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Methylstilbene-alt-maleic acid copolymers spontaneously convert biological membranes into bilayer discs with similar to 20 nm diameters. This readily functionalizable class of copolymers has the compositional homogeneity, hydrophobicity, dynamics, and charge that may help to achieve optimal structural resolution, membrane dissolution, stability, and broad utility. NSERCNatural Sciences and Engineering Research Council of Canada [RGPIN-2018-04994]; Campus Alberta Innovation Program [RCP-12-002C]; Alberta Prion Research Institute/Alberta Innovates Bio Solutions [201600018]; National Science FoundationNational Science Foundation (NSF) [DMR-1609379]; CFICanada Foundation for Innovation; Genome CanadaGenome Canada; TMIC This work was supported by NSERC RGPIN-2018-04994, Campus Alberta Innovation Program (RCP-12-002C), Alberta Prion Research Institute/Alberta Innovates Bio Solutions (201600018) (M.O.) and National Science Foundation DMR-1609379 (S.R.T.) grants. NANUC was supported by TMIC, CFI and Genome Canada. We thank Russell Bishop for discussions and the PagP expression construct.

The hydrolytic decomposition of four peptides containing S-aroylthiooximes (SATOs) with variable N-arylidene substituents was investigated in 10 aqueous buffer solutions at pH values ranging from 6.0 to 10.9. UV-Vis spectroscopy was employed to study the reaction kinetics, which revealed V-shaped pH-rate profiles for all peptides with a minimum near pH 8, suggesting a change from an acid-catalyzed to a base-activated reaction. Hammett plots showed positive ρ values above pH 8 and negative ρ values below pH 8, providing further evidence for a mechanism change. Based on these data, along with mass spectrometry evidence, we propose a specific acid catalysis under mildly acidic and neutral conditions and multiple base-promoted decomposition reactions under mildly basic conditions.

Multiple approaches are being utilized to develop therapeutics to treat HIV infection. One approach is designed to inhibit entry of HIV into host cells, with a target being the viral envelope glycoprotein, gp120. Polyanionic compounds have been shown to be effective in inhibiting HIV entry, with a mechanism involving electrostatic interactions with the V3 loop of gp120 being proposed. In this study, we applied computational methods to elucidate molecular interactions between the repeat unit of the precisely alternating polyanion, Poly(4,4′-stilbenedicarboxylate-alt–maleic acid) (DCSti-alt-MA) and the V3 loop of gp120 from strains of HIV against which these polyanions were previously tested (IIIb, BaL, 92UG037, JR-CSF) as well as two strains for which gp120 crystal structures are available (YU2, 2B4C). Homology modeling was used to create models of the gp120 proteins. Using monomers of the gp120 protein, we applied extensive molecular dynamics simulations to obtain dominant morphologies that represent a variety of open-closed states of the V3 loop to examine the interaction of 112 ligands of the repeating units of DCSti-alt-MA docked to the V3 loop and surrounding residues. Using the distance between the V1/V2 and V3 loops of gp120 as a metric, we revealed through MD simulations that gp120 from the lab-adapted strains (BaL and IIIb), which are more susceptible to inhibition by DCSti-alt-MA, clearly transitioned to the closed state in one replicate of each simulation set, whereas none of the replicates from the Tier II strains (92UG037 and JR-CSF) did so. Docking repeat unit microspecies to the gp120 protein before and after MD simulation enabled identification of residues that were key for binding. Notably, only a few residues were found to be important for docking both before and after MD simulation as a result of the conformational heterogeneity provided by the simulations. Consideration of the residues that were consistently involved in interactions with the ligand revealed the importance of both hydrophilic and hydrophobic moieties of the ligand for effective binding. The results also suggest that polymers of DCSti-alt-MA with repeating units of different configurations may have advantages for therapeutic efficacy.

Tetraalkylammonium hydroxides have been found to mediate regioselective deacylation of cellulose esters. This deacylation surprisingly shows substantial selectivity for the removal of the acyl groups at O-2/3, affording cellulose-6-O-esters by a simple, efficient one-step process. The mechanism for this deacylation was investigated by studying the effect of tetraalkylammonium cation size upon ester deacylation selectivity. We hypothesize that coordination of the tetraalkylammonium cation by the ester oxygen atoms of the vicinal 2,3-acetate groups may drive the unexpected regioselectivity at the secondary alcohol esters. Broad scope with respect to ester type was demonstrated; regioselective O-2,3 deacylation was observed with cellulose acetate, propionate, butyrate, hexanoate and benzoate triesters. The scope of this deacylation of cellulose acetates has been investigated to understand how to carry it out most efficiently. Reaction with TBAOH in pyridine was the most effective process, providing the highest selectivity.

