Advantage of the ether linkage between the positive charge and the cholesteryl skeleton in cholesterol-based amphiphiles as vectors for gene delivery

Twelve novel cationic cholesterol derivatives with different linkage types between the cationic headgroup and the cholesteryl backbone have been developed. These have been tested for their efficacies as gene transfer agents as mixtures with dioleoyl phosphatidylethanolamine (DOPE). A pronounced improvement in transfection efficiency was observed when the cationic center was linked to the steroid backbone using an ether type bond. Among these, cholest-5-en-3b-oxyethane-N, N,N-trimethylammonium bromide (2a) and cholest-5-en-3b-oxyethane-N, N-dimethyl-N-2-hydroxyethylammonium bromide (3d) showed transfection efficiencies considerably greater than commercially available reagents such as Lipofectin or Lipofectamine. To achieve transfection, 3d did not require DOPE. Increasing hydration at the headgroup level for both ester- and ether-linked amphiphiles resulted in progressive loss of transfection efficiency. Transfection efficiency was also greatly reduced when a 'disorder'-inducing chain like an oleyl (cis-9-octadecenyl) segment was added to these cholesteryl amphiphiles. Importantly, the transfection ability of 2a with DOPE in the presence of serum was significantly greater than for a commercially available reagent, Lipofectamine. This suggests that these novel cholesterol-based amphiphiles might prove promising in applications involving liposome-mediated gene transfection. This investigation demonstrates the importance of structural features at the molecular level for the design of cholesterol-based gene delivery reagents that would aid the development of newer, more efficient formulations based on this class of molecules.

A facile entry into a new class of spiroheterocycles: synthesis of dispiro[oxindolechromanone/flavanone/tetralone]pyrroloisoquinoline ring systems

A series of novel dispiroheterocyclic systems have been synthesized by the cycloaddition of a new azomethine ylide generated by the decarboxylative route from tetrahydroisoquinoline-3-carboxylic acid and isatin with various dipolarophiles containing exocyclic double bond such as 3-arylidene-4-chromanone, 3-arylidene-4-flavanone and 2-arylidenetetrahydro-1-naphthalenone in moderate to good yield. The regio and stereochemistry of the title compounds was established by single crystal X-ray structure and spectroscopic techniques. (C) 2002 Elsevier Science Ltd. All rights reserved.

Chiral Mitsunobu reactions with (1S)-(+)-ketopinic acid: kinetic resolutions of secondary alcohols

Several secondary alcohols undergo the Mitsunobu reaction with triphenylphosphine, diethyl azodicarboxylate and (1S)-(+)-ketopinic acid (0.5 equiv. each relative to alcohol) in CH2Cl2 solution at -23degreesC, to furnish the chiral secondary alcohol and its ketopinate ester (d.e. >95%,). Chromatographic separation of these and subsequent hydrolysis of the ketopinate ester (KOH EtOH/0degreesC) provides the chiral secondary alcohol in overall yields of similar to75% and e.e. of similar to80%. When the above Mitsunobu reaction is performed with 1 equiv. of all the reactants. an effective dynamic kinetic resolution of the alcohol is observed in two cases, the ketopinate esters being isolated in 63 and 75% yields and >95% d.e. (C) 2002 Elsevier Science Ltd. All rights reserved.

A comparison of the DNMR behaviour of methyl 5,6-bis(2-methoxyphenyl)-1,4-dimethyl-7-oxobicyclo[2.2.1]hept-5-en-2-endo-carboxylate and its 7-oxa analogue

Methyl 5,6-Bis(2-methoxyphenyt)-1,4-dimethyl-7-oxobicyclo[2.2.1]hept-5-en-2-endo-carboxylate, a moderately crowded norbornenone ester, exhibits complex VT-DNMR behaviour. A similar behaviour is not seen in its 7-oxa analogue, showing that conformational transmission from position 7 has a crucial influence on the distance parameters that govern the dynamic processes involving the substituents on the bicycloheptene framework.

