New polyethyleneglycol-functionalized texaphyrins: synthesis and in vitro biological studies

The synthesis of four new analogues of motexafin gadolinium (MGd), a gadolinium(III) texaphyrin complex in clinical trials for its anticancer properties, is described. These new derivatives contain either 1,2-diaminobenzene or 2,3-diaminonaphthalene subunits as the source of the imine nitrogens and bear multiple 2-[2-(2-methoxyethoxy)ethoxy]ethoxy (PEG) groups, on either meso aryl or beta-pyrrolic substituents, to increase their water solubility. All four analogues were found to be more active in vitro than the parent system MGd as judged from cell proliferation assays using the PC3 and A549 cell lines.     

Astatine-211 labeling of protein using TCP as a bi-functional linker: synthesis and preliminary evaluation in vivo and in vitro

With 2,3,5,6-tetrafluorophenyl 3-(nodo-carboranyl) propionate (TCP) as a new potential bi-functional linker, bovine serum albumin (BSA) was conjugated with ²¹¹At, and the conjugated model protein (²¹¹At-TCP-BSA) was preliminarily evaluated in vitro and in vivo by comparison with ²¹¹At-SAB-BSA and ²¹¹At-SAPC-BSA, which conjugated with ²¹¹At via aryl derivatives ATE (N-succinimidyl-3-(tri-n-butylstannyl) benzoate) or SPC (N-succinimidyl 5-(tributylstannyl)-3-pyridinecarboxylate). The radiolabeled intermediate ²¹¹At-TCP was coupled to BSA in yields ranging from 35 to 45% with radiochemical purity of more than 98%. The conjugated ²¹¹At-TCP-BSA exhibited considerable stability in vitro in 0.1 mol/L PBS (pH 7.6) at room temperature (RT), similar to ²¹¹At-SAPC-BSA and ²¹¹At-SAB-BSA. Biodistribution of the ²¹¹At conjugated protein was investigated in NIH strain mice by I.V injection. The results showed that ²¹¹At-TCP-BSA was constantly stable in vivo as well as in vitro, but more stable than ²¹¹At-SAPC-BSA and ²¹¹At-SAB-BSA. These results implied that radioastatinated carboranes based on B–At bonds are higher stability than radioastatinated aryl derivatives based on C–At to in vivo deastatination. In other word, TCP should be a promising bi-functional linker for ²¹¹At conjugation of proteins or antibodies.     

New bicyclic phosphorous ligands: synthesis, structure and catalytic applications in ionic liquids

New azadioxaphosphabicyclo[3.3.0]octane ligands showing a trans arrangement with regard to the two five-membered heterocycles, were obtained as a mixture of three conformers, in agreement with molecular modelling studies. The stability of oxaphosphane ligands was studied under basic catalytic conditions, monitored by NMR spectroscopy. Palladium catalytic systems containing these ligands were active in Suzuki C-C cross-coupling reactions between phenylboronic acid and aryl halides (bromide and chloride derivatives) bearing electron-donor or electron-withdrawing substituents, in both organic and ionic liquid solvents. The catalytic systems showed a high stability even under the most severe reaction conditions used in this work. The ionic liquid catalytic phase could be recycled up to ten times without significant activity loss.     

Diethylstilbestrol glucuronide (DESG): synthesis, labeling with radioiodine and in vivo/in vitro evaluations

Diethylstilbestrol (DES) is a synthetic non-steroidal estrogen, pharmacologic effects of which resemble natural estrons; today it is being used to treat some types of postmenopausal breast cancer and advanced prostate cancer. The aim of current study is conjugation of glucuronic acid (G) to DES and to evaluate radiopharmaceutical potential of this estrogen glucuronide derivative (DESG) which is specific to β glucuronidase enzyme consisting tumor cells. Taking into consideration the compatibility to the chemical structures of the synthesized product, ¹³¹I and ¹²⁵I were chosen as the appropriate radionuclides and DESG was labeled with these radionuclides utilizing iodogen method. The radiochemical yields of ^125/131I-DESG were over 90 % according to thin layer radio chromatography method. The biodistribution of ¹³¹I-DESG in healthy female Wistar Albino rats has been investigated and the range of the breast/blood and breast/muscle ratios were approximately 2 and 13 in 240 min for ER unsaturated studies. Effects of the radioiodinated DES and DESG on the cells were examined using MCF-7, A-549, Caco-2 cell lines. ¹²⁵I-DESG has higher incorporation percentages than ¹²⁵I-DES on MCF-7 cells. The radioiodinated DESG has the desired radiopharmaceutical properties which could be candidate radiopharmaceuticals for diagnosis and especially radionuclide therapy of breast tumors.     

