Piera Sabatino

Conformational modifications of serum albumins adsorbed on different kinds of biomimetic hydroxyapatite nanocrystals

Nanosized carbonate-hydroxyapatite represents a suitable material for bone substitution and delivery of biomolecules. Its interaction with serum proteins plays a central role in the process of implantation of a device. Herein, surface interactions of human (HSA) and bovine (BSA) serum albumin with two biomimetic carbonate-hydroxyapatites (CHA) differing for size, surface area, crystallinity degree and surface properties have been investigated. BSA reached a different maximum coverage, being higher with the CHA nanocrystals with the higher surface area, the smaller size, the lower crystallinity degree and the plate shape morphology. On the contrary, HSA did not show significant differences of maximum coverage on the two substrates. The adsorption isotherms have been fitted by the Langmuir and Freundlich models, showing that the biomimetic hydroxyapatite matrix behaves as a mixture of energetically homogeneous and heterogeneous sites due to its surface disorder. By using Fourier Transform Infrared Spectroscopy (FT-IR) and Circular Dichroism (CD) it has been found that CHAs affect the conformation of the adsorbed proteins. FT-IR spectroscopy shows that protein adhesion on CHA surface results in a significant reduction in helicity for both proteins on both substrates, as function of the coating extent as well as modification in the beta-structures. CD spectroscopy of the HSA and BSA released in solution after desorption from the matrices shows that, while both proteins partially regain their helical structure, they show a distinct behaviour in their tertiary structure.

A simple synthesis and crystal structure of the dinuclear diphosphido-bridged palladium(I) complex [Pd(PtBu2H)(μ-PtBu2)]2

Abstract UV irradiation of Pd(P t Bu 3 ) 2 in n-hexane or THF gives the diamagnetic dinuclear complex [Pd(P t Bu 2 H)(μ-P t Bu 2 )] 2 , 2-methylpropene, and hydrogen. The complex was also obtained from the reaction of Pd(η 5 -C 5 H 5 ) (η 3 -C 3 H 5 with P t Bu 2 H in toluene. Its crystal and molecular structure were determined by an X-ray diffraction study. Each Pd bears a terminal P t Bu 2 H ligand and the two metal centers are bridged by two phosphido ligands.

Reactions of P2Ph4 with alkyne-bridged dicobalt carbonyl complexes; crystal structures of [Co2{µ-C2(CO2Me)2}(µ-P2Ph4)(CO)4], [Co2{µ-PPh2CHCPhC(O)}(µ-PPh2)(CO)4] and [Co2{µ-PPh2C(O)CHCH}(µ-PPh2)(CO)3(PPh3)]

The reactions of P2Ph4 with a variety of substituted alkyne complexes [Co2(µ-RCCR′)(CO)6] in toluene give the complexes [Co2(µ-RCCR′)(CO)5(P2Ph4)]1(R = R′= CO2Me 1a or Ph 1b; R = Ph, R′= H 1c and [Co2(µ-RCCR′)(µ-P2Ph4)(CO)4]2(R = R′= Ph 2b; R = Ph, R′= H 2c. All three derivatives of type 1 are cleanly converted into 2 on thermolysis. An X-ray diffraction study of 2a reveals a square-planar Co2P2 core with the symmetrical alkyne perpendicular to the Co–Co bond. Further thermolysis of complexes 2 produces [Co2(µ-PPh2CRCR′)(µ-PPh2)(CO)4]3(R = R′= CO2Me 3a or Ph 3b and [Co2{µ-PPh2CRCR′C(O)}(µ-PPh2)(CO)4]4c(R = H, R′= Ph). The structure of 4c has been determined by X-ray analysis. The PPh2CHCPhC(O) ligand forms a five-membered metallacyclic ring incorporating one Co atom and is π-bonded to the other Co atom. Complexes 3a and 3b are partially converted into 4a(R = R′= CO2Me) and 4b(R = R′= Ph) on treatment with CO. This reaction is reversed by heating 4a and 4b in solution or, more slowly, on standing at room temperature. The parent acetylene complex [Co2(µ-HCCH)(CO)6] reacts with P2Ph4 differently from the substituted derivatives to give as the principal product [Co2{µ-PPh2C(O)CHCH}(µ-PPh2)(CO)4]5b. The structure of the PPh3 derivative of this complex, [Co2{µ-PPh2C(O)CHCH}(µ-PPh2)(CO)3(PPh3)]6d, has been determined by X-ray diffraction.

