An Anion Selective Aminocyclodextrin Ion Channel: Ion Selectivity, pH Sensitivity and Potential as a Scaffold for Light Gating

164 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2006.The synthesis and characterization of a highly active ion channel mimic and a photocleavable tether as a potential light activated switch is described. Signal activated ion channels are attractive for use in applications such as biosensors and nano-switches. A new photocleavable o-nitrobenzyl dimeric tether has been developed as a potential trigger for the photoactivation of the ion channel. The utility of the tether was demonstrated by functionalizing primary, secondary and benzylic alcohols with the tether and subjecting the resulting ethers to photolysis. The photolysis of the tethered ethers was found to be extremely efficient and the corresponding alcohols were isolated in 79-100% yields. Comparison with the corresponding monomeric ethers indicated superior yields for the ethers functionalized with the dimeric tether. An aminocyclodextrin ion channel was synthesized from heptaiodinated beta-cyclodextrin and amine functionalized pentabutylene glycol chains. Ion transport through the channel gauged using 23Na NMR and fluorescence spectroscopy indicated high ion transport activity, comparable to natural ion channels. The fluorescence studies also indicated that the ion channel was highly anion selective with anion transport rates being ClO4- > I- > NO3- > Br- > Cl-. The rates for the transport of ClO4 -, I-, NO3- and Br- ions were ca. 20, 9, 3.1 and 2.6 times that for Na + ions, respectively. The anion selectivity for the ion channel is attributed to the presence of seven amino groups conferring positive charge at the pore opening of the ion channel. The ion transport rates and the ion selectivity of the ion channel were found to be pH dependent. At high pH values fast transport rates for Na+ and X- ions was demonstrated, while at low pH higher selectivity between ions was observed.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

An Anion Selective Aminocyclodextrin Ion Channel: Ion Selectivity, pH Sensitivity and Potential as a Scaffold for Light Gating

164 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2006.The synthesis and characterization of a highly active ion channel mimic and a photocleavable tether as a potential light activated switch is described. Signal activated ion channels are attractive for use in applications such as biosensors and nano-switches. A new photocleavable o-nitrobenzyl dimeric tether has been developed as a potential trigger for the photoactivation of the ion channel. The utility of the tether was demonstrated by functionalizing primary, secondary and benzylic alcohols with the tether and subjecting the resulting ethers to photolysis. The photolysis of the tethered ethers was found to be extremely efficient and the corresponding alcohols were isolated in 79-100% yields. Comparison with the corresponding monomeric ethers indicated superior yields for the ethers functionalized with the dimeric tether. An aminocyclodextrin ion channel was synthesized from heptaiodinated beta-cyclodextrin and amine functionalized pentabutylene glycol chains. Ion transport through the channel gauged using 23Na NMR and fluorescence spectroscopy indicated high ion transport activity, comparable to natural ion channels. The fluorescence studies also indicated that the ion channel was highly anion selective with anion transport rates being ClO4- > I- > NO3- > Br- > Cl-. The rates for the transport of ClO4 -, I-, NO3- and Br- ions were ca. 20, 9, 3.1 and 2.6 times that for Na + ions, respectively. The anion selectivity for the ion channel is attributed to the presence of seven amino groups conferring positive charge at the pore opening of the ion channel. The ion transport rates and the ion selectivity of the ion channel were found to be pH dependent. At high pH values fast transport rates for Na+ and X- ions was demonstrated, while at low pH higher selectivity between ions was observed.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Soluble and Reusable Poly(norbornene) Supports with High Loading Capacities for Peptide Synthesis

Poly(norbornene) supports comprising solubilizing ethylene glycol units and multiple amino acid attachment sites have been developed for peptide synthesis. A variety of amino acids have been efficiently loaded (0.6–1.1 mmol/g) onto the support in high yields (83–98%). Several tripeptides have been synthesized in moderate-to-good overall yields (41–66%) using only 1.2 equiv of coupling reagents/amino acids, and the support could be efficiently recycled up to 3 times