Synthesis of electrically conducting copolymers of aniline with o/m-amino benzoic acid by an inverse emulsion pathway

Copolymers of aniline and ortholmeta-amino benzoic acid were synthesized by chemical polymerization using an inverse emulsion pathway. The copolymers are soluble in organic solvents, and the solubility increases with the amino benzoic acid content in the feed. The reaction conditions were optimized with emphasis on high yield and relatively good conductivity (2.5 X 10(-1) S cm(-1)). The copolymers were characterized by a number of techniques including UV-vis, FT-IR, FT-Raman, EPR and NNM spectroscopy, thermal analysis, SEM and conductivity. The influence of the carboxylic acid group ring substituent on the copolymers is investigated. The spectral studies reveal that the amino benzoic acid groups restrict the conjugation along the polymer chain. The SEM micrographs of the copolymers reveal regions of amorphous and crystalline domain. Thermal studies indicate a marginally higher thermal stability for poly(aniline-co-m-amino benzoic acid) compared to poly(aniline-co-o-amino benzoic acid). (C) 2002 Elsevier Science Ltd. All rights reserved.

Thermal Lipid Order−Disorder Transitions in Mixtures of Cationic Cholesteryl Lipid Analogues and Dipalmitoyl Phosphatidylcholine Membranes

Two types of cationic cholesteryl amphiphiles, one where the headgroup is attached to the steroid by an ester linkage and the second by an ether linkage, were synthesized. A third type of cholesteryl lipid bearing an oligoethylene glycol segment was also prepared. Each of these synthetic lipids generated vesicle-like aggregates with closed inner aqueous compartments from their aqueous suspensions. We examined their interaction with L-α-dipalmitoyl phosphatidylcholine (DPPC) membranes using fluorescence anisotropy, transmission electron microscopy (TEM), and differential scanning calorimetry (DSC). When included in membranes, the synthetic cholesteryl lipids were found to quench the chain motion of the acyl chains of DPPC. This suggests that these cationic cholesteryl derivatives act as filler molecules despite modification at the headgroup level from the molecular structure of natural cholesterol. Careful analyses of DSC and fluorescence anisotropy data suggest that the nature of perturbation induced by each of these cationic cholesterol derivatives is dependent on the details of their molecular structure and provides significant information on the nature of interaction of these derivatives with phospholipid molecules. In general, amphiphiles that support structured water at the interfacial region tend to rigidify the fluid phase more than others. Importantly, these cholesteryl amphiphiles behave less like cholesterol in that their incorporation in DPPC not only abolishes the phase transition but also depresses the phase transition temperature.

Acylation of Grignard reagents mediated by N-methylpyrrolidone: A remarkable selectivity for the synthesis of ketones

An efficient user-friendly method of acylation of Grignard reagents to selectively synthesize ketones is presented, which is assisted by simple amides such as NMP, or DMF. The present chemoselective method tolerates a variety of functional groups such as ketone, ester, nitrile and other functional groups.

A stereospecific approach to cis-anti-cis triquinanes

A methodology for the synthesis of compounds containing the cis-anti-cis fused triquinane system has been developed starting from tricyclo[5.2. 1.0(2.6)]deca-4,8-dien-3-(exo)ol 6 involving Ireland ester Claisen rearrangement and intramolecular diazo ketone cyclopropanation reactions as key steps.

