Amphiphilic Polyphenylene Dendron Conjugates for Surface Remodeling of Adenovirus 5

Amphiphilic surface groups play an important role in many biological processes. The synthesis of amphiphilic polyphenylene dendrimer branches (dendrons), providing alternating hydrophilic and lipophilic surface groups and one reactive ethynyl group at the core is reported. The amphiphilic surface groups serve as biorecognition units that bind to the surface of adenovirus 5 (Ad5), which is a common vector in gene therapy. The Ad5/dendron complexes showed high gene transduction efficiencies in coxsackie-adenovirus receptor (CAR)-negative cells. Moreover, the dendrons offer incorporation of new functions at the dendron core by in situ post-modifications, even when bound to the Ad5 surface. Surfaces coated with these dendrons were analyzed for their blood-protein binding capacity, which is essential to predict their performance in the blood stream. A new platform for introducing bioactive groups to the Ad5 surface without chemically modifying the virus particles is provided.     

Amphiphilic Polyphenylene Dendron Conjugates for Surface Remodeling of Adenovirus 5

Amphiphilic surface groups play an important role in many biological processes. The synthesis of amphiphilic polyphenylene dendrimer branches (dendrons), providing alternating hydrophilic and lipophilic surface groups and one reactive ethynyl group at the core is reported. The amphiphilic surface groups serve as biorecognition units that bind to the surface of adenovirus 5 (Ad5), which is a common vector in gene therapy. The Ad5/dendron complexes showed high gene transduction efficiencies in coxsackie‐adenovirus receptor (CAR)‐negative cells. Moreover, the dendrons offer incorporation of new functions at the dendron core by in situ post‐modifications, even when bound to the Ad5 surface. Surfaces coated with these dendrons were analyzed for their blood‐protein binding capacity, which is essential to predict their performance in the blood stream. A new platform for introducing bioactive groups to the Ad5 surface without chemically modifying the virus particles is provided.     

Synthesis and structural characterization of tris(2-mercapto-1-adamantylimidazolyl)hydroborato complexes: a sterically demanding tripodal [S3] donor ligand

The tris(2-mercapto-1-adamantylimidazolyl)hydroborato ligand, [Tm(Ad)], has been synthesized via the reaction of 1-adamantyl-2-mercaptoimidazole with MBH(4) (M = Li, K). [Tm(Ad)]M has been used to synthesize a variety of compounds of the main-group and transition elements, including [Tm(Ad)]ZnI, {[Tm(Ad)]GaI}[GaI(4)], {[Tm(Ad)]GaCl}[GaCl(4)], {[Tm(Ad)]GaGa[Tm(Ad)]}[GaCl(4)](2), {[Tm(Ad)](2)In}[InI(4)], [Tm(Ad)]In(κ(2)-mim(Ad))Cl, [Tm(Ad)]Ga→B(C(6)F(5))(3), [Tm(Ad)]In→B(C(6)F(5))(3), and [Tm(Ad)]Re(CO)(3). Structural characterization of [Tm(Ad)]Re(CO)(3) demonstrates that the [Tm(Ad)] ligand is more encapsulating than other [Tm(R)] ligands, including [Tm(Bu(t))], while IR spectroscopic studies indicate that the [Tm(Ad)] and [Tm(Bu(t))] ligands have very similar electron-donating properties.     

Gas phase ion chemistry of charged silver(I) adenine ions via multistage mass spectrometry experiments and DFT calculations