Anion-Selective Cholesterol Decorated Macrocyclic Transmembrane Ion Carriers

Anion transporters play a vital role in cellular processes and their dysregulation leads to a range of diseases such as cystic fibrosis, Bartter’s syndrome and epilepsy. Synthetic chloride transporters are known to induce apoptosis in cancer cell lines. Herein, we report triamide macrocycles that are easily synthesized and externally functionalized by pendant membrane-permeable groups. Among a variety of chains appended onto the macrocycle scaffold, cholesterol is found to be the best with an EC₅₀ value of 0.44 μM. The macrocycle is highly anion-selective and transports ions via an OH^–/X^– antiport mechanism. The macrocycle is an interesting scaffold for ion-transport as it is able to discriminate between various anions and shows a preference for SCN^– and Cl^–. Such anion-selective transporters are highly attractive model systems to study ion-transport mechanisms and could potentially be of high therapeutic value

Soluble Non-Cross-Linked Poly(norbornene) Supports for Peptide Synthesis with Minimal Reagents

Solid-phase peptide synthesis has been an attractive method for synthesizing peptides because it is quick and can be automated. The heterogeneous reaction medium in solid-phase peptide synthesis necessitates the use of large equivalents of reagents to drive the reactions to completion. Peptide synthesis using soluble, yet isolable, supports is an attractive alternative to solid-phase peptide synthesis. Reported herein is a soluble poly­(norbornene)-derived support containing multiple attachment sites for high loading capacities and solubilizing oligoether/alkyl groups. The Ala-attached support has been used to synthesize tri- to octapeptides in 28 to 97% yields using only 1.2 equiv of amino acids and coupling reagents. The acyclic hexapeptide precursor to natural product segatalin A was synthesized in 41% yield on the support using one-eighth of the equivalents of coupling reagents compared to that in reported procedures. The support could be recovered in up to 98% yield after peptide synthesis, and the recovered support was utilized to synthesize tri- and tetrapeptides that contain amino acids other than Ala at the C-terminus in ca. 80% yields

Small Peptidic Ionophore for Calcium Transport

Synthetic calcium transporters are few despite their potential biological significance. Herein, we report small alanine-derived peptides containing pyridyl-triazole motifs for inducing calcium selectivity. The peptides are decorated with hydrophobic alkyl chains to facilitate membrane insertion. The most efficient peptide scaffold has an EC50 value of 0.09 mol % and functions as a calcium carrier

Localized values of K_i (in µM) for dihalogenated phenolics calculated by Cheng-Prusoff (left sub-column) and Chance (right sub-column) equations.

<p>A non-entry in the table means that the the product formation was enhanced in that particular reaction setup. (Conditions are similar to the ones in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089967#pone-0089967-t002" target="_blank">Table 2</a>.)</p

Vitamins-mediated inhibition of CYP2C9 baculosomes and microsome reactions for hydroxylation of diclofenac.

<p>The reactions were carried out in 100 µM diclofenac, 200 µM NADPH, rat liver microsomes with 0.5 µM of CYPs or 10 nM of CYP 2C9 baculosome preparation, taken along with the appropriate concentration of the redox molecule. The plots show 4′OH diclofenac in milieu. after 10 minutes reaction time.</p

Molecular schema of various substituted benzarones, dihalophenols and vitamins studied in the current work. (For details of substitutions, please refer <b>Table 1</b>.)

<p>Molecular schema of various substituted benzarones, dihalophenols and vitamins studied in the current work. (For details of substitutions, please refer <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089967#pone-0089967-t001" target="_blank"><b>Table 1</b></a>.)</p

Survey of global values of K_i (in µM).

<p>Data obtained by non-linear (top sub-row) and linear (bottom sub-row) regression analysis (taking K_M to be 10 µM <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089967#pone.0089967-Bort1" target="_blank">[7]</a>, with weighted point at pM inhibitor giving 99.9% activity), along with the R² values (in brackets). A non-entry in the table means that at certain concentrations of the inhibitor molecule (in a given setup), the product formation was enhanced.</p