Sandhya M. Vyas

Differences in the isomer composition of perfluoroctanesulfonyl (PFOS) derivatives

Perfluorooctanesulfonyl (PFOS)-based materials and related compounds are an emerging group of environmental pollutants. Perfluorooctanesulfonyl fluoride, the key intermediate for the production of these materials, was manufactured by an electrochemical fluorination process that resulted in complex mixtures containing linear and branched PFOS derivatives and other perfluorinated compounds. This study uses 19F-NMR spectroscopy to investigate differences in the composition between commercial samples of PFOS and PFBS (perfluorobutanesulfonyl) derivatives. While PFBS derivatives, which are under evaluation as substitutes for PFOS-based materials, contained no detectable levels of branched impurities, all PFOS derivatives contained significant levels of branched and other impurities. Analysis of the NMR data reveals that PFOS fluorides typically have a higher content of internally branched and similar levels of isopropyl branched PFOS isomers compared to PFOS potassium salts. Furthermore, the isomer distribution of PFOS derivatives may vary depending on their source. These findings suggest that it is important to determine the isomer composition of PFOS samples used in both environmental and toxicological studies.

Synthesis and biocompatibility evaluation of partially fluorinated pyridinium bromides

Although cationic surfactants are of general interest for a variety of consumer and biomedical applications, only a limited number of partially fluorinated, single-tailed, cationic surfactants have been synthesized. To study the potential usefulness of fluorinated cationic surfactants for these applications we synthesized a series of partially fluorinated pyridinium bromide surfactants. Three 10-perfluoroalkyldecyl pyridinium surfactants were synthesized by coupling a perfluoroalkyl iodide with 9-decene-1-yl acetate using an AIBN mediated radical reaction. The resulting 9-iodo-10-perfluoroalkyldec-1-yl acetates were deiodinated using HI–Zn–EtOH and hydrolyzed using KOH–EtOH to yield the corresponding 10-perfluoroalkyldecanol. The partially fluorinated alcohol was converted into the bromide using Br2–PPh3. Alkylation of excess pyridine with the bromides gave the desired 10-perfluoroalkyldecyl pyridinium bromides in good yields. Three 10-perfluoroalkylundecyl surfactants were synthesized using a similar approach with 10-undecenoic acid methyl ester as starting material. Based on an initial in vitro toxicity assessment, the toxicity of the partially fluorinated pyridinium surfactants was slightly lower or comparable to benzalkonium chloride, a typically cationic surfactant (with IC50s of tested compounds ranging from 5 to 15 μM). An increase in the length and/or the degree of fluorination of the hydrophobic tail correlated with a mild decrease of cytotoxicity and haemolytic activity. Partially fluorinated pyridinium surfactants may, therefore, be useful for biomedical applications such as components for novel gene and drug delivery systems.

Gas chromatographic separation of methoxylated polychlorinated biphenyl atropisomers

Several polychlorinated biphenyls (PCBs) and their hydroxylated metabolites display axial chirality. Here we describe an enantioselective, gas chromatographic separation of methylated derivatives of hydroxylated (OH-)PCB atropisomers (MeO-PCB) using a chemically bonded beta-cyclodextrin column (Chirasil-Dex). The atropisomers of several MeO-PCBs could be separated on this column with resolutions ranging from 0.42 to 0.87 under isothermal or temperature-programmed conditions. In addition, the enantiomeric fraction of OH-PCB 136 metabolites was determined in male and female rats treated with racemic PCB 136. The methylated derivatives of two OH-PCB 136 metabolites showed an enantiomeric enrichment in liver tissue, whereas PCB 136 itself was near racemic.

Structure-activity relationship of selected meta- and para-hydroxylated non-dioxin like polychlorinated biphenyls: from single RyR1 channels to muscle dysfunction.