Electrospray ionization (ESI) of solutions containing adenine and AgNO(3) yields polymeric [Ad(x)+ Ag(y)-zH]((y-z)+) species. Density functional theory (DFT) calculations have been used to examine potential structures for several of the smaller ions while multistage mass spectrometry experiments have been used to probe their unimolecular reactivity (via collision-induced dissociation (CID)) and bimolecular reactivity (via ion-molecule reactions with the neutral reagents acetonitrile, methanol, butylamine and pyridine). DFT calculations of neutral adenine tautomers and their silver ion adducts provide insights into the binding modes of adenine. We find that the most stable [Ad + Ag](+) ion does not correspond to the most stable neutral adenine tautomer, consistent with previous studies that have shown that transition metal ions can stabilize rare tautomeric forms of nucleobases. Both the charge and the stoichiometry of the [Ad(x)+ Ag(y)-zH]((y-z)+) complexes play pivotal roles in directing the types of fragmentation and ion-molecule reactions observed. Thus, [Ad(2)+ Ag(2)](2+) is observed to dissociate to [Ad + Ag](+) and to react with butylamine via proton transfer, while [Ad(2)+ Ag(2)- H](+) fragments via loss of neutral adenine to form the [Ad + Ag(2)- H](+) ion and does not undergo proton transfer to butylamine. DFT calculations on several isomeric [Ad(2)+ Ag(2)](2+) ions suggest that planar centrosymmetric cations, in which two adjacent silver atoms are bridged by two N7H adenine tautomers via N(3),N(9)-bidentate interactions, are the most stable. The [Ad + Ag(2)-H](+) ion adds two neutral reagents in ion-molecule reactions, consistent with the presence of two vacant coordination sites. It undergoes a silver atom loss to form the [Ad + Ag - H](+) radical cation, which in turn fragments quite differently to the even electron [Ad + Ag](+) ion. Several other pairs of radical cation/even electron adenine-silver complexes were also found to undergo different fragmentation reactions.     

Addition reaction of adamantylideneadamantane with Br2 and 2Br2: a computational study

Ab initio calculations were carried out for the reaction of adamantylideneadamantane (Ad=Ad) with Br2 and 2Br2. Geometries of the reactants, transition states, intermediates, and products were optimized at HF and B3LYP levels of theory using the 6-31G(d) basis set. Energies were also obtained using single point calculations at the MP2/6-31G(d)//HF/6-31G(d), MP2/6-31G(d)//B3LYP/6-31G(d), and B3LYP/6-31+G(d)//B3LYP/6-31G(d) levels of theory. Intrinsic reaction coordinate (IRC) calculations were performed to characterize the transition states on the potential energy surface. Only one pathway was found for the reaction of Ad=Ad with one Br2 producing a bromonium/bromide ion pair. Three mechanisms for the reaction of Ad=Ad with 2Br2 were found, leading to three different structural forms of the bromonium/Br3- ion pair. Activation energies, free energies, and enthalpies of activation along with the relative stability of products for each reaction pathway were calculated. The reaction of Ad=Ad with 2Br2 was strongly favored over the reaction with only one Br2. According to B3LYP/6-31G(d) and single point calculations at MP2, the most stable bromonium/Br3- ion pair would form spontaneously. The most stable of the three bromonium/Br3- ion pairs has a structure very similar to the observed X-ray structure. Free energies of activation and relative stabilities of reactants and products in CCl4 and CH2ClCH2Cl were also calculated with PCM using the united atom (UA0) cavity model and, in general, results similar to the gas phase were obtained. An optimized structure for the trans-1,2-dibromo product was also found at all levels of theory both in gas phase and in solution, but no transition state leading to the trans-1,2-dibromo product was obtained.     

Structural and spectroscopic characterization of a charge-separated uranium benzophenone ketyl radical complex

The reaction of [((t-Bu)ArO) 3tacn)U (III)] ( 1) with 4,4'-di- tert-butylbenzophenone affords a unique isolable U(IV) ketyl radical species [((t-Bu)ArO) 3tacn)U (IV)(OC* (t-Bu)Ph 2)] (2) supported by XRD data, magnetization measurements, and DFT calculations. Isolation and full characterization of the corresponding diphenyl methoxide complex [((t-Bu)ArO) 3tacn)U (IV)(OCH ( t-Bu )Ph 2)] (3) is also presented. The one-electron reduction of benzophenone by [((Ad)ArO) 3tacn)U (III)] (4) leads to a purple U(IV) ketyl radical intermediate [((Ad)ArO) 3tacn)U (IV)(OC*Ph 2)] (5). This species is highly reactive, and attempts at isolation were unsuccessful and resulted in methoxide complex [((Ad)ArO) 3tacn)U (IV)(OCHPh 2)] (6) from H abstraction and dinuclear para-coupled complex [((Ad)ArO) 3tacn)U (IV)(OCPhPhCPh 2O)U (IV)((Ad)ArO) 3tacn)] (7).     