3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the First Dual BACE-1/GSK-3β Fragment Hits against Alzheimer’s Disease

One of the main obstacles toward the discovery of effective anti-Alzheimer drugs is the multifactorial nature of its etiopathology. Therefore, the use of multitarget-directed ligands has emerged as particularly suitable. Such ligands, able to modulate different neurodegenerative pathways, for example, amyloid and tau cascades, as well as cognitive and neurogenic functions, are fostered to come. In this respect, we report herein on the first class of BACE-1/GSK-3β dual inhibitors based on a 3,4-dihydro-1,3,5-triazin-2(1H)-one skeleton, whose hit compound 1 showed interesting properties in a preliminary investigation. Notably, compound 2, endowed with well-balanced potencies against the two isolated enzymes (IC50 of 16 and 7 μM against BACE-1 and GSK-3β, respectively), displayed effective neuroprotective and neurogenic activities and no neurotoxicity in cell-based assays. It also showed good brain permeability in a pharmacokinetic assessment in mice. Overall, triazinone derivatives, thanks to the simultaneous modulation of multiple points of the diseased network, might emerge as suitable candidates to be tested in in vivo Alzheimers disease models.

Oxidative addition of OH bond to a metal centre: synthesis and crystal structure of trans-(PhO)(H)Pd(PCy3)2·PhOH

Abstract (Cy3P)2Pd (Cy = C6H11) reacts with PhOH in toluene to give the phenoxopalladium(II) hydride derivative trans-(PhO)(H)Pd(PCy3)2·PhOH; the crystal structural study has established that the oxygen of the phenoxy group forms a hydrogen bridge with an uncoordinated phenol molecule, and has allowed direct location of the hydride atom (Pd&.sbnd;H, 1.57(2) A).

Adsorption of human serum albumin on the chrysotile surface: a molecular dynamics and spectroscopic investigation

The human serum albumin (HSA) secondary structure modifications induced by the chrysotile surface have been investigated via computational molecular dynamics (MD) and experimental infrared spectroscopy (FTIR) on synthetic chrysotile nanocrystals coated with different amount of HSA. MD simulations, conducted by placing various albumin subdomains close to the fixed chrysotile surface, show an initial adsorption phase, accompanied by local rearrangements of the albumin motifs in contact with the chrysotile layer. Next, large-scale rearrangements follow with consequent secondary structure modifications. Gaussian curve fitting of the FTIR spectra obtained for HSA-coated synthetic chrysotile nanocrystals has allowed the quantification of HSA structural modifications as a function of the amount of protein adsorbed. The experimental results support the atomistic computer simulations providing a realistic description of the adsorption of plasma proteins onto chrysotile and unravelling a key step in the understanding of asbestos toxicity.

Michael-type addition of phthalimide salts to chiral α,β-unsaturated imides

Abstract The synthesis of (R)-(−)-3-aminobutanoic acid starting from chiral α,β-unsaturated imide 1b is described, by means of the nucleophilic attack of several phthalimido derivatives in the presence of a Lewis acid. The reaction was studied in some details and chloromagnesium phthalimide afforded the better results with 95:5 diastereomeric ratio and 90% yield. Furthermore the resulting enolate was trapped performing the reaction in the presence of benzenesulfonyl bromide and the 2-bromo-3-phthalmido derivative 4 was obtained in good yield and high diastereoselectivity and successively transformed into the corresponding 2-azido-3-phthalimido derivative 6 by displacement of the bromide with sodium azide.