Chelating N-pyrrolylphosphino-N'-arylaldimine ligands: synthesis, ligand behaviour and applications in catalysis

Two families of variously-substituted N-pyrrolylphosphino-N'-arylaldimine ligands, 2-(aryl-N=CH)C4H3N-PR2 {R=Ph; R=Pri2N}, have been prepared from the corresponding pyrrolylaldimines . The donor characteristics/basicity of P-N-chelating and have been assessed using a combination of 31P{1H} NMR and IR spectroscopies through study of the magnitudes of 1JSeP for the phosphorus(V) selenides and , and measurement of nu(CO) for the complexes [RhCl(CO)(-kappa2-P,N)], respectively. The synthesis of the palladium(II) complexes [PdCl2(-kappa2-P,N)] was readily achieved from reaction of or with [PdCl2(MeCN)2] in CH2Cl2. X-Ray crystallographic studies of and confirm the chelating nature of the P-N ligands, which adopt a distorted 'envelope' conformation, and highlight the potentially significant steric demands of these metal scaffolds. Reaction of equimolar quantities of with [NiBr2(DME)] in MeCN afforded [NiBr2(-kappa2-P,N)], while the same reaction undertaken in CH2Cl2 with gave rise to the homoleptic bis(pyrrolatoimine) derivative [Ni{2-(mes-N=CH)C4H3N}2] in 45% yield, following P-N bond cleavage. Complex was characterised in the solid-state by X-ray crystallography. No identifiable metal-containing complexes could be obtained on reaction of with a variety of sources of Ni(II). The palladium dichloride complexes and proved inactive in combination with MAO or EtAlCl2 for ethylene polymerisation, and with methanesulfonic acid for CO/ethylene co-polymerisation. Contrastingly, the nickel complexes in combination with 4.5 eq. EtAlCl2 catalysed the formation of butenes and hexenes with moderate activity from ethylene at 1 bar.     

A fluorescent broad-spectrum proteasome inhibitor for labeling proteasomes in vitro and in vivo

The proteasome is an essential evolutionary conserved protease involved in many regulatory systems. Here, we describe the synthesis and characterization of the activity-based, fluorescent, and cell-permeable inhibitor Bodipy TMR-Ahx(3)L(3)VS (MV151), which specifically targets all active subunits of the proteasome and immunoproteasome in living cells, allowing for rapid and sensitive in-gel detection. The inhibition profile of a panel of commonly used proteasome inhibitors could be readily determined by MV151 labeling. Administration of MV151 to mice allowed for in vivo labeling of proteasomes, which correlated with inhibition of proteasomal degradation in the affected tissues. This probe can be used for many applications ranging from clinical profiling of proteasome activity, to biochemical analysis of subunit specificity of inhibitors, and to cell biological analysis of the proteasome function and dynamics in living cells.     

New Zn(II) complexes based on biologically active substituted acetic acid and nitrogen donor ligands: synthesis,crystal structure and biological applications

The complexes [Zn(phenylacetato)₂(2-aminopyridin)₂] (3), [Zn(phenylacetato)₂(1,10-phenanthroline)]·H₂O (4), and [Zn(phenylacetato)₂(2,9-dimethyl-1,10-phenanthroline)]·0.5 H₂O (5) were prepared and characterized by IR-, UV–Visible, ¹H and ¹³C NMR spectroscopy, and single crystal X-ray diffraction. BNPP hydrolysis of the complexes and their parent nitrogen ligands showed that the hydrolysis rate of bis-(4-nitrophenyl) phosphate (BNPP) was 1.7 × 10⁵ L mol^?1 s^?1 for 3, 3.1 × 10⁵ L mol^?1 s^?1 for 4 and 4.3 × 10⁴ L mol^?1 s^?1 for 5. Antibacterial activities show the effect of complexation on activity against Gram-positive (S. epidermidis, S. aureus, E. faecalis, M. luteus and B. subtilis) and Gram-negative (K. pneumonia, E. coli, P. mirabilis and P. aeruginosa) bacteria using the agar well diffusion method. Complex 4 showed good activity against G? bacteria except P. aeruginosa, and against G+ bacteria except E. ferabis. Complex 5 showed no activity against G? bacteria, low activity against M. luteus and B. subtilis bacteria and high activity against S. epidemidis and S. aureus. Complex 3 did not show any activity against G? or G+ bacteria.     