In order to expand its utility and understand how to carry it out most efficiently, the scope of the highly regioselective, tetrabutylammonium fluoride (TBAF) catalyzed deacylation of cellulose acetates has been investigated, including the influence of key process parameters: solvent, temperature, and water content. Reactions in DMSO, THF, MEK and acetone afforded similar extents of deacylation and regioselectivity. Reaction with TBAF in DMSO at 50 °C for 18 h was the most efficient process providing regioselective deacylation at O-2/3. All results were consistent with our previous mechanistic proposals. Furthermore, we demonstrate that TBAF-catalyzed deacylation is also effective and regioselective with cellulose acetate, butyrate, and hexanoate triesters, and even with a cellulose ester devoid of alpha protons, cellulose tribenzoate. These reactions displayed regioselectivity for deacylation at O-2/3 similar to that observed earlier with cellulose acetate (DS 2.4).

The mechanism of the recently discovered, unusual tetrabutylammonium fluoride (TBAF) deacylation of cellulose esters has been investigated by methods including kinetic isotope effect (KIE) studies. The secondary KIE (kH/kD=1.26±0.04) measured for deacylation at C-2/3 suggests a mechanism involving a ketene intermediate for those positions. An inverse KIE (kH/kD=0.87±0.03) for the deacylation at C-6 indicates the involvement of a tetrahedral intermediate in the mechanism. Additional studies suggest the possibility that TBAF chelation by neighboring acyl groups may account for the unexpected regioselectivity at the secondary alcohol esters that is observed in the TBAF deacylation of cellulose esters.

Molecular dynamics (MD) simulations were used to gain insight on the molecular interactions in a model biological membrane comprised of a bilayer with DPPC (dipalmitoylphosphotidylcholine) and antimicrobial dendritic amphiphile molecules [RCONHC(CH(2)CH(2)COOH)(3), where R is the saturated hydrocarbon tail (R = n-C(n)H(2n+1)), to be abbreviated as 3CAmn]. This study analyzes different biophysical properties of the equilibrated mixed bilayers, at 300 and 325 K, to determine how the presence of the 3CAmn, in varying concentrations and tail lengths, affects the lipid bilayer. Lipid tail order parameter data, bilayer thickness trends, and qualitative lipid tail tilt observations suggest that a molar ratio of 0.2 3CAm19/DPPC is sufficient to induce a phase transition in the bilayer from gel to liquid crystalline at 300 K. These results also imply that the phase transition temperature of the mixed bilayer decreases upon incorporation of higher concentrations of 3CAm19. Hydrogen bonding takes place between the 3CAmn and DPPC at specific sites, as evidenced by the radial distribution function. Increased hydrogen bonding and the smaller headgroup size of the 3CAmn molecule result in a decrease in the total lateral area with higher concentrations of 3CAm19. Diffusion constants of 3CAmn varied with concentration and tail length; diffusion constants of DPPC and 3CAm19 increased with increasing 3CAm19 concentration at 300 K and shorter 3CAmn tails had higher diffusion constants at both temperatures. These computational studies provide a comprehensive understanding of the biophysical changes to model biological membranes by the association of 3CAmn.

Lanthionine synthetase C-like 2 (LANCL2), a novel therapeutic target for inflammatory and autoimmune diseases and diabetes, exerts anti-inflammatory and insulin-sensitizing effects. This study reports the first LANCL2-based therapeutics for inflammatory bowel disease (IBD). Analogues of 1 (ABA) and 2 (NSC61610) were screened by molecular docking, then synthesized and analyzed for binding to LANCL2 by surface plasmon resonance. Piperazine-1,4-diylbis(6-benzo[d]imidazole-2-yl)pyridine-2-yl)methanone, 7, was identified as the lead LANCL2-binding compound for treating IBD. The oral treatment with 7 (8 mg/kg/d) in a mouse model of IBD resulted in lowering the disease activity index, decreasing colonic inflammatory lesions by 4-fold, and suppressing inflammatory markers (e.g., TNF-α, and interferon-γ) in the gut. Furthermore, studies in LANCL2-/- mice demonstrated that loss of LANCL2 abrogated beneficial actions of 7, suggesting high selectivity for the target. In conclusion, 7 merits continued development as a LANCL2-based, first-in-class orally active therapeutic for IBD.

Lanthionine synthetase cyclase-like receptor 2 (LANCL2) is a novel therapeutic target for Crohn’s disease (CD). BT-11 is a small molecule that binds LANCL2, is orally active, and has demonstrated therapeutic efficacy in 3 validated mouse models of colitis at doses as low as 8 mg/kg/d. Exploratory experiments evaluated BT-11 in male Harlan Sprague Dawley rats with a single oral dose of 500 mg/kg and 80 mg/kg/d for 14 days (n = 10 rats dosed/group). Treated and control rats were observed for behavioral detriments, and blood and tissues were collected for clinical pathology and histopathological examination. A functional observational battery demonstrated no differences between treated and control groups over multiple times of observation for quantal, categorical, and continuous end points, including posture, in cage activity, approach, response to touch, weight, grip strength, body temperature, and time on a rotarod. Histopathological examination of the brain, kidney, liver, adrenal gland, testes, stomach, small and large intestines, duodenum, pancreas, heart, lungs, spleen, thymus, and rib found no significant differences between the groups. Plasma enzymes associated with liver function were transiently elevated 2 to 4 days after the 500 mg/kg single dose but returned to normal values by 8 days and were not observed at any time in rats given 80 mg/kg/d for 14 days. One hour after oral administration of a single dose of 80 mg/kg, BT-11 had a maximal concentration of 21 ng/mL; the half-life was 3 hours. These experimental results demonstrated that BT-11 is well tolerated in rats, and, with further testing, may hold promise as an orally active therapeutic for CD.

