-dimer in dichloromethane solutions, under conditions in which the parent phenalenyl radical (1*) leads to only the sigma-dimer. Further encumbrances of 1* with a pair of alpha, beta- or beta, beta- tert-butyl substituents and additional methyl and ethyl groups (as in sterically hindered phenalenyl radicals 3* - 6*) do not inhibit sigma-dimerization. ESR spectroscopy is successfully employed to monitor the formation of both diamagnetic (2-electron) dimers; and UV-vis spectroscopy specifically identifies the pi-dimer by its intense near-IR band. The different temperature-dependent spectral (ESR and UV-vis) behaviors of these phenalenyl radicals allow the quantitative evaluation of the bond enthalpy of 12 +/- 2 kcal mol(-1) for sigma-dimers, in which the unusually low value has been theoretically accounted for by the large loss of phenalenyl (aromatic) pi-resonance energy attendant upon such bond formation.

Journal Article↗
PubMed1999

Unique Catalysis and Regioselectivity Observed in the Poly(C)-Directed RNA Dimer Formation from 2-MeImpG: Kinetic Analysis as a Function of Monomer and Polymer Concentration.

Polycytidylate, poly(C), serves as a scaffold or template to direct and catalyze the synthesis of long oligoguanylates from guanosine 5'-phosphate 2-methylimidazolide, 2-MeImpG. In the absence of poly(C), small amounts of three isomeric dimers, i.e., the 2'-5'-, the 3'-5'-, and the pyrophosphate-linked, are formed slowly. In the presence of poly(C) oligomers that are primarily 3'-5'-linked are formed quickly and in high yield. Product analysis suggests that the oligomers are elongation products of the 3'-5'-linked dimer, abbreviated D. Assuming that D is formed slowly from two molecules of 2-MeImpG (Scheme 1) and elongates relatively fast, the initial rate of dimerization, d[D]/dt in M h(-1), was determined using two independent methods. The first method is based on the approximation that at the onset of the reaction the substrate is consumed only via hydrolysis and dimerization, and thus elongation can be neglected. The second, more accurate, method exploits the assertion that every oligomer was once a 3'-5'-linked dimer. Hence the concentration of D was obtained indirectly from the concentration of the oligomer products. These two methods gave comparable results. Experiments were run in aqueous solution in the presence of 1.0 M NaCl, 0.2 M MgCl(2) at pH 7.9 +/- 0.1 and 23 degrees C. Controls were run in the absence of poly(C) and in the presence of other polynucleotides. The kinetics were determined as a function of both monomer and polymer concentration the latter expressed in C equivalents. The kinetic data obtained in the presence of poly(C) confirmed an earlier conclusion regarding the remarkable effect of poly(C) on the formation of the 3'-5'-linked diguanylate. Initial dimerization rates were quantitatively correlated using a simple template-directed (TD) model that presumes cooperative binding (two association constants) of 2-MeImpG on poly(C) and reaction between adjacent template-bound molecules. The model allows for the estimation of the association constants and the intrinsic rate constant of dimerization, k(2). Insights into the detailed mechanism are also gained from this analysis. The fact that the proposed model can successfully correlate kinetic data that vary by more than 5000-fold between the slowest and the fastest reaction adds confidence and suggests the suitability of this model for describing TD reactions in general. It is anticipated that similar analysis of other known TD reactions may lead to clues that will facilitate the design of more efficient polynucleotide-synthesizing systems.

Journal Article↗
PubMed2005

Chiral self-dimerization of vanadium complexes on a SiO2 surface for asymmetric catalytic coupling of 2-naphthol: structure, performance, and mechanism.

Vanadium monomers with chiral tridentate Schiff-base ligands were supported on SiO(2) through a chemical reaction with surface silanols, where we found a new chirality creation by the self-dimerization of the vanadyl complexes on the surface. The chiral self-dimerization and the role of surface silanols in the self-assembly were investigated by means of X-ray absorption near-edge structure (XANES), extended X-ray absorption fine structure (EXAFS), diffuse-reflectance ultraviolet/visible (DR-UV/VIS), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FT-IR), electron spin resonance (ESR), and density functional theory (DFT) calculations. The surface vanadyl complexes had a distorted square-pyramidal conformation with a V=O bond. FT-IR spectra revealed that the Ph-O moiety of Schiff-base ligands was converted to Ph-OH by a surface-concerted reaction between the vanadium precursors and surface SiOH groups. The Ph-OH in an attached vanadyl complex interacted with a COO moiety of another vanadyl complex by hydrogen bonding to form a self-dimerized structure at the surface. The interatomic distance of V-V in the surface self-assembly was evaluated to be 0.40 +/- 0.05 nm by ESR after O(2) adsorption. The self-dimerized V structure on SiO(2) was modeled by DFT calculations, which demonstrated that two vanadium monomers with Ph-OH linked together by two hydrogen bonds and their V=O groups were directed opposite to each other. The surface self-dimerization of the vanadium precursors fixes the direction of the V=O bond and the plane of the Schiff-base ligand. Thus, a new chiral reaction field was created by two types of chirality: the chiral Schiff-base ligand and the chiral V center. We have also found that the chiral self-dimerized vanadyl complexes exhibit remarkable catalytic performance for the asymmetric oxidative coupling of 2-naphthol: 96% conversion, 100% selectivity to 1,1'-binaphthol (BINOL), and 90% enantiomeric excess (ee). Increasing the vanadium loading on SiO(2) caused a dramatic swell of enantioselectivity, and the maximum 90% ee was observed on the supported catalyst with the full coverage of the vanadyl complex (3.4 wt % vanadium). This value is equivalent to the maximum ee reported in homogeneous catalysis for the coupling reaction. Furthermore, the supported vanadium dimers were reusable without loss of the catalytic performance. To our knowledge, this is the first heterogeneous catalyst for the asymmetric oxidative coupling of 2-naphthol.

