PEGylated polyplex micelles from triblock catiomers with spatially ordered layering of condensed pDNA and buffering units for enhanced intracellular gene delivery

An A-B-C type triblock copolymer, tandemly aligning two types of polycations with different pKa values in a single polymer strand, was developed for the construction of novel polyplex micelles, satisfying a high DNA condensing ability as well as a proton buffering activity directed to elevating gene transfection. The micelle might feature the distinctive three-layered structure, where an inner polyplex layer of condensed pDNA with poly(l-lysine) (pKa approximately 9.4) as the C segment is successively wrapped with an intermediate layer of poly[(3-morpholinopropyl)aspartamide] (B segment) with a comparatively low pKa of approximately 6.2, to provide a buffering effect, and an outer PEG layer (A segment) as a biocompatible palisade.     

Molecular structure of glucopyranosylamide lipid and nanotube morphology

A series of glucopyranosylamide lipids, N-(X-octadecenoyl)-beta-D-glucopyranosylamine [X = 13-cis (1), 11-cis (2), 9-cis (3), 6-cis (4), and 9-cis,12-cis (5)] and their saturated homologue N-octadecanoyl-beta-d-glucopyranosylamine (6), which differ in the position of a cis double bond in the C18 hydrocarbon chains, have been synthesized. The effect of the cis double bond position on the chiral self-assembly of each glycolipid has been examined by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, UV, and circular dichroism (CD). The 11-cis derivative 2 was observed to self-assemble in water to form a uniform hollow cylinder structure with about 200-nm outer diameters in >98% yields. The obtained nanotubes from 2 showed the narrowest distribution of outer diameters and also gave a negative CD band around 234-236 nm, showing the largest CD intensity among the glycolipids investigated. Thus, we found that the position of a cis double bond significantly influences the homogeneity of the outer diameters as well as growth behavior of the self-assembled nanotube structures. Chiral molecular packing driven by a possible bending structure of the unsaturated glycolipids is playing a critical role in determining tubular morphology through molecular self-assembly.     

Triple hydrogen bonds direct crystal engineering of metal-assembled complexes: the effect of a novel organic-inorganic module on supramolecular structure

Novel triply hydrogen bonded suprastructures based on [M(tdpd)2(L)2]2- (H2tdpd=1,4,5,6-tetrahydro-5,6-dioxo-2,3-pyrazinedicarbonitrile, L=solvent) and melamine-analogous cations have been synthesized and characterized. The use of anions containing two AAA sets from [M(tdpd)2(L)2]2- together with cations containing one DDD set (A=hydrogen-bond acceptor, D=hydrogen-bond donor) leads to the formation of complementary triply hydrogen bonded modules in the solid state. In all cases, the building module is further extended via additional hydrogen-bonding interactions to produce a tape, and tapes are assembled into sheets. These results show that a hydrogen-bonded module consisting of different kinds of building blocks, one of which is a metal complex that includes hydrogen-bond acceptor sites and the other is a hydrogen-bond donor molecule, will be attractive for constructing metal-containing supramolecular systems by the self-assembly technique.     

Facile and chemo-selective synthesis of tertiary alkyl isothiocyanates from alcohols

When tert-alcohols were treated with (COOH)₂ and NaSCN in the presence of iodine, tertiary alkyl isothiocyanates were obtained in good yield, whereas the corresponding thiocyanates were obtained in low yield in the absence of iodine.     

The structures of macbecin I and II : New antitumor antibiotics

Macbecin I 1, C₃₀H₄₂N₂O₈, and macbecin II 2, C₃₀H₄₄N₂O₈, were shown to be 2,6-disubstituted benzoquinone and hydroquinone derivatives by an oxidation-reduction relationship, UV. ¹H and ¹³C NMR spectra. Alkaline methanolysis of 1 gave a 2-aminobenzoquinone derivative 5, suggesting an ansa-structure for 1, and acid hydrolysis of 1 gave decarbamoyl products 9,10 and 11, indicative of the location of carbamoyloxy group in allylic position. Spin decoupling studies on 1,3 and 5clarified the partial structures [A], [B], [C] and [D]. From their mutual disposition two structures 1a and 1b, were proposed out of which 1a has been selected for the structure of 1 on the basis of the structure of oxidative degradation product 12. X-Ray analysis of the bromoacetyl derivative of 1 confirmed the above proposed structure and determined the absolute stereochemistry of 1 and 2.     

Synthesis of marine guanidine alkaloids and their application as chemical/biological tools

Ptilomycalin A and crambescidins, novel marine guanidine alkaloids, have a unique pentacyclic guanidine structure, and exhibit a considerable array of biological activities. The first method developed for the synthesis of the pentacyclic guanidine core structure involved successive 1,3-dipolar cycloaddition reactions and resulted in the first total synthesis of crambescidin 359. The synthesis of other pentacyclic guanidine derivatives has been based on this methodology and applied as tools for studying biological activities, and as chemical reaction catalysts.     