summary The anti-mycobacterial activities of nine series of dicarboxyl and tricarboxyl dendritic amphiphiles with one alkyl, two alkyl, and cholestanyl tails against Mycobacterium abscessus, Mycobacterium avium, Mycobacterium chelonae, Mycobacterium marinum and Mycobacterium smegmatis have been measured. The dendritic amphiphiles overcame the limited aqueous solubility of natural long-chain fatty acids, alcohols, and amines to enable profiling the susceptibilities of the different mycobacterial species to the physicochemical properties of these amphiphiles. Several dendritic amphiphiles showed strong antimycobacterial activity with high critical micelle concentrations and low hemolytic activities thereby offering platforms for the development of antibiotics of higher activity against nontuberculous mycobacteria.

The gas–surface reaction dynamics of ozone with a model unsaturated organic surface have been explored through a series of molecular beam scattering experiments. Well-characterized organic surfaces were reproducibly created by adsorption of C═C-terminated long-chain alkanethiols onto gold, while the incident molecular beams were created by supersonic expansion of ozone seeded in an inert carrier gas to afford control over collision energy. Time-of-flight distributions for the scattered molecules showed near complete thermal accommodation of ozone for incident energies as high as 70 kJ/mol. Reflection–absorption infrared spectroscopy, performed in situ with ozone exposure, revealed that oxidation of the double bond depends significantly on the translational energy of O3. For energies near room temperature, 5 kJ/mol, the initial reaction probability (γ0) for the formation of the primary ozonide was determined to be γ0 = 1.1 × 10–5. As translational energy increased to 20 kJ/mol, the reaction probability dec...

Homologous dicarboxyl dendritic amphiphiles-RCONHC(CH(3))(CH(2)CH(2)COOH)(2), 4(n); and ROCONHC(CH(3))(CH(2)CH(2)COOH)(2), 5(n), where R=n-C(n)H(2)(n)(+1) and n=13-22 carbon atoms-were synthesized. Critical micelle concentrations (CMCs) in aqueous triethanolamine solutions and at pH 7.4 were measured along with hemolytic activity (effective concentrations, EC(10)) in phosphate-buffered saline (PBS). LogCMC showed a linear dependence on chain length (n); the longest chain in each series had the lowest CMC-in triethanolamine: 4(21), 180μM and 5(22), 74μM and at pH 7.4: 4(21), 78μM and 5(22), 33μM. These two series, 4(n) and 5(n), and three series of homologous tricarboxyl dendritic amphiphiles-RCONHC(CH(2)CH(2)COOH)(3), 1(n); ROCONHC(CH(2)CH(2)COOH)(3), 2(n); RNHCONHC(CH(2)CH(2)COOH)(3), 3(n), where R=n-C(n)H(2)(n)(+1) and n=13-22 carbon atoms-were tested for growth inhibition of Staphylococcus aureus strain ATCC 6358 and methicillin-resistant S. aureus (MRSA) strain ATCC 43330 by microdilution in 0.1-strength brain heart infusion broth (BHIB). Amphiphiles 4(19), 4(21), 5(18), and 5(20) showed the strongest antibacterial activity (2.2-3.4μg/mL) against S. aureus (vancomycin, MIC=0.25μg/mL). These four plus 1(21), 2(20), 2(22), and 3(20) exhibited the strongest antibacterial activity (1.7-6.8μg/mL) against MRSA (vancomycin, MIC=0.25μg/mL). The MICs of these amphiphiles against six clinical MRSA were similar to those against the ATCC strain. In PBS, EC(10)s of the most active homologues ranged from 7 to 18μg/mL and 18 to 220μg/mL for di- and tricarboxyl dendritic amphiphiles, respectively. To assess the potential safety of using dendritic amphiphiles as drugs, measurements of micellar and hemolytic properties were conducted in the same medium (full-strength BHIB) that was used for antibacterial activity. The CMCs (9-36μg/mL, ∼18-72μM) of ten amphiphiles were measured by microdilution (log2 progression) with dye-covered beads. The EC(10)s were similar to those in PBS. The MICs of most amphiphiles (14-72μg/mL) and vancomycin (1.1-2.2μg/mL) against both S. aureus and MRSA increased significantly compared to the MICs measured in 0.1-strength BHIB. The one exception, 5(18), had an MIC against S. aureus of 1.1μg/mL compared to vancomycin (2.2μg/mL). With CMC (9-18μg/mL) and EC(10) (16μg/mL) values higher than the MIC, 5(18) was discovered as a lead for further development.