Cyaarside (CAs−) and 1,3‐Diarsaallendiide (AsCAs2−) Ligands Coordinated to Uranium and Generated via Activation of the Arsaethynolate Ligand (OCAs−)

Reaction of the trivalent uranium complex [((^Ad,MeArO)₃N)U(DME)] with one molar equiv [Na(OCAs)(dioxane)₃], in the presence of 2.2.2‐crypt, yields [Na(2.2.2‐crypt)][{((^Ad,MeArO)₃N)U^IV(THF)}(μ‐O){((^Ad,MeArO)₃N)U^IV(CAs)}] ( 1 ), the first example of a coordinated η¹‐cyaarside ligand (CAs^?). Formation of the terminal CAs^? is promoted by the highly reducing, oxophilic U^III precursor [((^Ad,MeArO)₃N)U(DME)] and proceeds through reductive C?O bond cleavage of the bound arsaethynolate anion, OCAs^?. If two equiv of OCAs^? react with the U^III precursor, the binuclear, μ‐oxo‐bridged U₂^IV/IV complex [Na(2.2.2‐crypt)]₂[{((^Ad,MeArO)₃N)U^IV}₂(μ‐O)(μ‐AsCAs)] ( 2 ), comprising the hitherto unknown μ:η¹,η¹‐coordinated (AsCAs)^2? ligand, is isolated. The mechanistic pathway to 2 involves the decarbonylation of a dimeric intermediate formed in the reaction of 1 with OCAs^?. An alternative pathway to complex 2 is by conversion of 1 via addition of one further equiv of OCAs^?.     

An Extremely Bulky Tris(pyrazolyl)methanide: A Tridentate Ligand for the Synthesis of Heteroleptic Magnesium(II) and Ytterbium(II) Alkyl,Hydride, and Iodide Complexes

The tris(pyrazolyl)methane compound HC(3‐Ad‐5‐Mepz)₃ [ 1 , 3‐Ad‐5‐Mepz=3‐(1‐adamantyl)‐5‐methylpyrazolyl] and its regioisomer, HC(3‐Ad‐5‐Mepz)₂(3‐Me‐5‐Adpz), were synthesized and crystallographically characterized. Deprotonation of 1 with MeLi afforded the lithium complex [{κ³‐N‐C(3‐Ad‐5‐Mepz)₃}Li(thf)], which incorporates a tris(pyrazolyl)methanide ligand of unprecedented bulk. Reaction of 1 with MeMgI gave the ionic coordination complex [{κ³‐N‐HC(3‐Ad‐5‐Mepz)₃}MgMe]I, which was readily deprotonated to afford the neutral compound [{κ³‐N‐C(3‐Ad‐5‐Mepz)₃}MgMe]. The related magnesium butyl compound [{κ³‐N‐C(3‐Ad‐5‐Mepz)₃}MgBu] was prepared from the reaction of 1 and MgBu₂. Treating this with LiAlH₄ or LiAlD₄ led to rare examples of terminal magnesium hydride/deuteride complexes, [{κ³‐N‐C(3‐Ad‐5‐Mepz)₃}MgH/D]. All neutral magnesium alkyl and hydride compounds were crystallographically authenticated. Reaction of [{κ³κN‐C(3‐Ad‐5‐Mepz)₃}Li(thf)] with [YbI₂(thf)₂] yielded the first structurally characterized f‐block tris(pyrazolyl)methanide complex, [{κ³‐N‐C(3‐Ad‐5‐Mepz)₃}YbI(thf)].     

Purification of recombinant adenovirus type 3 dodecahedric virus-like particles for biomedical applications using short monolithic columns

Adenovirus type 3 dodecahedric virus-like particles (Ad3 VLP) are an interesting delivery vector. They penetrate animal cells in culture very efficiently and up to 300,000 Ad3 VLP can be observed in one cell. The purification of such particles usually consists of several steps. In these work we describe the method development and optimization for the purification of Ad3 VLP using the Convective Interaction Media analytical columns (CIMac). Results obtained with the CIMac were compared to the already established two-step purification protocol for Ad3 VLP based on sucrose density gradient ultracentifugation and the Q-Sepharose ion-exchange column. Pure, concentrated and bioactive VLP were obtained and characterized by several analytical methods. The recovery of the Ad3 VLP was more than 50% and the purified fraction was almost completely depleted of DNA; less than 1% of DNA was present. The purification protocol was shortened from five days to one day and remarkably high penetration efficacy of the CIMac-purified vector was retained. Additionally, CIMac QA analytical column has proven to be applicable for the final and in-process control of various Ad3 VLP samples.     

