Comparative toxicity of (+)-(R)- and (−)-(S)-1,2-dibromo-3-chloropropane

The haloalkane 1,2-dibromo-3-chloropropane (DBCP), an environmental pollutant that was widely used as a soil fumigant, is a carcinogen and a mutagen and displays target-organ toxicity to the testes and the kidneys. Because little is known about effects of stereochemistry on the metabolism and toxicity of halogenated alkyl compounds and because DBCP, which has a chiral center at C-2, may show enantioselectivity in its metabolism and/or toxicities, the optically pure enantiomers of DBCP were tested in vivo in rats for organ toxicity as well as for bacterial mutagenicity. Organ toxicity studies showed that (S)-DBCP was slightly more renal toxic than (R)-DBCP but was not significantly more toxic than the racemate, and that no significant differences were observed in the extents of testicular necrosis and atrophy caused by either enantiomer or the racemate. In contrast, (R)-DBCP was more mutagenic than either (S)-DBCP or the racemate to Salmonella typhimurium (S. typhimurium) strains TA 100 and TA104. However, there was little or no enantioselectivity in glutathione S-transferase (GST)-catalyzed conjugation reactions of glutathione with DBCP based on the lack of selectivity in the rates of disappearance of the enantiomers of DBCP in the presence of glutathione (GSH) and GSTs as monitored by chiral gas chromatography (GC). © 1995 Wiley-Liss, Inc.     

Synthesis of methyl O-(3-deoxy-3-fluoro-β- -galactopyranosyl)-(1→6)-O-β- -galactopyranosyl-(1→6)-3-deoxy-3-fluoro -β- -galactopyranoside and related n.m.r. studies

Sequential tritylation, benzoylation, and detritylation of methyl 3-deoxy-3-fluoro-β- -galactopyranoside gave crystalline methyl 2,4-di-O-benzoyl-3-deoxy-3-fluoro-β- -galactopyranoside (9), which was used as the initial nucleophile in the synthesis of the target oligosaccharide (16). Treatment of 9 with 2,3,4-tri-O-benzoyl-6-O-bromoacetyl-α- -galactopyranosyl bromide gave the corresponding disaccharide derivative 13, having a selectively removable blocking group at O-6′. Debromoacetylation of 13 afforded the disaccharide nucleophile 14 which, when treated with 2,4,6-tri-O-benzoyl-3-deoxy-3-fluoro-α- -galactopyranosyl bromide, gave the fully protected trisaccharide 15. Debenzoylation of 15 gave the title glycoside 16. Condensation reactions were performed with silver trifluoromethane-sulfonate as a promoter in the presence of sym-collidine under base-deficient conditions, and gave excellent yields of the desired β-(trans)-products. Analyses of the ¹H- and ¹³C-n.m.r. spectra, as well as determination of the J_CF and J_HF coupling constants, were made by using various one- and two-dimensional n.m.r. techniques.     

Synthesis of α-(S)- acylamino-n-(hydroxydioxocyclobutenyl)- γ-lactams

Monocyclic γ - lactams 2, activated by a hydroxycyclobutenedione moiety have been prepared from (L)-N^tBoc-glutamine, as potential antibacterial agents.     

Synthesis and biological activities of octyl 2,3-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2-O-sulfo-alpha-L-fucopyranosyl-(1-->4)-2,3-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2-O-sulfo-alpha-L-fucopyranosyl-(1-->4)-2,3-di-O-sulfo-beta-L-fucopyranoside

Octyl 2,3-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2-O-sulfo-alpha-L-fucopyranosyl-(1-->4)-2,3-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2-O-sulfo-alpha-L-fucopyranosyl-(1-->4)-2,3-di-O-sulfo-beta-L-fucopyranoside, a fucosyl pentasaccharide with a regular structure resembling the repeating unit of a natural sulfated fucan, was chemically synthesized using a convergent '2+3' strategy. Regioselective 3-O-silylation of beta-thiofucopyranoside and AgOTf-catalyzed glycosylation of the protected glycosyl trichloroacetimidate facilitated a one-pot trisaccharide synthesis. The synthesized target compound showed good antitumor activity in vivo, and promising anticoagulant activity in vitro.     