A series of zinc phosphite hybrid structures with trimethylene dipyridine as the linking ligand and templated on the aromatic alcohols, hydroquinone, 1,2,3-trihydroxybenzene, nitrophenol, and bromophenol are reported. The aromatic alcohols interact with the framework by hydrogen bonding to oxygen atoms that bridge zinc and phosphorus atoms in the inorganic portion of the network. In addition, three hydrogen-bonded networks that contain trimethylene-dipyridine and either hydroquinone or 1,2,3-trihydroxybenzene are reported. In these structures, the aromatic alcohol acts as a hydrogen bond donor to trimethylene-dipyridine. The flexibility of trimethylene-dipyridine is important to the construction of the new frameworks. Calculations using PM5 parameters demonstrate that trimethylene-dipyridine can adopt a wide variety of conformations with a minimal energy expense.

Trans10,cis12-conjugated linoleic acid (t10,c12-CLA) increases liver weights and hepatic lipids in mice. The purpose of this study was to determine the effects of CLA isomers (t10,c12-CLA or c9,t11-CLA) and carnitine palmitoyl transferase-1 (CPT-1) inhibitors (etomoxir or hemipalmitoylcarnitinium) on CPT-1 mRNA, fatty acid profile, and cholesterol synthesis in AML-12 and HepG2 cells. t10,c12-CLA was incorporated to a greater extent in both cell lines than c9,t11-CLA. In addition, t10,c12-CLA increased the free cholesterol content of AML-12 and HepG2 cells four- and fivefold, respectively. Cells incubated with medium containing CPT-1 inhibitors or t10,c12-CLA had higher levels of mRNA for CPT-1 in both cell lines, indicating an increased fatty acid oxidation in hepatic cell lines due to t10,c12-CLA. Following treatment withdrawal, percentages of c9,t11-CLA or t10,c12-CLA remained elevated in cells initially treated with c9,t11-CLA or t10,c12-CLA, suggesting a potential for carryover effects of the CLA isomers. The results presented here demonstrate a potential role for t10,c12-CLA in the modulation of hepatic fatty acid oxidation and cholesterol synthesis.

To examine the effect of negatively charged steroidal amphiphiles on antimicrobial activity, two pairs of epimeric, dendritic tricarboxylato amphiphiles--4-(2-carboxyethyl)-4-[3-(5alpha-cholestan-3-yl)ureido]heptanedioic acid (1) and 4-(2-carboxyethyl)-4-[3-(5alpha-cholestan-3-yloxycarbonylmethyl)ureido]heptanedioic acid (2)--were synthesized. A broad antimicrobial screen of 11 microbes revealed that these amphiphiles only showed good activity against a methicillin-resistant isolate of Staphylococcus aureus (MRSA) and modest activity against an unrelated strain of S. aureus. The best activity, a minimal inhibitory concentration (MIC) of 27 microM, was found for the 3beta epimer of 1 against MRSA.

Objectives: To measure the antimicrobial activities of three series of homologous, dendritic tricarboxylato (three-headed) amphiphiles against a battery of bacteria and fungi. Methods: Three series of homologous dendritic amphiphiles were synthesized containing C 13 to C 22 fatty chains. Susceptibility of Escherichia coli, Klebsiella pneumoniae, Lactobacillus plantarum, Micrococcus luteus, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Mycobacterium smegmatis, Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans and Aspergillus niger to the amphiphiles was measured by broth microdilution and reported as the MIC. Results: Several amphiphiles from each homologous series, designed and constructed to overcome the low solubility of saturated long-chain fatty acids, had antimicrobial activity against MRSA (MIC = 36 mg/L), C. albicans (MIC = 4.4 mg/L), S. cerevisiae (MIC = 1.1 mg/L) and M. smegmatis (MIC = 8.9 mg/L). These amphiphiles had considerably better antimicrobial activities than the corresponding saturated fatty acids. Alkyl chain length influenced the values of MIC; longer chains (C 18 -C 22 ) were generally more antimicrobial, but there was no uniform pattern among the microorganisms tested. Conclusions: As the antimicrobial activity of the amphiphiles increased with increasing chain length, it is anticipated that maximum activity was not reached with these series. Thus, the identification of the optimal chain length would provide a target compound for development of low-cost, topical microbicides and anti-infectives. Further, these series of dendritic amphiphiles with the very long chains can be used as new water-soluble probes for elucidation of membrane structure and for identification of novel targets for antimicrobial design.

