Comparative study of photodynamic properties of 13,15-N-cycloimide derivatives of chlorin p6

Comparative study of 13,15-[N-(2-hydroxyethyl)]cycloimide chlorin p6 (2), 13,15-(N-acetoxy)cycloimide chlorin p6 (3), 13,15-(N-hydroxy)cycloimide chlorin p6 methyl ester (4) and 13,15-(N-methoxy)cycloimide chlorin p6 methyl ester (5) together with the previously investigated 13,15-[N-(3-hydroxypropyl)]cycloimide chlorin p6 (1) was performed. The dependence of the key photodynamic properties of 1-5 on the introduced substituents was analyzed. The photoinduced cell-killing activity of 4 is 100- and 280-fold higher than that of chlorin p6 and Photogem, respectively, as estimated on A549 human lung adenocarcinoma cells. The activity is reduced eight times in the order 4 > 5 > 1 > 2 > 3. The intracellular accumulation of 1-5 occurs in cytoplasm in a monomeric form bound to the lipids of cellular membranes. This form of 1, 2, 3, 4 and 5 is characterized by the high quantum yield of singlet oxygen generation, which depends on the introduced substituents, 0.66, 0.59, 0.35, 0.51 and 0.73, respectively. The photostability is two-fold less for 1 and four-fold less for 2, 3 and 5 than for 4. The rates of cellular uptake and efflux of 1-5 vary widely, thus providing the way to optimize the pharmacological properties of the photosensitizer (PS) using the respective substituents. Modifying the substituents, 1-5 were targeted to different cellular organelles. The enhanced accumulation in the Golgi apparatus and mitochondria complemented with diffuse staining of intracellular membranous structures is a property of 1-4. Compound 5 accumulates selectively in the lipid droplets and stains weakly perinuclear structures. Temperature-sensitive mechanisms of transport are responsible for the 1-4 uptake. Diffusion can play a role in the internalization of 5 but not of 1-4. Endocytosis via caveolae, clathrin-dependent and adenosine triphosphate-dependent pathways are not noticeably involved in the 1-5 internalization. Independently from their intracellular localization 1, 4 and 5 are highly efficient near-IR PS, which induce predominantly an apoptotic type of cell death under conditions providing ca 50% level of phototoxicity and necrosis at the 100% level of phototoxicity.     

Structure and charge-state dependence of the gas-phase ionization energy of proteins

Photoionization of protein ions: The ionization energy of polyprotonated protein cations in the gas phase measured using VUV synchrotron radiation appears to be correlated with the charge state z of the protein and its tertiary structure. A simple electrostatic model accounts for the results and also shows predictive capabilities to derive a mean radius R(m) of the protein ion from the ionization energy, and vice versa.     

New Chiral Ortho-P,S-Difunctionalized Aromatic Compounds

Abstract

A new method to prepare enantioenriched sulfinates was developed to obtain optically active ortho-methylsulfinyl(phenylphosphonates). It consists of a diastereoselective oxidation of sulfenates to sulfinates. Additionally, preliminary results concerning the synthesis of ortho-phophonylated benzylic thiol derivatives via a new P═S to P═C [1,4]-rearrangement and a first synthetic application of these compounds are also described.     

Efficient Access to Peptidyl‐RNA Conjugates for Picomolar Inhibition of Non‐ribosomal FemXWv Aminoacyl Transferase

Peptidyl–RNA conjugates have various applications in studying the ribosome and enzymes participating in tRNA‐dependent pathways such as Fem transferases in peptidoglycan synthesis. Herein a convergent synthesis of peptidyl–RNAs based on Huisgen–Sharpless cycloaddition for the final ligation step is developed. Azides and alkynes are introduced into tRNA and UDP‐MurNAc‐pentapeptide, respectively. Synthesis of 2′‐azido RNA helix starts from 2′‐azido‐2′‐deoxyadenosine that is coupled to deoxycytidine by phosphoramidite chemistry. The resulting dinucleotide is deprotected and ligated to a 22‐nt RNA helix mimicking the acceptor arm of Ala‐tRNA^Ala by T4 RNA ligase. For alkyne UDP‐MurNAc‐pentapeptide, meso‐cystine is enzymatically incorporated into the peptidoglycan precursor and reduced, and L ‐Cys is converted to dehydroalanine with O‐(mesitylenesulfonyl)hydroxylamine. Reaction of but‐3‐yne‐1‐thiol with dehydroalanine affords the alkyne‐containing UDP‐MurNAc‐pentapeptide. The Cu^I‐catalyzed azide alkyne cycloaddition reaction in the presence of tris[(1‐hydroxypropyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]amine provided the peptidyl‐RNA conjugate, which was tested as an inhibitor of non‐ribosomal FemX_Wv aminoacyl transferase. The bi‐substrate analogue was found to inhibit FemX_Wv with an IC₅₀ of (89±9) pM , as both moieties of the peptidyl–RNA conjugate contribute to high‐affinity binding.     

