Carla Slebodnick

HDP—A Novel Heme Detoxification Protein from the Malaria Parasite

When malaria parasites infect host red blood cells (RBC) and proteolyze hemoglobin, a unique, albeit poorly understood parasite-specific mechanism, detoxifies released heme into hemozoin (Hz). Here, we report the identification and characterization of a novel Plasmodium Heme Detoxification Protein (HDP) that is extremely potent in converting heme into Hz. HDP is functionally conserved across Plasmodium genus and its gene locus could not be disrupted. Once expressed, the parasite utilizes a circuitous “Outbound–Inbound” trafficking route by initially secreting HDP into the cytosol of infected RBC. A subsequent endocytosis of host cytosol (and hemoglobin) delivers HDP to the food vacuole (FV), the site of Hz formation. As Hz formation is critical for survival, involvement of HDP in this process suggests that it could be a malaria drug target.

Structure and reactivity of a preactivated sp2-sp3 diboron reagent: catalytic regioselective boration of α,β-unsaturated conjugated compounds.

A novel sp(2)-sp(3) diboron reagent has been developed for the copper-catalyzed β-boration of α,β-unsaturated conjugated compounds. The reaction proceeds under mild conditions with various substrates, i.e., α,β-unsaturated esters, ketones, nitriles, ynones, amides, and aldehydes, in the absence of additives such as phosphine and sodium tert-butoxide to provide β-borylhomoenolates in good to excellent yields. The presence of an sp(3)-hybridized boron center, unambigously confirmed by X-ray crystallography, sufficiently activates the unsymmetrical pinacolato diisopropanolaminato diboron (PDIPA diboron, 2) to transfer the sp(2)-hybridized boron moiety chemoselectively. These observations suggest that the activation of one of the boron atoms is an essential step in the Cu-catalyzed β-boration catalytic cycle.

Modeling the biological chemistry of vanadium: Structural and reactivity studies elucidating biological function

Prior to the 1980s vanadium was primarily studied because of its role as an industrial catalyst. However, with the discovery of its insulin-mimetic properties and its presence and functional role in certain haloperoxidases and nitrogenases, interest in vanadium chemistry from a biological and pharmacological perspective has exploded over the past 20 years. This paper addresses the biological roles of vanadium including (1) the coordination chemistry for biologically relevant oxidation states, (2) theories and discoveries related to the transport, coordination environment, and role of vanadium in both tunicates and Amanita muscaria mushrooms which accumulate vanadium in unusually high concentrations, (3) selective cleavage of proteins by photoactivation of vanadium-protein complexes, (4) the insulin-mimetic abilities of vanadyl, vanadate, and peroxovanadate complexes and their proposed mechanisms of action, and (5) the role of structural and functional model compounds in helping to elucidate the structure and function of vanadium in haloperoxidase and nitrogenase enzymes.

Complexation Equilibria Involving Salts in Non‐Aqueous Solvents: Ion Pairing and Activity Considerations

Complexation of anions, cations and even ion pairs is now an active area of investigation in supramolecular chemistry; unfortunately it is an area fraught with complications when these processes are examined in low polarity organic media. Using a pseudorotaxane complex as an example, apparent K(a2) values (=[complex]/{[salt](o)-[complex]}{[host](o)-[complex]}) for pseudorotaxane formation from dibenzylammonium salts (2-X) and dibenzo-[24]crown-8 (1, DB24C8) in CDCl(3)/CD(3)CN 3:2 vary with concentration. This is attributable to the fact that the salt is ion paired, but the complex is not. We report an equilibrium model that explicitly includes ion pair dissociation and is based upon activities rather than molar concentrations for study of such processes in non-aqueous media. Proper analysis requires both a dissociation constant, K(ipd), for the salt and a binding constant for interaction of the free cation 2(+) with the host, K(a5); K(a5) for pseudorotaxane complexation is independent of the counterion (500 M(-1)), a result of the complex existing in solution as a free cation, but K(ipd) values for the salts vary by nearly two orders of magnitude from trifluoroacetate to tosylate to tetrafluoroborate to hexafluorophosphate anions. The activity coefficients depend on the nature of the predominant ions present, whether the pseudorotaxane or the ions from the salt, and also strongly on the molar concentrations; activity coefficients as low as 0.2 are observed, emphasizing the magnitude of their effect. Based on this type of analysis, a method for precise determination of relative binding constants, K(a5), for multiple hosts with a given guest is described. However, while the incorporation of activity coefficients is clearly necessary, it removes the ability to predict from the equilibrium constants the effects of concentration on the extent of binding, which can only be determined experimentally. This has serious implications for study of all such complexation processes in low polarity media.