This short review describes our computational studies of carnitine, acetylcarnitines, and betaines over the past two decades. Interspersed among the three computational studies – a molecular mechanics study of the conformer population of carnitine and acetylcarnitine, an AM1 study of the energetics of hydrolysis of acetylcarnitine, and an HF 6-31G* study of the solvation energies and structures of a homologous series of betaines – are brief overviews of our research in designing and testing new therapeutic agents for non-insulin dependent diabetes and for protection against sexually transmitted diseases. The three studies also show how computational chemistry has evolved during this time to enable an evaluation of the structure and energetics of zwitterions in aqueous solution.

Most heterosexual women want to reduce the risk of acquiring a sexually transmitted infection; many also want to control their fertility. Several chemical agents have been proposed to dramatically slow the spread of HIV infections. Ideally, vaginal microbicides, with or without contraceptive properties, should be safe, effective, and affordable for women everywhere. Amphiphiles, which are surfactants that can act as detergents, have a long history as microbicides against many pathogens. Amphiphiles have several desirable traits; e.g., they are inexpensive, fast-acting, and capable of a broad spectrum of activity. An "ideal" amphiphilic microbicide will rapidly and selectively inactivate pathogens and sperm without irritating tissue. In this review, we discuss a homologous series of amphiphilic acylcarnitine analogues as microbicides. Two homologues, Z-14 and Z-15, possess excellent spermicidal, anti-HIV, anti-chlamydial, anti-gonorrhea, and anti-Haemophilus activities; both have outstanding anti-Candida activity. A 4% Z-15 gel that is comprised of 3% carboxymethylcellulose in water gives a dramatically low score in a rabbit-vaginal-irritation study. The mechanisms of action of these compounds are not fully understood as yet, but we present several possibilities. Moreover, the results of our limited structure-activity study with a homologous series have stimulated additional questions and ideas for designing the next generation of microbicidal amphiphiles. The above studies support the idea that Z-14 and Z-15 can potentially serve as safe (non-irritating), effective topical microbicides.

The toxicity of chromium salts created environmental and health-related concerns and generated a great deal of interest in developing chrome-free conversion coatings. Most of the new developments are based on organic coatings. In the present work, some silanes were used to coat electrogalvanized (EG) steel sheets for corrosion protection. Contact angle measurement, Tafel studies, electrochemical impedance spectroscopy (EIS) and salt spray tests (SST) were conducted to investigate the efficiency of the organic coatings for the corrosion protection. It was found that pH of a silane solution is important in the adsorption of silanes on the EG steel surface and, therefore, affected its corrosion resistance.

The syntheses of 2-hydroxy- N -(2-hydroxyethyl)- N , N -dimethyl-1-alkanaminium 1 ( p ) and 2-hydroxy- N , N -bis(2-hydroxyethyl)- N -methyl-1-alkanaminium 2 ( p ) bromides are described for the homologous series, tetradecanaminium ( p =14) through octadecaminium ( p =18). The critical micelle concentrations (cmc's), measured by conductivity at 25 and 37°C, of the even-numbered members of the series show the expected linear dependence on chain length. All compounds display spermicidal and virucidal activity. Plots of minimum effective concentration (MEC) versus chain length in the Sander–Cramer spermicidal assay of 1 and 2 show a cut-off effect and a parabolic relationship, respectively. The best compounds— 1 (17) and 1 (18)—have MECs (∼0.12 mg mL −1 ) slightly lower than that of the commercial spermicide nonoxynol-9 (N-9). Compounds 1 (16) and 2 (17) show the best anti-HIV activity in in-vitro, cell-free and cell-associated virus inactivation assays. Both are highly effective at 0.1 mg mL −1 in the cell-free assay and 0.5 mg mL −1 in the cell-associated assay. Compound 1 (16) shows the best combination of dual activity against sperm and HIV. In summary, hydroxylated cationic surfactants, 1 and 2 , show promise as inexpensive topical, contraceptive microbicides.

Di-tert-butyl (E)-4,4'-stilbenedicarboxylate and tert-butyl 4-vinylbenzoate were copolymerized with maleic anhydride and tert-butyl 4-maleimidobenzoate, individually and respectively. After conversion into polyanions, these four copolymers exhibited activity against four HIV-1 strains: IIIb, BaL, JR-CSF, and 92UG037. For both the IIIb and BaL HIV-1 strains, the lowest IC50 (0.095 and 0.23 μg/mL, respectively) values were obtained with poly(4,4'-stilbenedicarboxylate-alt-maleic acid) (DCSti-alt-MA). For JR-CSF and 92UG037, both tier 2 clinical isolates but different clades, DCSti-alt-MA exhibited the lowest IC50 (0.76 and 0.75 μg/mL, respectively). Although DCSti-alt-MA had the lowest IC50 in μg/mL for each strain, the other copolymers had IC50s less than 2-fold higher. Further, these copolymers achieved high selectivity indices (100) for these clinical isolates. Polymer rigidity, as measured by the statistical segment length, emerged as a key property when comparing anti-HIV activities with those of other polyanions. A speculative illustration was proposed for possible modes of inhibition.

