Stefan C. T. Svensson

Protein adsorption to oligo(ethylene glycol) self-assembled monolayers: experiments with fibrinogen, heparinized plasma, and serum.

Low protein adsorption is believed advantageous for blood-contacting materials and ethylene glycols (EG)-based polymeric compounds are often attached to surfaces for this purpose. In the present study, the adsorption of fibrinogen, serum, and plasma were studied by ellipsometry on a series of well-defined oligo(EG) terminated alkane-thiols self-assembled on gold. The layers were prepared with compounds of the general structure HS-(CH2)15-CONH-EGn, where n = 2, 4, and 6. Methoxy-terminated tri(EG) undecanethiol and hydroxyl-terminated hexadecanethiol self-assembled monolayers (SAMs) were used as references. The results clearly demonstrate that the adsorption depends on the experimental conditions with small amounts of fibrinogen adsorbing from a single protein solution, but larger amounts of proteins from serum and plasma. The adsorption of fibrinogen and blood plasma decreased with an increasing number of EG repeats and was temperature-dependent. Significantly less serum adsorbed to methoxy tri(EG) than to hexa(EG) and more proteins remained on the latter surface after incubation in a sodium dodecyl sulfate (SDS) solution, indicating a looser protein binding to the methoxy-terminated surface. All surfaces adsorbed complement factor 3 (C3) from serum and plasma, although no surfacemediated complement activation was observed. The present study points to the importance of a careful choice of the protein model system before general statements regarding the protein repellant properties of potential surfaces can be made.

Synthesis of some benzyl and methyl ethers of myo-inositol

Abstract The 1 d and 1 d forms of 1,2,4,5,6- and 1,2,3,4,5-penta- O -methyl- myo -inositol have been prepared from the corresponding chiral mono- O -benzyl derivatives. Convenient preparations are also described of achiral derivatives of 1-, 2-, 4-, and 5- O -benzyl- myo -inositol and of achiral 1,2,4,5,6- and 1,3,4,5,6- myo -inositol by selective benzylation through stannylidene derivatives and through reductive cleavage of benzylidene acetals.

Synthesis of 1d- and 1l-4-O-benzyl-myo-inositol, 1d-4-O-α-l-fucopyranosyl-myo-inositol (identical to a natural glycoside), and 1l-4-O-α-l-fucopyranosyl-myo-inositol

Abstract The α- l -fucopyranosyl- myo -inositol isolated from human urine has been proved to be the 1 d -4- O - myo -inositol derivative by unambiguous syntheses of this substance and of the diastereomeric 1 l -4- O - myo -inositol derivative. The chiral penta- O -benzoyl- myo -inositols used in the glycosidations, by the imidate method, were prepared from 1 d - and 1 l -4- O -benzyl- myo -inositol, respectively. The latter were resolved as the l (+)- O -acetylmandelates of the corresponding racemic 4- O -benzyl-1,6:2,3-di- O -cyclohexylidene- myo -inositol.

Synthesis of galactoglycerolipids found in the HT29 human colon carcinoma cell line

Synthesis of three galactoglycerolipids (3-O-(β-d-galactopyranosyl)-1-O-hexadecyl-2-O-palmitoyl-sn-glycerol, 3-O-(α-d-galactopyranosyl-(1→4)-β-d-galactopyranosyl)-1-O-hexadecyl-2-O-palmitoyl-sn-glycerol, 3-O-(α-d-galactopyranosyl-(1→4)-β-d-galactopyranosyl)-1-O-hexadecyl-sn-glycerol), and the corresponding glycerolipid (1-O-hexadecyl-2-O-palmitoyl-sn-glycerol) is described. The first two compounds were recently identified in the human colon carcinoma cell line HT29. The three-carbon synthon (S)-glycidol was used for construction of the glycerol moiety. Glycosylation of (S)-glycidol with protected galactosyl and digalactosyl donors produced galactosyl and digalactosyl glycidols. Lewis acid catalyzed opening of the epoxide produced protected galactosyl and digalactosyl glycerolipids. Deprotection, or palmitoylation followed by deprotection, yielded the target compounds. The corresponding glycerolipid was synthesized analogously and an oxidation–reduction procedure for tritiation was developed. The synthesized compounds will be used in studies of the role of galactosyl glycerolipids in differentiation and colon cancer development.