Carbon dioxide activation with sterically pressured mid- and high-valent uranium complexes

Sterically pressured mid- to high-valent uranium complexes with an aryloxide substituted triazacyclononane ligand scaffold, [(((R)ArO)3tacn)(3-)], were studied for carbon dioxide activation and transformation chemistry. The high valent uranium(V) imido species [(((R)ArO)3tacn)U(NR)] (R = (t)Bu, R' = 2,4,6-trimethylphenyl (2-(t)Bu); R = Ad, R' = 2,4,6-trimethylphenyl (2-Ad); R = (t)Bu, R' = phenyl (3-(t)Bu)) were synthesized and spectroscopically characterized. X-ray crystallography of the tert-butyl mesityl imido derivative, 2-(t)Bu , reveals coordination of a bent imido fragment with a relatively long U-N bond distance of 2.05 A. The mesityl imido complexes reacted with carbon dioxide, readily extruding free isocyanate to produce uranium(V) terminal oxo species, [(((R)ArO)3tacn)U(O)] (R = (t)Bu (4-(t)Bu), Ad (4-Ad)), presumably through multiple bond metathesis via a uranium(V) carbimate intermediate. Using the smaller phenyl imido fragment in 3-(t) Bu slowed isocyanate loss, allowing the uranium(V) carbimate intermediate to undergo a second metathesis reaction, ultimately producing the diphenyl ureate derivative, [(((tBu)ArO)3tacn)U(NPh2)CO] (5-(t)Bu). Single crystal X-ray diffraction studies were carried out on both uranium(V) terminal oxo complexes and revealed short U-O bonds (1.85 A) indicative of a formal UO triple bond. The electronic structure of the oxo U(V) complexes was investigated by electronic absorption and EPR spectroscopies as well as SQUID magnetization and DFT studies, which indicated that their electronic properties are highly unusual. To obtain insight into the reactivity of CO2 with U-N bonds, the reaction of the uranium(IV) amide species, [(((R)ArO)3tacn)U(NHMes)] (R = (t)Bu (6-(t)Bu), Ad (6-Ad) with carbon dioxide was investigated. These reactions produced the uranium(IV) carbamate complexes, [(((R)ArO)3tacn)U(CO2NHMes)] (R = (t)Bu (7-(t)Bu), Ad (7-Ad)), resulting from insertion of carbon dioxide into U-N(amide) bonds. The molecular structures of the synthesized uranium carbamate complexes highlight the different reactivities due to the steric pressure introduced by the alkyl derivatized tris(aryloxide) triazacyclononane ligand. The sterically open tert-butyl derivative creates a monodentate eta(1)-O bound carbamate species, while the sterically more bulky adamantyl-substituted compound forces a bidentate kappa(2)-O,O coordination mode of the carbamate ligand.     

Synthesis and structures of crystalline Li, Al and Sn(II) 1-azaallyls and beta-diketiminates derived from [Li{mu,eta3-N(SiMe3)C(Ad)C(H)SiMe3}]2 (Ad = 1-adamantyl)

The crystalline dimeric 1-azaallyllithium complex [Li{mu,eta(3-N(SiMe3)C(Ad)C(H)SiMe3}]2 (1) was prepared from equivalent portions of Li[CH(SiMe3)2] and 1-cyanoadamantane (AdCN). Complex was used as precursor to each of the crystalline complexes 2-8 which were obtained in good yield. By 1-azaallyl ligand transfer, 1 afforded (i) [Al{eta3-N(SiMe3)C(Ad)C(H)SiMe3}{kappa1-N(SiMe3)C(Ad)=C(H)SiMe3-E}Me] (5) with [AlCl2Me](2), (ii) [Sn{eta3-N(SiMe3)C(Ad)C(H)SiMe3}2] (7) with Sn[N(SiMe3)2]2, and (iii) [Li(N{C(Ad)=C(H)SiMe3-E}{Si(NN)SiMe3})(thf)2] (8) with the silylene Si[(NCH(2)Bu(t))2C6H(4)-1,2] [= Si(NN)]. By insertion into the C[triple bond, length as m-dash]N bond of the appropriate cyanoarene RCN, gave the beta-diketiminate [Li{mu-N(SiMe3)C(Ad)C(H)C(R)NSiMe3}]2 [R = Ph (2), C(6)H(4)Me-4 (3)], and yielded [Al{kappa2-N(SiMe3)C(Ad)C(H)C(Ph)NSiMe3}{kappa1-N(SiMe3)C(Ad)=C(H)SiMe3-E}Me] (6). The beta-diketiminate [Al{kappa2-N(SiMe3)C(Ad)C(H)C(Ph)NSiMe3}Me2] (4) was prepared from 2 and [AlClMe2]2. The X-ray structures of 1 and 3-8 are presented. Multinuclear NMR spectra in C6D6 or C6D5CD3 have been recorded for each of 1-8; such data on 8 revealed that in solution two minor isomers were also present.     