The role of tumor necrosis factor-alpha (TNF-alpha) in skeletal muscle regeneration. Studies in TNF-alpha(-/-) and TNF-alpha(-/-)/LT-alpha(-/-) mice.

The role of tumor necrosis factor-alpha (TNF-alpha), an important mediator of the inflammatory response after injury, was investigated in regenerating skeletal muscle. The pattern of expression of TNF-alpha during muscle regeneration was examined by immunohistochemistry in tissue sections of crush-injured or transplanted muscle autografts and in primary cultures of adult skeletal muscle. TNF-alpha was highly expressed in injured myofibers, inflammatory cells, endothelial cells, fibroblasts, and mast cells. Myoblasts and myotubes also expressed TNF-alpha in primary muscle cultures and tissue sections. The essential role of TNF-alpha and its homologue lymphotoxin-alpha (LT-alpha) during muscle regeneration was assessed by basic histology in TNF-alpha(-/-) and TNF-alpha(-/-)/LT-alpha(-/-) mice. No difference was apparent in the onset or pattern of muscle regeneration (i.e., inflammatory response, activation and fusion of myoblasts) between the two strains of null mice or between nulls and normal control mice. However, both strains of null mice appeared more prone to bystander damage of host muscle and regeneration distant from the site of injury/transplantation. Although expression of TNF-alpha may play an important role in muscle regeneration, the studies in the null mice show that redundancy within the cytokine system (or some other response) can effectively compensate for the absence of TNF-alpha in vivo.     

Toxic doses of rac-, (−)-(S)- and (+)-(R)-propranolol in rats and rabbits

The contribution of the individual enantiomers ([+]-[R]- and [−]-[S]-propranolol) to rac-propranolol intoxication was studied in anaesthetized, spontaneously breathing (SB) rats and artificially ventilated (AV) rats and rabbits. In the SB rat, propranolol (30 mg.kg⁻¹.h⁻¹ i.v.) decreased heart rate and mean arterial blood pressure and caused hypoventilation, serious hypoxaemia, respiratory acidosis, and death by respiratory arrest. Survival time (ST) in the (+)-(R)-propranolol group (ST 91 ± 5 min) was significantly longer than in the rac-propranolol group (ST 68 ± 6 min). In AV rats and rabbits toxic doses of rac-, (−)-(S)- and (+)-(R)-propranolol, 30 mg.kg⁻¹.h⁻¹ and 15 mg.kg⁻¹.h⁻¹ i.v., respectively, induced comparable effects on haemodynamic variables as in the SB rat. Artificial ventilation lengthened ST by a factor of three to four in rats. In the AV rat, ST's were not significantly different between the rac-, (−)-(S)- and (+)-(R)-propranolol groups. In the rabbit, as in the SB rat, ST in the (+)-(R)-propranolol group was significantly longer than ST's in the rac- and (−)-(S)-propranolol groups. The acute respiratory acidosis in SB rats and the prolonged ST in AV rats suggest that respiratory failure is the primary and cardiovascular failure the secondary cause of death in propranolol intoxication. The potentiation of the toxic effect of the enantiomers observed after dosing the racemate instead of the pure enantiomers could not be explained by a stereoselective difference in plasma propanolol concentration. © 1996 Wiley-Liss, Inc.     

NMR structural characterization of cecropin A(1-8) - magainin 2(1-12) and cecropin A (1-8) - melittin (1-12) hybrid peptides.