Acylamidomorpholinium carnitine analogues, 6-(tetradecanamidomethyl- and -hexadecanamidomethyl)-4,4-dimethylmorpholin-4-ium-2-acetate, 1 , synthesized as complete sets of stereoisomers, were assayed as inhibitors for isozymes of carnitine palmitoyltransferase (CPT). Microsomal CPT isozymes showed modest discrimination among the stereoisomer; while rat-liver mitochondrial CPT-I and CPT-II showed distinct differences. The tetradecanamidomethyl analogue of (2R,6S)- 1 activated CPT-I but inhibited CPT-II.

Acylcarnitine analogues, (+)-6-Carboxylatomethyl-2-alkyl-4,4-dimethylmorpholinium (Z-n, where n = the number of carbons in the alkyl chain), synthesized in multi-gram quantities show in vitro activities as spermicides, anti-HIV agents, and inhibitors of the growth of Candida albicans. Activity improves with increasing chain length. Compound Z-15 is a candidate for further study as a topical, microbicidal spermicide.

Non-racemic terminal long-chain alkyl epoxides are prepared from racemic epoxides and 1 mol% (R,R)- and (S,S)-salen(Co)III catalysts following a modified procedure for kinetic resolution. The ee's for all epoxides (C-10, C-12, C-14, C-16, C-18, C-20) exceed 95% and the chemical yields range from 85% to 95%.

A chiral, five-step synthesis of 2-(hydroxymethyl)-2,4-dimethylmorpholine (12) from (R)- and (S)-2-methylglycidols gives an overall yield of 63%. Morpholines (R)- and (S)-12 are converted into 2-(azidomethyl)-2,4-dimethylmorpholine (15) via 2,4-dimethyl-2-[[(4-nitrophenyl)sulfonoxy]methyl]morpholine (14). The tertiary morpholines 12, 14, and 15 are quaternarized to afford 2-(hydroxymethyl)-2,4,4-trimethylmorpholinum iodide (2), 2,4,4-trimethyl-2-[[(4-nitrophenyl)sulfonoxy]methyl]morpholinium iodide (3), and 2-(azidomethyl)-2,4,4-trimethylmorpholinium iodide (4), respectively, which all inhibit acetylcholinesterase (AChE). These morpholinium inhibitors are compared with conformationally constrained aryl hemicholinium AChE inhibitors. Enantiomers of 2 and 4 are reversible competitive inhibitors of AChE, with values of Ki = 360 +/- 30 microM for (S)-2, 650 +/- 90 microM for (R)-2, 450 +/- 70 microM for (S)-4, and 560 +/- 30 microM for (R)-4, respectively. Enantiomers of 3 are noncompetitive inhibitors of AChE with values of Ki = 19.0 +/- 0.9 microM for (S)-3 and 50 +/- 2 microM for (R)-3, respectively. AChE shows a 2-fold chiral discrimination in the case of inhibition by 2 and 3. Inhibition also changes from competitive to noncompetitive when (3-hydroxyphenyl)-N,N,N-trimethylammonium iodide (18) [Ki = 0.21 +/- 0.06 microM; Lee, B. H., Stelly, T. C., Colucci, W. J., Garcia, J. G., Gandour, R. D., and Quinn, D. M. (1992) Chem. Res. Toxicol. 5, 411-418] is converted into [3-[(4-nitrophenyl)sulfonoxy]phenyl]-N,N,N-trimethylammonium iodide (5), Ki = 6.0 +/- 0.5 microM. These results indicate that the 4-nitrobenzenesulfonyl group controls the mode of inhibition.

The asymmetric unit of the title compound, C 13 H 11 IO 3 , contains two independent molecules. The naphthalene ring systems of the molecules have average deviations from planarity of 0.029(13) and 0.017(9) A with maximum deviations of 0.042(11) and 0.034(9) A, respectively. The methyl parts of the methoxy groups are anti to the neighboring α-C atoms and are nearly coplanar with the rings, with C-C-O-C torsion angles of -8.1(15) and -3.7 (10)° in the two molecules. The dihedral angles between the naphthalene ring system and the acetate group in each molecule are 109.9(2) and 114.6 (2)°.

Stereoisomeric cyclic analogues of hexadecylphosphocholine (Miltefosine) and phosphatidylcholine, (2S,4S)-, (2R,4S)-, (2R,4R)-, and (2S,4R)-2,6,6-trimethyl-2-oxo-4-pentadecyl-1,3-dioxa-6-aza-2-phos...

