Structure and dynamics of metallomacrocycles: recognition of zinc xylyl-bicyclam by an HIV coreceptor

As platforms for the design of metal-based therapeutic and diagnostic agents, macrocycles are rigid enough to provide strong metal binding sites and orient functional groups stereoselectively, yet flexible enough to accommodate structural changes required for induced-fit recognition of biological targets. We consider the recognition of the Zn(II) complex of the bis-tetraazamacrocycle xylyl-bicyclam, a potent anti-HIV agent, by the coreceptor CXCR4, a G-protein-coupled receptor used by HIV for membrane fusion and cell entry. NMR studies show that the macrocycles of Zn(II)(2)-xylyl-bicyclam perchlorate exist in aqueous solution as two major configurations, trans-I (nitrogen chirality R,S,R,S), and trans-III (S,S,R,R). Acetate addition induced a major structural change. X-ray crystallography shows that the acetate complex contains the unusual cis-V cyclam configuration (R,R,R,R and folded) with bidentate coordination of acetate to Zn(II) plus second-coordination-sphere double H-bond formation between diagonal NH protons on the opposite cyclam face and acetate carboxylate oxygens. Detailed 1D and 2D NMR studies show that the major configuration of Zn(II)(2)-xylyl-bicyclam acetate in aqueous solution is cis-V/trans-I. Molecular modeling shows that an analogous cis-V site can be formed when Zn(II)(2)-xylyl-bicyclam binds to CXCR4, involving the carboxylate groups of Asp262 (Zn(II) coordination) and Glu288 (double H-bonding). The second cyclam can adopt the trans-I (or trans-III) configuration with Zn(II) binding to Asp171. These interactions are consistent with the known structure-activity relationships for bicyclam anti-HIV activity and receptor mutation. Consideration of the anti-HIV activity of xylyl-bicyclam complexes of other metal ions suggests that affinity for carboxylates, configurational flexibility, and kinetic factors may all play roles in receptor recognition. For example, Pd(II) cyclam complexes interact only weakly with axial ligands and are inflexible and inactive, whereas Co(III) cyclams bind carboxylates strongly, are configurationally flexible, and yet have low activity. Our findings should aid the design of new generations of active macrocycles including highly specific chemokine receptor antagonists.     

Potentiometric estimation of sulfide ion using the Fe(III)-EDTA complex

The Fe(III)-EDTA complex reacts with sulfide ion in a fast electron transfer reaction, oxidising the latter to elemental sulfur and getting itself reduced to Fe(II). The reaction has been developed for the quantitative estimation of sulfide ion by titration against the Fe(III)-EDTA complex, measuring the redox potential of the system. Repeated use of a given quantity of the complex solution by the process of regeneration has been demonstrated. The possibility of its practical application in liquid phase oxidation processes of recovering sulfur from H₂S is emphasized.     

Nonlinear dynamics of confined polymer melts with attractive walls

A scaling model is presented to analyze the reversible strain-hardening phenomenon in end-tethered polymer clay nanocomposites (Krishnamoorti, R.; Giannelis, E. P. Langmuir 2001, 17, 1448). It is assumed that for attractive clay-polymer interactions a fraction of the polymer chains that span the space between opposite clay plates get adsorbed on them, thereby bridging the plates. Under large amplitude oscillatory shear, such bridges are stretched, and this results in the strain-hardening behavior. The onset of strain hardening is predicted to be dependent only on the average distance separating the two plates and is independent of the frequency of the oscillations and the polymer molecular weight.     

Investigation of the reactions of fluorinated isatins and N-acetylisatins with thiocarbohydrazide: Synthesis of a novel spiro system: 2-oxo-1′,2′,4′,5′-tetrahydrospiro[3H-indole-3,3′-1,2,4,5-tetrazine]-6′-thione

A novel system 2-oxo-1′,2′,4′,5′-tetrahydrospiro[3H-indole-3,3′-1,2,4,5-tetrazine]-6′-thione has been synthesized by the treatment of fluorinated isatins with thiocarbohydrazide in aqueous ethanolic medium. Under exactly similar conditions, N-acetylisatin gave exclusively thiocarbohydrazone. The spiro product, on treatment with acetic acid, gave fluorinated isoindigo. Characterization of these products have been done by elemental analyses, ir, pmr and mass spectral studies.     

Formation and stability of N-heterocyclic carbenes in water: the carbon acid pKa of imidazolium cations in aqueous solution

We report second-order rate constants kDO (M-1 s-1) for exchange for deuterium of the C(2)-proton of a series of simple imidazolium cations to give the corresponding singlet imidazol-2-yl carbenes in D2O at 25 degrees C and I = 1.0 (KCl). Evidence is presented that the reverse protonation of imidazol-2-yl carbenes by solvent water is limited by solvent reorganization and occurs with a rate constant of kHOH = kreorg = 10(11) s-1. The data were used to calculate reliable carbon acid pK(a)s for ionization of imidazolium cations at C(2) to give the corresponding singlet imidazol-2-yl carbenes in water: pKa = 23.8 for the imidazolium cation, pKa = 23.0 for the 1,3-dimethylimidazolium cation, pKa = 21.6 for the 1,3-dimethylbenzimidazolium cation, and pKa = 21.2 for the 1,3-bis-((S)-1-phenylethyl)benzimidazolium cation. The data also provide the thermodynamic driving force for a 1,2-hydrogen shift at a singlet carbene: K12 = 5 x 10(16) for rearrangement of the parent imidazol-2-yl carbene to give neutral imidazole in water at 298 K, which corresponds to a favorable Gibbs free energy change of 23 kcal/mol. We present a simple rationale for the observed substituent effects on the thermodynamic stability of N-heterocyclic carbenes relative to a variety of neutral and cationic derivatives that emphasizes the importance of the choice of reference reaction when assessing the stability of N-heterocyclic carbenes.     

Adsorption Behavior of N(2), Water, C(6) Hydrocarbons, and Bulkier Benzene Derivative (TMB) on Na-X Zeolite and Its K(+)-, Rb(+)-, and Cs(+)-Exchanged Analogues

The hydrothermal crystallization of X-type zeolite with a Si/Al ratio of 1.15 was achieved from the Na(2)O-Al(2)O(3)-SiO(2)-H(2)O system at 368 K under static conditions. The post-synthesis modification was carried out by a conventional ion-exchange technique to obtain K(+)-, Rb(+)-, and Cs(+)-exchanged samples with different degrees of exchange. All the samples were characterized using chemical analysis, IR, SEM, powder XRD, low-temperature nitrogen adsorption, and equilibrium sorption uptakes of different probe molecules. The relative intensities of the XRD peaks of cation-exchanged zeolite were found to be affected to different extents, depending on the nature and the concentration of nonframework cationic size, without any shift in the positions of reflection. The sorptive properties of the K-, Rb-, and Cs-exchanged samples were studied using nitrogen, water, and different C(6) hydrocarbons including bulkier benzene derivative 1,3,5-trimethylbenzene (TMB) as probe molecules. The trend observed in chemical potential estimated as a function of nitrogen coverage indicates different sorption selectivity because of differences in the cationic size and population. Sorption uptake kinetics for probe molecules such as water, n-hexane, cyclohexane, benzene, and TMB were also studied. The samples with higher degrees of exchange and/or cationic size have shown a decrease in hydrophilic character due to the formation of irregular networks of water molecules connected with preadsorbed water molecules, framework oxygen ions, and nonframework cations. Among C(6) hydrocarbons including TMB, the benzene molecule is found to be the most promising probe for the estimation of openness of structure and surface heterogeneity as well. Copyright 2001 Academic Press.