Uncommon perspectives in palladium- and copper-catalysed arylation and heteroarylation of terminal alkynes following Heck or Sonogashira protocols: Interactions copper/ligand,formation of diynes,reaction and processes in ionic liquids

Conjugated alkynes are recurring building blocks in natural products and in a wide range of important compounds, such as pharmaceuticals, agrochemicals, or molecular materials. The palladium-catalysed cross-coupling reaction between the sp²-hybridized carbon atoms of aryl, heteroaryl, and vinyl halides with the sp-hybridized carbon atoms of terminal alkynes is one of the most important developments in the field of alkyne chemistry over the past 50 years. Room for improvement still exists in these important reactions of direct arylation of terminal alkynes. In this prospect, the present authors have developed several strategies aiming at improving the reactivity, the selectivity, and several aspects of processes involving the palladium-catalysed alkyne arylation and heteroarylation reactions, in relation with sustainable chemistry. Various original approaches have thus been adopted: (i) the development of catalytic systems efficient at low metal loading below 1 mol% of palladium and copper (to reduce metal contamination) from polydentate ligands chemistry, (ii) the limitation of diyne formation by undesired side-reaction, this from a better mechanistic understanding and the innovating use of copper adducts, (iii) and the development of cost-efficient catalytic reactions in ionic liquid solvents. These topics have been developed with the general outlook of a large scope in organic synthesis. In addition, the investigation of recycling opportunities and the unprecedented production of extendedly conjugated bis(aryl)diynes has been also achieved. The present account reviews all this work, as it has been presented by the corresponding author at GECOM–CONCOORD 2012 as recipient of the 2012 European journal of Inorganic Chemistry Young Investigator Award.     

Convenient Ring-Bromination of Alkylnaphthalenes using N-Bromosuccinimide in Acetonitrile

Abstract: Abstract. 1-Alkyl- and 2-alkylnaphthalenes are conveniently brominated in the 4-and 1-positions respectively using N-bromosuccinimide (NBS) in acetonitrile. The reactions are easy to perform and give higher chemical yields and better regioselectivity compared to brominations employing bromine/dichloromethane.     

Surface and porosity of nanocrystalline boehmite xerogels

Boehmite xerogels are prepared by hydrolysis of Al(OC4H9)3 followed by peptization with HNO3 (H+/Al = 0, 0.07, 0.2). XRD and TEM show that these gels are made of nanosized crystals (5-9 nm in width and 3 nm thick). According to the amount of acid, no significant differences are found in size and shape, but only in the spatial arrangement of the crystallites. Nitrogen adsorption-desorption isotherms of nonpeptized gels are of type IV, whereas isotherms of peptized gels are of type I. These isotherms are analyzed by the t-plot method. The majority of pore volume results from intercrystalline mesopores, but the peptized gels also contain intercrystalline micropores. The particle packing is very dense for the gel peptized with H+/Al = 0.2 (porosity = 0.26), but it is less dense in non-peptized gel (porosity = 0.44). Heating these gels under vacuum creates, from 250 degrees C onwards, an intracrystalline microporosity resulting from the conversion of boehmite into transition alumina. But heating also causes intercrystalline micropores collapsing. The specific surface area increases up to a limit temperature (300 degrees C for nonpeptized gels and 400 degrees C for peptized) beyond which sintering of the particles begins and the surface decreases. The PSD are calculated assuming a cylindrical pore geometry and using the corrected Kelvin equation proposed by Kruk et al. Peptized xerogels give a monomodal distribution with a maximum near 2 nm and no pores are larger than 6 nm. Nonpeptized gels have a bimodal distribution with a narrow peak near to 2 nm and a broad unsymmetrical peak with a maximum at 4 nm. Heating in air above 400 degrees C has a strong effect on the porosity. As the temperature increases, there is a broadening of the distribution and a marked decrease of small pores (below 3 nm). However, even after treatment at 800 degrees C, micropores are still present.     

PtCl2-catalyzed cycloisomerizations of 5-en-1-yn-3-ol systems

5-En-1-yn-3-ol substrates bearing a free hydroxyl group or an acyl group are highly versatile partners for PtCl2-catalyzed cycloisomerizations. Electrophilic activation of the alkyne moiety triggers at wish a hydride or an O-acyl migration yielding at the end to regioisomeric keto derivatives. The efficient preparation of Sabina ketone, an important monoterpene precursor, has been worked out.