Activation of Isocyanates and Carbon Dioxide by a Monomeric Aluminium Hydrazide as an Active Lewis Pair

The monomeric aluminium hydrazide H₁₀C₅N? N(AltBu₂)? Ad ( 4 ; Ad=adamantyl, NC₅H₁₀=piperidinyl) was obtained in high yield by hydroalumination of the corresponding hydrazone derivative 1 . Compound 4 has a strained AlN₂ heterocycle formed by a donor–acceptor bond between the β‐nitrogen atom of the hydrazide group and the aluminium atom. Opening of this bond resulted in the formation of an active Lewis pair that was able to cooperatively activate carbon dioxide or isocyanates. Insertion of the heterocumulenes into the Al? N bond selectively afforded a carbamate and two urea derivatives in high yield. In the first step, phenyl isocyanate gave the adduct 6 , which has the oxygen atom coordinated to the aluminium atom and its central carbon atom bound to the nitrogen atom of the piperidine moiety. Adduct 6 represents a reasonable intermediate state for these activation processes. The applicability of hydroaluminated compounds, such as 4 , in organic synthesis was demonstrated by the reaction with an imidoyl chloride, which gave the corresponding amidrazone derivative 9 .     

Uranium(III)-mediated C-C-coupling of terminal alkynes: formation of dinuclear uranium(IV) vinyl complexes

The previously reported uranium(III) complex [(((Ad)ArO)(3)N)U(III)(DME)] (1; Ad = adamantane, DME = 1,2-dimethoxyethane) reacts with the terminal bis-alkynes 1,7-octadiyne or 1,6-heptadiyne in C-C-coupling reactions to form the uranium(IV) vinyl complexes [{(((Ad)ArO)(3)N)U(IV)}(2)(μ-η(2):η(1)-1,2-(CH)(2)-cyclohexane)] (2) and [{(((Ad)ArO)(3)N)U(IV)}(2)(μ-η(2):η(2)-1,2-(CH)(2)-cyclopentane)] (3). With the monoalkynes 1-hexyne or 4-(t)butyl-phenylacetylene, the complexes [{(((Ad)ArO)(3)N)U(IV)}(2)(μ-η(2)(C1):η(1)(C4)-2-(n)Bu-1,3-octadiene)] (4) and [{(((Ad)ArO)(3)N)U(IV)}(2)(μ-η(2)(C4):η(1)(C1)-1,3-di-(p-(t)Bu-phenyl)butadiene))] (5), are formed. These are the first four examples of uranium vinyl complexes that are reported and crystallographically characterized. In addition, detailed DFT calculations are presented to establish a possible mechanism for their formation and explain the differences found for the coordination of the hydrocarbon fragments. In contrast to a previously proposed monometallic pathway for catalytic hydroamination of alkynes and alkyne dimerization involving a uranium vinyl intermediate at uranium(III) complexes, the calculations clearly support a bimetallic mechanism, since its transition states are energetically the most favored.     

Does Gd@C82 have an anomalous endohedral structure? Synthesis and single crystal X-ray structure of the carbene adduct

We report here the results on single crystal X-ray crystallographic analysis of the Gd@C82 carbene adduct (Gd@C82(Ad), Ad = adamantylidene). The Gd atom in Gd@C82(Ad) is located at an off-centered position near a hexagonal ring in the C2v-C82 cage, as found for M@C82 (M = Sc and La) and La@C82(Ad). Theoretical calculation also confirms the position of the Gd atom in the X-ray crystal structure.     