Co-ordinated phospholes from the coupling of alkynes with bridging phosphido ligands: the crystal and molecular structures of [Co2{µ-η2:η2′-C4(CO2Me)4PPh2}(µ-PPh2)(CO)4], [Mn2(η4-C4H4PPh2)(µ-PPh2)(CO)6], and [Mn2(µ-η5-C4H4PPh2)(µ-PPh2)(CO)5]

Reaction of µ-phosphido complexes with alkynes can lead to complexes with quaternised phosphole ligands; by this means a cobalt complex, [Co2{µ-η2:η2′-C4(CO2Me)4PPh2}(µ-PPh2)(CO)4], and a manganese complex, [Mn2(η4-C4H4PPh2)(µ-PPh2)(CO)6], in which the phosphole adopts respectively a terminal and a bridging mode, have been prepared and characterised by X-ray analysis as has related manganese complex, [Mn2(µ-η5-C4H4PPh2)(µ-PPh2)(CO)5].

Reduction of chalcogen oxyanions and generation of nanoprecipitates by the photosynthetic bacterium Rhodobacter capsulatus

The facultative photosynthetic bacterium Rhodobacter capsulatus is characterized in its interaction with the toxic oxyanions tellurite (Te(IV)) and selenite (Se(IV)) by a highly variable level of resistance that is dependent on the growth mode making this bacterium an ideal organism for the study of the microbial interaction with chalcogens. As we have reported in the past, while the oxyanion tellurite is taken up by R. capsulatus cells via acetate permease and it is reduced to Te(0) in the cytoplasm in the form of splinter-like black intracellular deposits no clear mechanism was described for Se(0) precipitation. Here, we present the first report on the biotransformation of tellurium and selenium oxyanions into extracellular Te(0) and Se(0)nanoprecipitates (NPs) by anaerobic photosynthetically growing cultures of R. capsulatus as a function of exogenously added redox-mediator lawsone, i.e. 2-hydroxy-1,4-naphthoquinone. The NPs formation was dependent on the carbon source used for the bacterial growth and the rate of chalcogen reduction was constant at different lawsone concentrations, in line with a catalytic role for the redox mediator. X-ray diffraction (XRD) analysis demonstrated the Te(0) and Se(0) nature of the nanoparticles.

Synthesis of new heterodinuclear aminocarbyne complexes: crystal structures of [AuW{µ-CN(Et)Me}C6F5)(CO)2(η-C5H5)] and [{CuW{µ-CN(Et)Me}Cl(CO)2(η-C5H5)}2]

The aminocarbyne [W{CN(Et)Me}(CO)2(cp)]1(cp =η-C5H5) reacts with [Au(C6F5)(tht)](tht = tetrahydrothiophene) and CuCl to give the adducts [AuW{µ-CN(Et)Me}(C6F5)(CO)2(cp)]2 and [{CuW{µ-CN(Et)Me}Cl(CO)2(cp)}2]3 respectively which have been structurally characterized by X-ray diffraction. Complex 2 crystallizes in space group P, a= 9.840(5), b= 11.577(6), c= 8.296(6)A, α= 99.03(5), β= 91.01(6), γ= 81.92(4)°, Z= 2. Complex 3 crystallizes in space group P21/a, a= 7.788(2), b= 14.880(5), c= 11.712(5)A, β= 95.35(3)°, Z= 2. Both adducts exhibit a molecule of 1 bonded to Au(C6F5) or Cu2Cl2 fragments, respectively, through one of the W–C(carbyne)π bonds. A WCM ring is formed in which 1 preserves most of its identity and the coinage metals attain their preferred electron counts. The cationic Group 11 fragments [M(PPh3)+](M = Cu, Ag or Au) also react with complex 1 to form [M{W[µ-CN(Et)Me](CO)2(cp)}2]+5; when M = Au NMR spectroscopy indicates that in addition to the trinuclear species 5, the dimetallacyclopropene [AuW{µ-CN(Et)Me}(CO)2(cp)(PPh3]+4 is also present. All these adducts have been spectroscopically characterised.