Synthesis of some purine carbocyclic isosteres of 2',3'-dideoxy-3'-C-hydroxymethyl nucleosides as potential inhibitors of HIV

Abstract The synthesis of some enantiomerically pure carbocyclic 2′,3′-dideoxy-3′-C-hydroxymethyl derivatives of adenine, inosine and guanine is described. The Mitsunobu reaction was used in the coupling procedure giving exclusively N9-coupling. The nucleosides were tested for inhibition of HIV multiplication in vitro and were found to be inactive in the assay.

Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability

Voltage-gated ion channels generate cellular excitability, cause diseases when mutated, and act as drug targets in hyperexcitability diseases, such as epilepsy, cardiac arrhythmia and pain. Unfortunately, many patients do not satisfactorily respond to the present-day drugs. We found that the naturally occurring resin acid dehydroabietic acid (DHAA) is a potent opener of a voltage-gated K channel and thereby a potential suppressor of cellular excitability. DHAA acts via a non-traditional mechanism, by electrostatically activating the voltage-sensor domain, rather than directly targeting the ion-conducting pore domain. By systematic iterative modifications of DHAA we synthesized 71 derivatives and found 32 compounds more potent than DHAA. The most potent compound, Compound 77, is 240 times more efficient than DHAA in opening a K channel. This and other potent compounds reduced excitability in dorsal root ganglion neurons, suggesting that resin-acid derivatives can become the first members of a new family of drugs with the potential for treatment of hyperexcitability diseases.

Synthesis of 3′,4′-C-Bishydroxymethyl-2′,3′,4′-trideoxy-β-L-threo-pentopyranosyl Nucleosides as Potential Inhibitors of HIV

Abstract The synthesis of 3′,4′-bishydroxymethyl-2′,3′,4′-trideoxy pentopyranosyl derivatives of thymine, uracil, cytosine, and adenine is described. trans-(3S,4S)-Bis(methoxycarbonyl)cyclopentanone (3) was converted to 1-O-acetyl-3,4-C-bis[(tert-butyldiphenylsiloxy)methyl]-2,3,4-trideoxy-α,β-L-threo-pentopyranose (6), which was subsequently condensed with the silylated purine and pyrimidine bases.

Syntheses of O-(2-Acetamido-2-Deoxy-α-D-Galactopyranosyl)-Myo-Inositols

ABSTRACT The structure of an O-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-myo-inositol isolated from human pregnancy urine has previously been identified as that of 1-O-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-myo-inositol. In order to ascertain the absolute configuration in the inositol part of the compound, the 1D- and 1L- isomers were synthesised. Since none of these two stereoisomers corresponded to the natural product, the corresponding 2-O-, the mixture of the two 1DL-4-O-, and 5-O- isomers were also synthesised. None of these gave 1H NMR spectra corresponding to the natural product, the structure of which therefore remains unresolved.

Prediction of designer drugs: Synthesis and spectroscopic analysis of synthetic cathinone analogs that may appear on the Swedish drug market

The use of hyphenated analytical techniques in forensic drug screening enables simultaneous identification of a wide range of different compounds. However, the appearance of drug seizures containing new substances, mainly new psychoactive substances (NPS), is steadily increasing. These new and other already known substances often possess structural similarities and consequently they exhibit spectral data with slight differences. This situation has made the criteria that ensure indubitable identification of compounds increasingly important. In this work, 6 new synthetic cathinones that have not yet appeared in any Swedish drug seizures were synthesized. Their chemical structures were similar to those of already known cathinone analogs of which 42 were also included in the study. Hence, a total of 48 synthetic cathinones making up sets of homologous and regioisomeric compounds were used to challenge the capabilities of various analytical techniques commonly applied in forensic drug screening, ie, gas chromatography-mass spectrometry (GC-MS), gas chromatography-Fourier transform infrared spectroscopy (GC-FTIR), nuclear magnetic resonance (NMR), and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Special attention was paid to the capabilities of GC-MS and GC-FTIR to distinguish between the synthetic cathinones and the results showed that neither GC-MS nor GC-FTIR alone can successfully differentiate between all synthetic cathinones. However, the 2 techniques proved to be complementary and their combined use is therefore beneficial. For example, the structural homologs were better differentiated by GC-MS, while GC-FTIR performed better for the regioisomers. Further, new spectroscopic data of the synthesized cathinone analogs is hereby presented for the forensic community. The synthetic work also showed that cathinone reference compounds can be produced in few reaction steps.