Journal Article↗
PubMed2005

Characterizing the dimerizations of phenalenyl radicals by ab initio calculations and spectroscopy: sigma-bond formation versus resonance pi-stabilization.

Electronic-structure calculations for the self-association of phenalenyl radical (P*) predict the formation of dimeric species (sigma-P2) in which both moieties are connected by a sigma-bond with rP-P approximately 1.59 A and bond dissociation enthalpy of DeltaH(D) approximately 16 kcal mol(-1). Such an unusually weak sigma-bond is related to the loss of aromatic stabilization energy of approximately 34 kcal mol(-1) per phenalenyl moiety, largely owing to rehybridization. Ab initio calculations also reveal that the corresponding (one-electron) bond between phenalenyl radical and its closed-shell cation in sigma-P2+* is unstable relative to dissociation. Time-dependent DFT computations indicate the absence of any (strongly allowed) electronic transition in the visible region of the absorption spectrum of phenalenyl sigma-dimer. Such theoretical predictions are supported by experimental (ESR and UV-NIR) spectroscopic studies, in which the availability of a series of sterically hindered phenalenyl radicals allows definitive separations of the sigma-dimerization process from interference by pi-dimerization. As such, the thermodynamic parameters (determined from the temperature dependence of the ESR signals) with DeltaH(D) = 14 kcal mol(-1) and DeltaS(D) = 52 e.u. can be assigned to the formation of the colorless sigma-dimer. Similar results are obtained for all phenalenyl derivatives (provided their substitution patterns allow sigma-bond formation) to confirm the energetic preference of sigma-dimerization over pi-dimerization.

Journal Article↗
PubMed1995

Effects of insulin concentration and self-association on the partitioning of its A-21 cyclic anhydride intermediate to desamido insulin and covalent dimer.

PURPOSE: In the pH range 2-5, human insulin degrades via deamidation at the A-21 asn and covalent dimerization. Both products form via a common cyclic anhydride intermediate, a product of intramolecular neucleophilic attack by the A-21 carboxyl terminus. This study examines the influence of [insulin] and self-association on the partitioning of the intermediate to products. METHODS: Insulin self-association was characterized (pH 2-4) by concentration difference spectroscopy. Deamination rates (pH 2-4) and concurrent rates of covalent dimer formation (pH 4) were determined versus [insulin] at 35 degrees C by initial rates. A mathematical model was developed to account for the overall rate and product composition profile versus pH and [insulin]. RESULTS: Between pH 2-4, insulin self-associates to form non-covalent dimers with a pH independent association constant of 1.8 x 10(4) M-1. The overall rate of degradation is governed by intermediate formation, while product distribution is determined by competition between water and the phe B-1 amino group of insulin for the anhydride. In dilute solutions, deamidation is first-order in [insulin] while covalent dimerization is second-order. Thus, deamidation predominates in dilute solutions but the fraction of covalent dimer formed increases with [insulin]. At high [insulin], self-association inhibits covalent dimer formation, preventing exclusive degradation via this pathway. The model accurately predicts a maximum in covalent dimer formation near pH 4. CONCLUSIONS: A mechanism is described which accounts for the complex dependence of insulin's degradation rate and product distribution profile on pH (between 2-5) and [insulin]. If these results can be generalized, they suggest that covalent aggregation in proteins may be inhibited by self-association.

Anhydrides↗
PubMed1999

[D-dimer determination in suspected deep venous thrombosis or lung embolism].

Cleavage of crosslinked fibrin by the fibrinolytic enzyme plasmin leads to the formation of fibrin degradation products, among them D-dimers. D-Dimer can easily be measured in plasma or in whole blood by means of monoclonal antibodies directed against epitopes of the D-dimer fragment. Elevated plasma levels of D-dimers are characteristic for patients with venous thromboembolism (DVT, PE), but occur also in patients with infectious diseases, malignant neoplasms and heart failure. Given the high sensitivity of ELISA D-dimer assays with respect to venous thromboembolism it is possible to reliably rule out DVT or PE when the plasma concentration of D-dimer is below the cut-off level. Thus, it is possible to rule out DVT in about 30% of outpatients with suspected venous thromboembolism by the measurement of D-dimer-concentration with a validated assay avoiding further diagnostic procedures.

Diagnosis, Differential↗