Highly Regioselective Derivatization of Trimetallic Nitride Templated Endohedral Metallofullerenes via a Facile Photochemical Reaction

Photochemically generated benzyl radicals react with Sc(3)N@C(80)-I(h) to produce a dibenzyl adduct [Sc(3)N@C(80)(CH(2)C(6)H(5))(2)] in 82% yield and high regioselectivity. The adducts (1)H spectrum revealed high symmetry: only one AB pattern was observed for the methylene protons. The (13)C NMR spectrum suggested a C(2)-symmetrical structure. DFT calculations reveal that a 1,4-adduct is more favorable than a 1,2-adduct by >10 kcal/mol. The 1,4-structure on [566] ring junctions was unambiguously confirmed by X-ray crystallographic analysis. UV-vis spectra revealed that the removal of two p orbitals from the pi system of the cage together with the benzylic substituents change the electronic properties of the metallofullerene in a manner similar to those reported for disilirane and trifluoromethyl moieties. Under the same conditions from Lu(3)N@C(80)-I(h) we prepared (63% yield) Lu(3)N@C(80)(CH(2)C(6)H(5))(2), which demonstrated properties similar to the 1,4-dibenzyl adduct of Sc(3)N@C(80)-I(h).

Pseudocryptand-Type [2]Pseudorotaxanes Based on Bis(meta-phenylene)-32-Crown-10 Derivatives and Paraquats with Remarkably Improved Association Constants

The first dual component pseudocryptand-type [2]pseudorotaxanes were designed and prepared via the self-assembly of synthetically easily accessible bis(meta-phenylene)-32-crown-10 pyridyl, quinolyl, and naphthyridyl derivatives with paraquat. The formation of the pseudocryptand structures in the complexes remarkably improved the association constant by forming the third pseudobridge via H-bonding with the guest and π-stacking of the heterocyclic units.

Pseudocryptand-Type [3]Pseudorotaxane and “Hook-Ring” Polypseudo[2]catenane Based on a Bis(m-phenylene)-32-crown-10 Derivative and Bisparaquat Derivatives

The first pseudocryptand-type supramolecular [3]pseudorotaxane was designed and prepared via the self-assembly of a bispicolinate BMP32C10 derivative and a bisparaquat. The complexation behavior was cooperative. In addition, the complex comprised of the BMP32C10 derivative and a cyclic bisparaquat demonstrated strong binding; interestingly, a poly[2]pseudocatenane structure was formed in the solid state for the first time.

The First [2]Pseudorotaxane and the First Pseudocryptand-Type Poly[2]pseudorotaxane Based on Bis(meta-phenylene)-32-Crown-10 and Paraquat Derivatives

By the self-assembly of a bis(meta-phenylene)-32-crown-10 bearing two electron-donating groups (carbazoles) with electron-accepting paraquat derivatives, the first [2]pseudorotaxane and the first pseudocryptand-type poly[2]pseudorotaxane based on bis(meta-phenylene)-32-crown-10 were isolated as crystalline solids as shown by X-ray analyses.

Syntheses and Structures of Phenyl-C81-Butyric Acid Methyl Esters (PCBMs) from M3N@C80

Two new 6,6-open phenyl-C(81)-butyric acid methyl ester metallofulleroids, M(3)N@C(80)PCBM (M = Sc, Y), were synthesized by diazoalkane addition reactions and fully characterized. The results demonstrate that the reactive sites are the same for M(3)N@C(80) (M = Sc, Y) but dramatically different from that of C(60).

Solvent effects on 51V NMR chemical shifts: Characterization of vanadate and peroxovanadate complexes in mixed water/acetonitrile solvent

Abstract The majority of 51 V NMR studies on V(V) complexes have been reported in water, which currently limits the usefulness of 51 V NMR in identifying V(V) species in non-aqueous solvents. In this report, the 51 V NMR spectra have been obtained for vanadate and peroxovanadate complexes that exist at pH ≤ 7 in solutions containing 2–90% water in acetonitrile. Millimolar vanadate and peroxovanadate solutions in acetonitrile containing as little as 2% water were prepared by diluting a conc. aq. solution of vanadate (Bu 4 N + salt) with acetonitrile. As with simple oxovanadate oligomers and peroxovanadate complexes in aqueous solutions, the species present in acetonitrile solution are a function of vanadium, acid and peroxide concentrations. The 51 V resonances for several species can be assigned by correlating changes in chemical shifts as a function of water concentration. Species definitively characterized include VO 2 + , H x VO 4 x −3 , HV 2 O 7 3− , V 4 O 12 4− , V 5 O 15 5− , V 10 O 28 6− , VO(O 2 ) + , VO(O 2 ) 2 − and V 2 O 2 (O 2 ) 3 . While the chemical shift for every assigned species moves downfield as water concentration is decreased, the magnitude of the downfield shift is highly dependent on the vanadium species. The assignments provided herein from the foundation for establishing the reactivity patterns for peroxovanadate in non-aqueous media.