Non-dioxin like polychlorinated biphenyls (NDL-PCBs) are legacy environmental contaminants with contemporary unintentional sources. NDL-PCBs interact with ryanodine receptors (RyRs), Ca(2+) channels of sarcoplasmic/endoplasmic reticulum (SR/ER) that regulate excitation-contraction coupling (ECC) and Ca(2+)-dependent cell signaling in muscle. Activities of 4 chiral congeners PCB91, 95, 132, and 149 and their respective 4- and 5-hydroxy (-OH) derivatives toward rabbit skeletal muscle ryanodine receptor (RyR1) are investigated using [(3)H]ryanodine binding and SR Ca(2+) flux analyses. Although 5-OH metabolites have comparable activity to their respective parent in both assays, 4-OH derivatives are unable to trigger Ca(2+) release from SR microsomes in the presence of Ca(2+)-ATPase activity. PCB95 and derivatives are investigated using single channel voltage-clamp and primary murine embryonic muscle cells (myotubes). Like PCB95, 5-OH-PCB95 quickly and persistently increases channel open probability (p o > .9) by stabilizing the full-open channel state, whereas 4-OH-PCB95 transiently enhances p o. Ca(2+) imaging of myotubes loaded with Fluo-4 show that acute exposure to PCB95 (5 µM) potentiates ECC and caffeine responses and partially depletes SR Ca(2+) stores. Exposure to 5-OH-PCB95 (5 µM) increases cytoplasmic Ca(2+), leading to rapid ECC failure in 50% of myotubes with the remainder retaining negligible responses. 4-OH-PCB95 neither increases baseline Ca(2+) nor causes ECC failure but depresses ECC and caffeine responses by 50%. With longer (3h) exposure to 300 nM PCB95, 5-OH-PCB95, or 4-OH-PCB95 decreases the number of ECC responsive myotubes by 22%, 81%, and 51% compared with control by depleting SR Ca(2+) and/or uncoupling ECC. NDL-PCBs and their 5-OH and 4-OH metabolites differentially influence RyR1 channel activity and ECC in embryonic skeletal muscle.

Synthesis, physicochemical properties and in vitro cytotoxicity of nicotinic acid ester prodrugs intended for pulmonary delivery using perfluorooctyl bromide as vehicle

This study explores perfluorooctyl bromide (PFOB) as a potential vehicle for the pulmonary delivery of a series of prodrugs of nicotinic acid using cell culture studies. The prodrugs investigated have PFOB-water (logK(p)=0.78 to >2.2), perfluoromethylcyclohexane-toluene (logK(p)=-2.62 to 0.13) and octanol-water (logK(p)=0.90-10.2) partition coefficients spanning several orders of magnitude. In confluent NCI-H358 human lung cancer cells, the toxicity of prodrugs administered in culture medium or PFOB depends on the medium of administration, with EC20s above 8 mM and 2.5 mM for culture medium and PFOB, respectively. Short-chain nicotinates administered both in PFOB and medium increase cellular NAD/NADP levels at 1mM nicotinate concentrations. Long-chain nicotinates, which could not be administered in medium due to their poor aqueous solubility, increased NAD/NADP levels if administered in PFOB at concentrations > or =10 mM. These findings suggest that even highly lipophilic prodrugs can partition out of the PFOB phase into cells, where nicotinic acid is released and converted to NAD. Thus, PFOB may be a novel and biocompatible vehicle for the delivery of lipophilic prodrugs of nicotinic acid and other drugs directly to the lung of laboratory animals and humans.

Partitioning of Homologous Nicotinic Acid Ester Prodrugs (Nicotinates) into Dipalmitoylphosphatidylcholine (DPPC) Membrane Bilayers

The partitioning behavior of a series of perhydrocarbon nicotinic acid esters (nicotinates) between aqueous solution and dipalmitoylphosphatidylcholine (DPPC) membrane bilayers is investigated as a function of increasing alkyl chain length. The hydrocarbon nicotinates represent putative prodrugs, derivatives of the polar drug nicotinic acid, whose functionalization provides the hydrophobic character necessary for pulmonary delivery in a hydrophobic, fluorocarbon solvent, such as perfluorooctyl bromide. Independent techniques of differential scanning calorimetry and 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescence anisotropy measurements are used to analyze the thermotropic phase behavior and lipid bilayer fluidity as a function of nicotinate concentration. At increasing concentrations of nicotinates over the DPPC mole fraction range examined (X(DPPC)=0.6-1.0), all the nicotinates (ethyl (C2H5); butyl (C4H9); hexyl (C6H13); and octyl (C8H17)) partition into the lipid bilayer at sufficient levels to eliminate the pretransition, and decrease and broaden the gel to fluid phase transition temperature. The concentration at which these effects occur is chain length-dependent; the shortest chain nicotinate, C2H5, elicits the least dramatic response. Similarly, the DPH anisotropy results demonstrate an alteration of the bilayer organization in the liposomes as a consequence of the chain length-dependent partitioning of the nicotinates into DPPC bilayers. The membrane partition coefficients (logarithm values), determined from the depressed bilayer phase transition temperatures, increase from 2.18 for C2H5 to 5.25 for C8H17. The DPPC membrane/water partitioning of the perhydrocarbon nicotinate series correlates with trends in the octanol/water partitioning of these solutes, suggesting that their incorporation into the bilayer is driven by increasing hydrophobicity.

2,5‐Dichloro‐4′‐methoxy­biphen­yl

The dihedral angle between the benzene rings in the title compound, C13H10Cl2O1, is 59.92 (9)°.