Physical-chemical aspects of protein corona: relevance to in vitro and in vivo biological impacts of nanoparticles

It is now clearly emerging that besides size and shape, the other primary defining element of nanoscale objects in biological media is their long-lived protein ("hard") corona. This corona may be expressed as a durable, stabilizing coating of the bare surface of nanoparticle (NP) monomers, or it may be reflected in different subpopulations of particle assemblies, each presenting a durable protein coating. Using the approach and concepts of physical chemistry, we relate studies on the composition of the protein corona at different plasma concentrations with structural data on the complexes both in situ and free from excess plasma. This enables a high degree of confidence in the meaning of the hard protein corona in a biological context. Here, we present the protein adsorption for two compositionally different NPs, namely sulfonated polystyrene and silica NPs. NP-protein complexes are characterized by differential centrifugal sedimentation, dynamic light scattering, and zeta-potential both in situ and once isolated from plasma as a function of the protein/NP surface area ratio. We then introduce a semiquantitative determination of their hard corona composition using one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electrospray liquid chromatography mass spectrometry, which allows us to follow the total binding isotherms for the particles, identifying simultaneously the nature and amount of the most relevant proteins as a function of the plasma concentration. We find that the hard corona can evolve quite significantly as one passes from protein concentrations appropriate to in vitro cell studies to those present in in vivo studies, which has deep implications for in vitro-in vivo extrapolations and will require some consideration in the future.     

Polyacrylic acid coating of highly luminescent CdS nanocrystals for biological labeling applications

Surface coating of highly luminescent CdS nanocrystals by polyacrylic acid was demonstrated. The method proceeded in 2 steps, (i) modification of the CdS surface by alkyl molecules and (ii) polyacrylic acid coating of the surface modified CdS. Attachment of alkyl ammonium on the CdS surface induced a phase transfer reaction from an aqueous to a non-polar phase with a yield of approximately 100%. Investigating alkyl molecules with various functional groups revealed that the alkyl molecules, possessing the cation moiety, such as amine or ammonium salt, can electrostatically interact with the CdS surface. The PL of the uncoated nanocrystals was almost entirely quenched in the pH range of approximately 7, while the polyacrylic acid coated nanocrystals exhibited moderate PL intensity. This PL intensity was preserved for at least several days, facilitating biological labeling application under a neutral condition.     

Chiral diphosphine ligands based on camphor: synthesis and applications in asymmetric hydrogenations

The synthesis of a novel class of atropisomer chiral diphosphine ligands with a bornene framework is described. The new ligands showed in Rh catalyzed asymmetric hydrogenation of α- and β-enamides very high ee’s (more than 99%).     

Site-specific protein double labeling by expressed protein ligation: applications to repeat proteins

In the last few years, the use of labeled proteins has significantly expanded in the life sciences. Now, labeled proteins are indispensable tools for a wide spectrum of biophysical and chemical biology applications. In particular, the quest for more sophisticated experimental setups requires the development of new synthetic methodology, especially for multiple site-specific labeling. In this paper, we describe a synthetic strategy based on expressed protein ligation to prepare proteins in high purity and homogeneity, in which two different molecular probes are incorporated specifically at any desired position. Proteins are sequentially labeled in solution, with the advantage that a large excess of probes is not required and the labeled fragments are not restricted to peptide synthesis length limitations. This strategy was applied to selectively label a repeat protein with a fluorophores pair in different positions along the protein sequence. The doubly labeled proteins were prepared at high purity and homogeneity, as required for single molecule FRET studies. Remarkably, this approach can be adapted to the introduction of more than two molecular probes.     

New antitumour active platinum compounds containing carboxylate ligands in trans geometry: synthesis, crystal structure and biological activity

New asymmetric trans-platinum(II) complexes, composed of an isopropylamine, an azole and two carboxylate leaving groups, are presented. The crystal and molecular structures of one of the complexes has been determined and the cytotoxicity and reactivity with 5'-guanosine monophosphate is reported. The complexes show a reduced reactivity, but no decrease in cytotoxic activity compared to their chloro-counterparts. Furthermore the complexes largely overcome cisplatin resistance, they therefore present an interesting class of antitumour active trans-platinum complexes.     

Photo-affinity labeling strategies in identifying the protein ligands of bioactive small molecules: examples of targeted synthesis of drug analog photoprobes

The discovery of many new targets by chemical genetics has frequently exploited the fact that their biologically active chemical ligands were reactive and thus could covalently bind to their protein target(s). When experimental compounds or therapeutic agents with unidentified mechanisms of action do not contain reactive groups that can covalently label the putative site of molecular action, it may be possible to create a reactive photo-affinity probe if there is sufficient knowledge of the structure-activity relationship of the chemical series. Two specific examples are presented. These include the use of photo-affinity probes in the identification of the mechanism of action of synthetic oxazolidinones, a class of novel acting antibiotics and in the identification of a novel target for the insulin-sensitizing thiazolidinediones. Developments in photo-affinity labeling and combinatorial library design now imply that the parallel incorporation of photo-probes into screening library design could, at least in principle, greatly facilitate reverse pharmacological and chemical genetics approaches to protein target discovery.     