In order to elucidate the structure-antibiotic activity relationships of the peptides, the three-dimensional structures of two hybrid peptides, CA(1-8) - MA(1-12) and CA(1-8) - ME(1-12) in trifluoroethanol-containing aqueous solution were investigated by NMR spectroscopy. Both CA(1-8) - MA(1-12) and CA(1-8) - ME(1-12) have strong antibacterial activity but only CA(1-8) - ME(1-12) has hemolytic activity against human erythrocytes. CA(1-8) - MA(1-12) has a hydrophobic 310-helix of only two turns combined with one short helix in the N-terminus with a flexible hinge section in between. CA(1-8) - MA(1-12) has a severely bent structure in the middle of the peptide. These structural features as well as the low hydrophobicity of CA(1-8) - MA(1-12) seem to be crucial for the selective lysis against the membrane of prokaryotic cells. CA(1-8) - ME(1-12) has an alpha-helical structure of about three turns in the melittin domain and a flexible structure with one turn in the cecropin domain connected with a flexible hinge section in between, and these might be the structural features required for membrane disruption against prokaryotic and eukaryotic cells. The central hinge region (Gly9-Ile10-Gly11) in an amphipathic antibacterial peptide is considered to play an important role in providing the conformational flexibility required for ion channel formation of the C-terminal hydrophobic alpha-helix on cell membrane.     

Preparation of alkyl (R)-(-)-3-hydroxybutyrate by acidic alcoholysis of poly-(R)-(-)-3-hydroxybutyrate

An efficient method for the preparation of optically active alkyl (R)-(-)-3-hydroxybutyrates by chemical depolymerization of biopolymer, poly-(R)-(-)-(3-hydroxybutyrate), was established. This method consists of simple recovery of poly-(R)-(-)-(3-hydroxybutyrate) from bacterial cells followed by acidic alcoholysis. When poly-(R)-(-)-(3-hydroxybutyrate) was purified by a simple digestion method that used 0.2 N sodium hydroxide, alkyl (R)-(-)-hydroxybutyrates were most efficiently produced by alcoholysis with anhydrous hydrochloric acid.     

Synthesis and biological activities of octyl 2,3,4-tri-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-beta-L-fucopyranoside

An efficient method for the regioselective 3-O-silylation of beta-thiofucopyranoside was disclosed. Based on this discovery, we described a high-yielding strategy for the synthesis of the natural core structure of L-fucan and its fully sulfated derivative. The bioassay suggested that octyl 2,3,4-tri-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-alpha-L-fucopyranosyl-(1-->3)-2,4-di-O-sulfo-beta-L-fucopyranoside presented better antitumor activities than that of the free tetramer based on Sarcoma 180 cells and Lewis lung carcinoma model studies.     

O-methylation of (+)-(R)- and (−)-(S)-6,7-dihydroxy-1-methyl-1,2,3,4-tetra-hydroisoquinoline (salsolinol) in the presence of pig brain catechol-o-methyltransferase

(+)-(R)- and (−)-(S)-salsolinol, dopamine-derived tetrahydroisoquinolines, were tested as substrates of pig brain soluble and membrane-bound catechol-O-methyltransferase (COMT) and as inhibitors of O-methylation of dopamine by soluble COMT in vitro. Methylation products were separated by high-performance liquid chromatography with electrochemical detection. Quantification of the products showed that O-methylation of (+)-(R)-salsolinol by soluble COMT afforded the 7-O-methylated product salsoline preferentially, whereas (−)-(S)-salsolinol yielded almost equivalent amounts of the 6- and 7-methyl ethers. Unlike O-methylation by soluble COMT, 7-O/6-O-methylation ratio produced by membrane-bound COMT varied with (+)-(R)-salsolinol concentration. As to the O-methylation of dopamine by soluble COMT, comparable competitive inhibition was observed with both (+)-(R)- and (−)-(S)-salsolinol. Chirality 9:367–372, 1997. © 1997 Wiley-Liss, Inc.     

Riccardo (Rico) Wittek (1944-2008)

Riccardo (Rico) Wittek died 26 September 2008 in Switzerland. Rico was well known for his work on the molecular biology of poxviruses and for his work with the World Health Organization on biosafety that led to international guidelines for work with dangerous infectious agents. His colleagues Erwin G. Van Meir, Daniel Lavanchy, and Bernard Moss have written Rico''s memorial.Lynn W. EnquistEditor in Chief, Journal of Virology