278. Studies on ass's milk: Composition

The total solids of samples of ass's milk ranged from 7·80 to 9·10, the solids-not-fat from 7·14 to 8·50, and the fat from 0·54 to 0·71%. The nitrogen distribution in ass's milk is: casein 39·5, albumin 35·0, globulin 2·7 and non-protein nitrogen 22·8% of the total nitrogen. Ass's milk contains: casein 0·70, albumin 0·62 and globulin 0·07%. The total protein content is 1·39%. Ass's milk is therefore characterized by a low casein, a low globulin and a high albumin content. The non-protein nitrogen consists of amino nitrogen 8·1, urea nitrogen 24·3 and uric acid 0·7 mg./100 ml. of milk. The urea content is twice that present in cow's milk. The mean chloride and lactose contents of the milk samples are 0·037 and 6·1% respectively. The average calcium and phosphorus content of ass's milk are 0·081 and 0·059% respectively. Half the calcium is ionic, and half is in colloidal form. The phosphorus distribution is: total acid soluble 84·0, acid soluble organic 38·5, easily hydrolysable ester 27·4, inorganic 46·0, and colloidal inorganic 23·0 % of the total phosphorus. The ratio of CaO: P2O5 is 1:1. 46 % of the total phosphorus is in ester form; this is high when compared with only 12 % in cow's milk; most of the phosphoric ester forms soluble barium salts, which is a distinguishing feature of ass's milk. The total sulphur content is 15·8 mg./100 ml. The fat has a penetrating odour and is coloured orange-yellow. It has an iodine value of about 86, which is much higher than that for human milk fat. The Reichert (9·5) and Kirschner values (5·7) are low. In general, the composition of ass's milk resembles that of human rather than of cow's milk.

Synthesis based on cyclohexadienes Part 36: an efficient methodology for the construction of spiro[4.5]decanes: a formal synthesis of acorone

An efficient strategy for the contruction of spiro[4.5] decanes is described and involves a bridgehead substitution of a methoxyl group by a methyl group followed by an oxidative cleavage of the tricyclo[5.2.2.0(1,5)] undecane 25 to produce the spiro[4.5] decanes 31 & 32 which are intermediates in the synthesis of acorone. A novel one-pot conversion of alpha-methoxy carboxylic acid to alpha-methyl carboxylic acid is described.

Thermally induced phase separation in P alpha MSAN/PMMA blends in presence of functionalized multiwall carbon nanotubes: Rheology, morphology and electrical conductivity

The focus of this work is the evaluation and analysis of the state of dispersion of functionalized multiwall carbon nanotubes (CNTs), within different morphologies formed, in a model LCST blend (poly[(alpha-methylstyrene)-co-(acrylonitrile)]/poly(methyl-methacryla te), P alpha MSAN/PMMA). Blend compositions that are expected to yield droplet-matrix (85/15 P alpha MSAN/PMMA and 15/85 P alpha MSAN/PMMA, wt/wt) and co-continuous morphologies (60/40 P alpha MSAN/PMMA, wt/wt) upon phase separation have been combined with two types of CNTs; carboxylic acid functionalized (CNTCOOH) and polyethylene modified (CNTPE) up to 2 wt%. Thermally induced phase separation in the blends has been studied in-situ by rheology and dielectric (conductivity) spectroscopy in terms of morphological evolution and CNT percolation. The state of dispersion of CNTs has been evaluated by transmission electron microscopy. The experimental results indicate that the final blend morphology and the surface functionalization of CNT are the main factors that govern percolation. In presence of either of the CNTs, 60/40 P alpha MSAN/PMMA blends yield a droplet-matrix morphology rather than co-continuous and do not show any percolation. On the other hand, both 85/15 P alpha MSAN/PMMA and 15/85 P alpha MSAN/PMMA blends containing CNTPEs show percolation in the rheological and electrical properties. Interestingly, the conductivity spectroscopy measurements demonstrate that the 15/85 P alpha MSAN/PMMA blends with CNTPEs that show insulating properties at room temperature for the miscible blends reveal highly conducting properties in the phase separated blends (melt state) as a result of phase separation. By quenching this morphology, the conductivity can be retained in the blends even in the solid state. (C) 2011 Elsevier Ltd. All rights reserved.