Resistance properties of a macroporous silica-based N,N,N′,N′-tetraoctyl-3-oxapentane-1,5-diamide-impregnated polymeric adsorption material against nitric acid, temperature and γ-irradiation

The resistance of a novel silica-based N,N,N′,N′-tetraoctyl-3-oxapentane-1,5-diamide (TODGA) polymeric adsorption material (TODGA/SiO₂-P) against nitric acid, temperature and γ-irradiation had been investigated. The adsorption property of the treated TODGA/SiO₂-P was evaluated by a 3 M HNO₃ solution containing 0.01 M Nd(III). It was found that both 3 and 0.01 M HNO₃ concentrations did not decrease the stability of TODGA/SiO₂-P at 25°C. The quantity of TODGA leaked from TODGA/SiO₂-P was equivalent to its solubility in the corresponding HNO₃ aqueous solution. The effect of 3 M HNO₃ on the leakage of TODGA at 80°C was significantly higher than that in 0.01 M HNO₃ as well as in all cases at 25°C. The amount of Nd(III) adsorbed towards the treated TODGA/SiO₂-P was determined in the range of 0.143–0.148 mmol/g for the HNO₃ concentration effect and 0.142–0.0506 mmol/g for the temperature effect. γ-Irradiation showed a more noticeable destruction effect on TODGA/SiO₂-P. The content of TODGA leaked increased with an increase in the γ-irradiation dose (ID) from 1.06 to 3.72 MGy in terms of the linear equation [TODGA]=794.5ID+84.0. The amount of Nd(III) adsorbed onto the irradiated TODGA/SiO₂-P decreased rapidly from 0.134 to 0.0438 mmol/g, which was lower than 0.153 mmol/g, the adsorption of fresh TODGA/SiO₂-P for Nd(III), according to the equation Q_Nd(III)=−0.0301ID+0.160, showing that a large quantity of TODGA leaked from TODGA/SiO₂-P. The adsorbed amount of Nd(III) decreased obviously in this order: the HNO₃ concentration effect, temperature effect and γ-irradiation.     

Poly(ethylene glycol)-lipase complexes that are highly active and enantioselective in ionic liquids

Lipase-catalyzed alcoholysis between vinyl acetate and 2-phenyl-1-propanol was investigated in dialkylimidazolium-based ionic liquids. Although native lipase powder exhibited very low activity in an ionic liquid, forming a poly(ethylene glycol)(PEG)-lipase complex improved the lipase activity in the ionic liquid. The activity of the PEG-lipase complex was higher in ionic liquids than in common organic solvents (n-hexane, isooctane and dimethylsulfoxide). Fluorescence measurements using 4-aminophthalimide revealed that the ionic liquids were more hydrophilic than the organic solvents used for non-aqueous enzymology. A kinetic study of lipase-catalyzed alcoholysis in an ionic liquid ([Bmim][PF6]) revealed that the Michaelis constant (Km) for 2-phenyl-1-propanol in the ionic liquid was half that in n-hexane, suggesting that the ionic liquid stabilized the enzyme-substrate complex. Finally, we carried out enantioselective alcoholysis of 1-phenylethanol in ionic liquids employing the PEG-lipase complex, and obtained high enantioselectivity, comparable to that in n-hexane.     

α- and γ-Regiocontrol and Enantiospecificity in the Copper-Catalyzed Substitution Reaction of Propargylic Phosphates with Grignard Reagents

The regioselectivity (r.s.) and enantiospecificity (e.s.) of the substitution reactions of secondary propargylic alcohol derivatives using reagents derived from ArMgBr and Cu salts were studied. First, the picolinate, 3-methylpicolinate, and diethylphosphonate derivatives of Ph(CH₂)₂CH(OH)C≡CTMS were reacted with PhMgBr/CuCN in ratios of 2.5:2.7–2.5:0.25. The use of 2.5:0.25 ratio in THF/DME (6:1) at 0 °C for 1 h afforded the α-substitution product from the phosphate with ≥98 % r.s. and 99 % e.s. CuBr⋅Me₂S gave similar selectivity. The reaction system was then applied to phosphates derived from R¹CH(OH)C≡CR² and ArMgBr to obtain synthetically sufficient r.s. and e.s. values with R²=TMS, Ph, whereas iPr was borderline in terms of size as an R¹ substituent. The presence of a substituent at the o-position of Ar marginally affected the selectivity. We also found that the use of PhMgBr/Cu(acac)₂ in a 2:1 ratio in THF produced the γ-substitution products (allenes) with high r.s. and e.s.