New camphor derived chiral ligands for asymmetric synthesis

New enantiomerically pure 1,4-diols and 1,4-aminoalcohols have efficiently been prepared in one and two steps, respectively, from a commercially available camphor derived exo fused lactone. Using sterically hindered amines, an aldol addition of two lactone molecules was observed and the stereochemistry of the products was determined by X-ray crystallography.     

Synthetic biohybrid peptidoglycan oligomers enable pan-bacteria-specific labeling and imaging: in vitro and in vivo

Peptidoglycan is the core component of the bacterial cell wall, which makes it an attractive target for the development of bacterial targeting agents. Intercepting its enzymatic assembly with synthetic substrates allows for labeling and engineering of live bacterial cells. Over the past two decades, small-molecule-based labeling agents, such as antibiotics, d-amino acids or monosaccharides have been developed for probing biological processes in bacteria. Herein, peptidoglycan oligomers, substrates for transglycosylation, are prepared for the first time using a top-down approach, which starts from chitosan as a cheap feedstock. A high efficiency of labeling has been observed in all bacterial strains tested using micromolar substrates. In contrast, uptake into mammalian cells was barely observable. Additional mechanistic studies support a hypothesis of bacteria-specific metabolic labeling rather than non-specific binding to the bacterial surface. Eventually, its practicality in bacterial targeting capability is demonstrated in resistant strain detection and in vivo infection models.

Peptidoglycan oligomers have been derived from chitosan, using a top-down bio-hybrid strategy, as highly bacteria-specific substrates.     

New structural motifs of silver and gold complexes of pyridine-functionalized benzimidazolylidene ligands

Reaction of 1,3-bis(picolyl)benzimidazolium chloride ([HL1]Cl) with Ag₂O yields mononuclear complex [Ag(L1)Cl] (2), further reaction of 2 with Au(Et₂S)Cl afforded [Au(L1)Cl] (3). Treatment of 2 with AgBF₄ gave the trinuclear silver cluster [Ag₃(L1)₃](BF₄)₃ (4), whereas the digold complex [Au₂(L1)₂](BF₄)₂ (5) can be easily obtained from the carbene transfer reaction of 4 with Au(Et₂S)Cl. A one-dimensional coordination polymer {[Ag(L2)](BF₄) · CH₃CN}_n (8) was isolated from the reaction of [Ag(L2)Cl] (7, L2 = 1-benzyl-3-picolylbenzimidazolylidene) with additional Ag⁺ in good yield. The dinuclear [Ag₂(L3)₂](PF₆)₂ (12, L3 = 1,4-di(N-benzylbenzimidazolylidene)but-2-yne) is a 18-membered macrocycle. All these complexes have been structurally characterized. Complex 2 shows a dimeric structure because of intermolecular Ag?Cl interactions. Complex 4 consists of a triangular Ag₃ ring with very short Ag-Ag contacts 2.777(1) Å, the Au-Au distance in 5 is 3.206(2) Å showing very weak Au-Au interaction and the macrocyclic cations in 12 are aligned one above another to form channels filled with hexafluorophosphate anions. The complexes 2-5, 8, and 12 are intensely luminescent upon irradiation of uv light, and their emission properties are briefly described.     

Ferrocenyl monophosphine ligands: synthesis and applications in the Suzuki-Miyaura coupling of aryl chlorides

Ferrocenyl monophosphine ligands have been developed by a method based on palladium-catalyzed Suzuki-Miyaura coupling. The modular procedure creates a rapid synthesis of phosphines with diverse properties. The electron-rich phosphines have been successfully applied to the Suzuki-Miyaura coupling of activated and deactivated aryl chlorides, with low catalyst loading being feasible in the synthesis of tris-ortho-substituted biaryls.     

3,3'-disubstituted BINAP ligands: synthesis, resolution, and applications in asymmetric hydrogenation

A novel family of BINAP ligands were prepared with alkoxy- and acetoxy-derived substituents in the 3,3'-positions. They were prepared through a convergent synthesis starting from readily available 4-bromo-2-naphthol. These ligands afforded excellent enantioselectivities in the asymmetric hydrogenation of substituted olefins. The presence of the 3,3'-substituents was shown to be beneficial by a direct comparison with the parent unsubstituted BINAP. [reaction: see text]     

Metal complexes with polymeric ligands: modular synthesis of multifunctional materials for applications in biomedicine and nanotechnology

Polymeric metal complexes exhibiting useful properties were prepared by chelating macroligands to labile and inert metal ions. The specific structures elucidated through this method, as well as potential applications for these complexes are described. By carefully selecting the appropriate metal ion and polymer, these materials can be tuned for a host of applications in fields ranging from biomedicine to nanotechnology.