Structural analyses of 2-[(2,6-dimethoxyphenyl)ethynyl]-3-methoxybenzoic acid, (1), and the two products of lactonization, 3-(2,6-dimethoxyphenyl)-5-methoxy-1H-2-benzopyran-1-one, (2), and (Z)-3-[(2,6-dimethoxyphenyl)methylene]-4-methoxy-1(3H)-isobenzofuranone, (3), three isomers of C 18 H 16 O 5 , suggest an explanation for the favored pathway for lactonization. The two rings in (1) form a dihedral angle of 84.30 (4)°. The carboxy group is nearly coplanar with the benzoate ring with an O=C-C-C torsion angle of −3.7 (2)°. The triple-bond length is 1.191 (2) A and the bond angles at the ethynyl C atoms are 176.4 (1) and 171.0 (1)°, both significantly distorted from 180°. The benzopyran ring and the dimethoxyphenyl ring in (2) form a dihedral angle of 58.90 (5)°. The pyrano C=C double-bond length is 1.324 (2) A. Distortions appear in the two exocyclic angles [112.1 (1) and 127.3 (2)°] about the aryl substituted pyrano C atom. The isobenzofuran ring and the dimethoxyphenyl ring in (3) form a dihedral angle of 120.83 (5)°. The exocyclic C=C double-bond length is 1.323 (2) A. Distortions appear in the benzenoid angles at the C atoms adjacent to the ring fusion [117.5 (1) and 116.7 (1)°] and in two of the three angles [121.2 (1), 131.0() (9) and 107.7 (1)°] about the furano C atom of the exocyclic C=C double bond

In the title compounds 2-hydroxy-2-(4-methoxyphenyl)-4,4,6-trimethylmorpholinium bromide, C 14 H 22 NO 3 + .Br - , (1), and 2-hydroxy-4,4,6-trimethyl-2-phenylmorpholinium bromide hydrate, C 13 H 20 NO 2 + .Br - .xH 2 O, (2), the morpholinium rings adopt a chair conformation with the magnitudes of the endocyclic torsion angles in (1) and (2) in the ranges 50.5 (7)-60.1 (7) and 49.4 (4)-58.3 (4)°, respectively. The hydroxyl group is in the axial position of the morpholinium ring in both structures with C-OH bond distances of 1.410 (9) and 1.409 (4) A

(2S,4S)/(2R,4R) and (2S,4R)/(2R,4S) 6,6-N,N-dimethyl-2-methyl-2-oxo-1,3-dioxa-4-hexadecyl-6-aza-2-phosphacyclooctane bromide strongly inhibited protein kinase C and moderately inhibited carnitine octanoyltransferase and carnitine palmitoyltransferase.

The solid-state structures of alkali-metal salt complexes of crown ether tetra- and hexa-carboxylic acids (18C6A4 and 18C6A6) have been determined. The sodium salt of 18C6A6 crystallizes as the trihydrate in orthorhombic space group P212121 (a = 7.6868(12), b = 15.429(3), c = 21.975(2) Å, R = 0.031 for 5192 observed data); the potassium salt of 18C6A6 crystallizes as the the trihydrate in orthorhombic space group P212121 (a = 7.6711(8), b = 15.709(2), c = 21.966(5) Å, R = 0.035 for 2521 observed data); the thallium(I) salt of 18C6A6 crystallizes as the dihydrate in orthorhombic space group P212121 (a = 12.0331(10), b = 12.4333(12), c = 17.366(2) Å, R = 0.035 for 4952 observed data); and the cesium salt of 18C6A6 crystallizes as the dihydrate in monoclinic space group P21 (a = 7.708(3), b = 13.492(2), c = 11.9501(9) Å, β = 94.49(2)°, R = 0.029 for 4480 observed data). The sodium salt of 18C6A4 crystallizes as the dihydrate in monoclinic space group P21 (a = 11.4368(11), b = 7.7068(11), c = 12.6579(12) Å, β = 98.515(8)°, R = 0.035 for 3000 observed data); the thallium(I) salt of 18C6A4 crystallizes as the dihydrate in monoclinic space group P21(a = 11.719(2), b = 7.668(2), c = 12.8403(13) Å, β = 99.052(9)°, R = 0.040 for 3981 observed data); and the cesium salt of 18C6A4 crystallizes as the dihydrate in monoclinic space group P21 (a = 11.787(2), b = 7.637(2), c = 13.001(2) Å, β = 98.705(12)°, R = 0.038 for 3428 observed data). Both chorands exhibit a cooperative relationship of mean cavity radius and guest-ion radius, which closely follows the effective ionic radii of the guests. The hexaacid is a preorganized host for monohydrated cations. It provides a trigonal hydrogen bonding receptor site for the water molecule, and up to nine oxygen donors for cation binding. Guests ranging in size from Na+ to Cs+ are accommodated without distortion of the macrocyclic framework. The tetraacid is similarly tolerant of a range of guests, but greater structural reorganization of the ligand is required to optimize contacts with fully dehydrated cations. Skeletal drawings of donor atoms, in conjunction with polar coordinate maps of torsion angles, reveal how the demands of the guest are accommodated by the host.