Formation of a uranium trithiocarbonate complex via the nucleophilic addition of a sulfide-bridged uranium complex to CS2

The uranium(IV)/uranium(IV) μ-sulfide complex [{(((Ad)ArO)(3)N)U}(2)(μ-S)] reacts with CS(2) to form the trithiocarbonate-bridged complex [{(((Ad)ArO)(3)N)U}(2)(μ-κ(2):κ(2)-CS(3))]. The trithiocarbonate complex can alternatively be formed in low yields from low-valent [(((Ad)ArO)(3)N)U(DME)] through the reductive cleavage of CS(2).     

Observation of the inverse trans influence (ITI) in a uranium(V) imide coordination complex: an experimental study and theoretical evaluation

An inverse trans influence has been observed in a high-valent U(V) imide complex, [(((Ad)ArO)(3)N)U(NMes)]. A thorough theoretical evaluation has been employed in order to corroborate the ITI in this unusual complex. Computations on the target complex, [(((Ad)ArO)(3)N)U(NMes)], and the model complexes [(((Me)ArO)(3)N)U(NMes)] and [(NMe(3))(OMe(2))(OMe)(3)U(NPh)] are discussed along with synthetic details and supporting spectroscopic data. Additionally, the syntheses and full characterization data of the related U(V) trimethylsilylimide complex [(((Ad)ArO)(3)N)U(NTMS)] and U(IV) azide complex [(((Ad)ArO)(3)N)U(N(3))] are also presented for comparison.     

Metal atoms collinear with the spiro carbon of 6,6-open adducts, M2@C80(Ad) (M = La and Ce, Ad = adamantylidene)

The photochemical reaction of M2@C80 (M = La and Ce) with 2-adamantane-2,3'-[3H]-diazirine (1) affords the corresponding adducts by carbene addition. The adducts were characterized by spectroscopic and single-crystal X-ray structure analyses. Crystallographic data for the adduct La2@C80(Ad) (2, Ad = adamantylidene) reveal that the two La atoms are collinear with the spiro carbon of the 6,6-open adduct. It is noteworthy that the La-La distance is highly elongated by the addition of carbene. Paramagnetic 13C NMR spectral analysis of the adduct Ce2@C80(Ad) (3) indicates that the two Ce atoms are also collinear with the spiro carbon at room temperature in solution. The unique metal positions were confirmed by density functional calculations.     

Self‐Healing,Expansion–Contraction,and Shape‐Memory Properties of a Preorganized Supramolecular Hydrogel through Host–Guest Interactions

Supramolecular materials cross‐linked between polymer chains by noncovalent bonds have the potential to provide dynamic functions that are not produced by covalently cross‐linked polymeric materials. We focused on the formation of supramolecular polymeric materials through host–guest interactions: a powerful method for the creation of nonconventional materials. We employed two different kinds of host–guest inclusion complexes of β‐cyclodextrin (βCD) with adamantane (Ad) and ferrocene (Fc) to bind polymers together to form a supramolecular hydrogel (βCD‐Ad‐Fc gel). The βCD‐Ad‐Fc gel showed self‐healing ability when damaged and responded to redox stimuli by expansion or contraction. Moreover, the βCD‐Ad‐Fc gel showed a redox‐responsive shape‐morphing effect. We thus succeeded in deriving three functions from the introduction of two kinds of functional units into a supramolecular material.     

Self‐Healing,Expansion–Contraction,and Shape‐Memory Properties of a Preorganized Supramolecular Hydrogel through Host–Guest Interactions

Supramolecular materials cross‐linked between polymer chains by noncovalent bonds have the potential to provide dynamic functions that are not produced by covalently cross‐linked polymeric materials. We focused on the formation of supramolecular polymeric materials through host–guest interactions: a powerful method for the creation of nonconventional materials. We employed two different kinds of host–guest inclusion complexes of β‐cyclodextrin (βCD) with adamantane (Ad) and ferrocene (Fc) to bind polymers together to form a supramolecular hydrogel (βCD‐Ad‐Fc gel). The βCD‐Ad‐Fc gel showed self‐healing ability when damaged and responded to redox stimuli by expansion or contraction. Moreover, the βCD‐Ad‐Fc gel showed a redox‐responsive shape‐morphing effect. We thus succeeded in deriving three functions from the introduction of two kinds of functional units into a supramolecular material.