Perfluoroalkyl bile esters: a new class of efficient gelators of organic and aqueous-organic media

A new class of fluorinated gelators derived from bile acids is reported. Perfluoroalkyl chains were attached to the bile acids through two different ester linkages and were synthesized following simple transformations. The gelation property of these derivatives is a function of the bile acid moiety, the spacer and the fluoroalkyl chain length. By varying these parameters, gels were obtained in aromatic hydrocarbons, DMSO and DMSO/DMF-H(2)O mixtures of different proportions. Several derivatives of deoxycholic and lithocholic acids were found to be efficient organogelators, while the reported bile-acid based organogelators are mostly derived from the cholic acid moiety. The efficient gelators among these compounds formed gels well below 1.0% (w/v) and hence they can be termed as supergelators. The mechanical properties of these gels could be modulated by changing either the bile acid moiety or by varying the length of the fluoroalkyl segment. The presence of CO(2)-philic perfluoroalkyl groups is also expected to enhance their solubility in supercritical CO(2) and hence these compounds are promising candidates for making aerogels.

Ethyl 6-methyl-2-sulfanylidene-4-[4(trifluoromethyl)phenyl]-1,2,3,4-tetrahyd ropyrimidine-5-carboxylate

The title compound, C(15)H(15)F(3)N(2)O(2)S, adopts a conformation with an intramolecular C-H center dot center dot center dot pi interaction. The dihedral angles between the planes of the 4-(trifluoromethyl) phenyl and ester groups with the plane of the six-membered tetrahydropyrimidine ring are 81.8 (1) and 16.0 (1)degrees, respectively. In the crystal structure, intermolecular N-H center dot center dot center dot S hydrogen bonds link pairs of molecules into dimers and N-H center dot center dot center dot O interactions generate hydrogen-bonded molecular chains along the crystallographic a axis.

Perfluoroalkyl bile esters: a new class of efficient gelators of organic and aqueous-organic media

A new class of fluorinated gelators derived from bile acids is reported. Perfluoroalkyl chains were attached to the bile acids through two different ester linkages and were synthesized following simple transformations. The gelation property of these derivatives is a function of the bile acid moiety, the spacer and the fluoroalkyl chain length. By varying these parameters, gels were obtained in aromatic hydrocarbons, DMSO and DMSO/DMF-H(2)O mixtures of different proportions. Several derivatives of deoxycholic and lithocholic acids were found to be efficient organogelators, while the reported bile-acid based organogelators are mostly derived from the cholic acid moiety. The efficient gelators among these compounds formed gels well below 1.0% (w/v) and hence they can be termed as supergelators. The mechanical properties of these gels could be modulated by changing either the bile acid moiety or by varying the length of the fluoroalkyl segment. The presence of CO(2)-philic perfluoroalkyl groups is also expected to enhance their solubility in supercritical CO(2) and hence these compounds are promising candidates for making aerogels.

Charge transfer complex states in diketopyrrolopyrrole polymers and fullerene blends: Implications for organic solar cell efficiency

The spectral photocurrent characteristics of two donor-acceptor diketopyrrolopyrrole (DPP)-based copolymers (PDPP-BBT and TDPP-BBT) blended with a fullerene derivative [6,6]-phenyl C-61-butyric acid methyl ester (PCBM) were studied using Fourier-transform photocurrent spectroscopy (FTPS) and monochromatic photocurrent (PC) method. PDPP-BBT: PCBM shows the onset of the lowest charge transfer complex (CTC) state at 1.42 eV, whereas TDPP-BBT: PCBM shows no evidence of the formation of a midgap CTC state. The FTPS and PC spectra of P3HT:PCBM are also compared. The larger singlet state energy difference of TDPP-BBT and PCBM compared to PDPP-BBT/P3HT and PCBM obliterates the formation of a midgap CTC state resulting in an enhanced photovoltaic efficiency over PDPP-BBT: PCBM. (C) 2011 American Institute of Physics. [doi:10.1063/1.3670043]