The reaction of the methyl ester of (R)-norcarnitine with 1-bromo-2-heptadecanone produces (+)-6-[(methoxycarbonyl)methyl]-2-pentadecyl-4,4-dimethylmorpholinium bromide, 3, which hydrolyzes to (+)-6-(carboxylatomethyl)-2-pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, HPC) upon treatment with aqueous sodium hydroxide. Single-crystal X-ray analyses have confirmed the structures of (+)-HPC and 3. (+)-HPC inhibits carnitine palmitoyltransferase (CPT-I) activity for the forward reaction (palmitoyl-CoA + carnitine-->) in intact mitochondria from rat heart and rat liver. (+)-HPC competitively (versus carnitine) inhibits CPT-I activity in both rat heart and liver mitochondria with Ki = 2.8 +/- 0.5 and 4.2 +/- 0.7 microM, respectively. As one of the strongest specific inhibitors of CPT-I, HPC is a potential therapeutic agent in myocardial ischemia and Type II diabetes.

Non-racemic terminal long-chain alkyl epoxides are prepared from racemic epoxides and 1 mol% (R,R)- and (S,S)-salen(Co)III catalysts following a modified procedure for kinetic resolution. The ee's for all epoxides (C-10, C-12, C-14, C-16, C-18, C-20) exceed 95% and the chemical yields range from 85% to 95%.

Acylamidomorpholinium carnitine analogues, 6-(tetradecanamidomethyl- and -hexadecanamidomethyl)-4,4-dimethylmorpholin-4-ium-2-acetate, 1 , synthesized as complete sets of stereoisomers, were assayed as inhibitors for isozymes of carnitine palmitoyltransferase (CPT). Microsomal CPT isozymes showed modest discrimination among the stereoisomer; while rat-liver mitochondrial CPT-I and CPT-II showed distinct differences. The tetradecanamidomethyl analogue of (2R,6S)- 1 activated CPT-I but inhibited CPT-II.

Three new tetrasubstituted diaryl alkynes have been prepared via palladium-catalyzed coupling of aromatic alkynes with aryl iodides. These molecules show strong absorption and fluorescence. Single crystal X-ray analysis reveals that the rings are on parallel planes.

The syntheses of (2S,6R)-6-(carboxymethyl)-2-hydroxy-2,4,4-trimethylmorpholinium chloride (hemiacetylcarnitinium, HAC), (2S,6R)-6-(carboxymethyl)-2-ethyl-2-hydroxy-4,4-dimethylmorpholinium bromide (hemipropanoylcamitinium, HPrC), and (2S,6R)-6-(carboxymethyl)-2-hydroxy-4,4-dimethyl-2-phenylmorpholinium chloride monohydrate (hemibenzoylcarnitinium, HBC) are described. The crystal structure of HAC is reported and compared with crystal structures of HPrC, HBC, carnitine.HCl, acetylcarnitine.HCl, and acetylcarnitine .HCl.H 2 O

2-Substituted-2-hydroxy-4,4-dimethylmorpholiniums (hemicholiniums) inhibit acetylcholinesterase (EC 3.1.1.7)-catalyzed hydrolysis of acetylthiocholine (ATCh). The 4-substituted arenes [NH2, NHC(O)CH3, Cl, CN, and NO2] have values of inhibition constants (Ki) that range from 220 to 3690 microM, which correlate with Hammett sigma, rho approximately 0.8. The alkyl compounds, hydrogen, methyl, tert-butyl, and trifluoromethyl, have values of Ki of 550, 560, 1200, and 1200 microM, respectively. These values compare favorably with Ki = 960 microM for choline. The conformation of AChE-bound choline must be gauche to support our suggestion that hemicholiniums are conformationally constrained analogues of choline. (3-Hydroxyphenyl)trimethylammonium (5) inhibits most strongly, Ki = 0.21 microM, of the compounds examined in this study. The solvent isotope effect (H2OKi/D2OKi = 0.83 +/- 0.04) suggests that inhibition by 5 involves hydrogen bonding. The binding by AChE of the hemicholiniums of various sizes and the strong binding of 5 support an earlier proposal [Schowen, K. B., Smissman, E. E., and Stephen, W. F., Jr. (1975) J. Med. Chem. 18, 292-300] that the active site of AChE has ample space for rotation about the C-C bond in choline. Compound 5, which has one more carbon between the hydroxy and trimethylammonium than does choline, inhibits much more potently than either choline or the hemicholiniums. Compound 5 provides a correct spacer to span the trimethylammonium recognition site and the esteratic site of AChE. This aromatic spacer interacts favorably with the hydrophobic active site, and the phenolic hydroxyl probably hydrogen bonds to the histidine in the esteratic site. Choline in any conformation and the hemicholiniums are too short to make a strong hydrogen bond.