Conformational Differentiation of α-Cyanohydroxycinnamic Acid Isomers: A Raman Spectroscopic Study.

Two α-cyanohydroxycinnamic acid positional isomers, α-cyano-4-hydroxycinnamic acid (CHCA4) and α-cyano-3-hydroxycinnamic acid (CHCA3), were characterized using Raman spectroscopy. We analyzed the implications of the collected Raman spectral shifts, and verified them through other spectroscopic techniques, to arrive at plausible three dimensional structures of CHCA3 and CHCA4. The positions of these groups were mapped by systematically analyzing the orientation and type of interactions functional groups make in each CHCA isomer. We determined whether or not the carboxylic moieties are forming dimeric links and ascertained the existence of ring-ring π-stacking interactions. We also assessed the nature of the hydrogen bonding between -CN and -OH groups. The results were then taken together to model plausible three dimensional structures for each compound. The data revealed a structure for CHCA4 that matches the published x-ray crystallographic structure. We then applied the same spectral analysis to CHCA3 to reveal its plausible three dimensional structure. The structural details revealed may account for the functional properties of the two α-cyanohydroxycinnamic acid positional isomers.

Gold-Catalyzed Ammonium Acetate Assisted Cascade Cyclization of 2-Alkynylarylketones.

An ammonium acetate assisted gold-catalyzed cascade cyclization reaction of 2-alkynylarylketones is described. Under the reported conditions, a gold-catalyzed intramolecular cyclization of 2-alkynylarylketones takes place through two competing reaction mechanisms-a 5-exo-dig or a 6-endo-dig cyclization-leading to two regioisomeric intermediates: isobenzofuranium or isobenzopyrylium. In the presence of ammonium acetate, the two intermediate compounds undergo further rearrangement to 2,3-disubstituted indenones and 1,3-disubstituted isoquinolines, respectively. While both reaction pathways proceed via a cyclization-rearrangement cascade, the gold-mediated 5-exo-dig process is especially notable, as it provides a novel cyclization protocol of 2-alkynylarylketones.

Chloride sensing via suppression of excited state intramolecular proton transfer in squaramides.

A new design strategy is described for chloride ion sensors based on suppression of excited state intramolecular proton transfer in squaramides as a fluorescence "turn on" mechanism.

Carbonyl groups as molecular valves to regulate chloride binding to squaramides.

Environment-sensitive binding of anions to synthetic receptors is important for the functional mimicry of ion channels. We describe new squaramide-based chloride ion receptors whose anion binding cavity can be opened and closed by using carbonyl groups as valves. In nonpolar solvents, the carbonyls preclude chloride binding via intramolecular hydrogen bonding with the squaramide NHs. In polar solvents, disruption of the intramolecular hydrogen bonds reorients the carbonyl groups and opens the anion-binding cavity.

Acute intermittent porphyria: vector optimization for gene therapy.

BACKGROUND: Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by the half-normal activity of hydroxymethylbilane synthase (HMB-synthase). Affected individuals can experience episodic, life-threatening, acute neurological attacks that are precipitated by various drugs, dieting, and hormonal changes. Intravenous hematin is used to treat the attacks, but a more effective, preventive therapy is needed, especially for patients with frequent attacks. Since the disease is a hepatic encephalopathy, efforts were focused towards evaluating four different combinations of liver-specific enhancers and promoters for maximal hepatic HMB-synthase expression. METHODS: Four different mammalian expression vectors, each carrying a unique combination of liver-specific enhancers and promoters driving murine HMB-synthase cDNA expression, were transiently transfected into HepG2 cells. The vectors included: HMBS-1; human alpha1-microglobulin enhancer/alpha1-antityrpsin promoter (alpha1Me/alpha1ATp), HMBS-2; alpha1Me/human serum albumin promoter (alpha1Me/SAp), HMBS-3; human prothrombin enhancer/SAp (PTe/SAp), and HMBS-4; (PTe/alpha1ATp). Each HMB-synthase construct and a luciferase reporter construct were hydrodynamically coinjected into mice with HMB-synthase deficiency and evaluated for hepatic expression 24 h post-injection, the time-point of peak hepatic HMB-synthase expression. RESULTS: Following transient transfection into HepG2 cells, HMBS-1 (alpha1Me/alpha1ATp) had the highest HMB-synthase expression level, with an approximately 8-fold increase over endogenous cellular activities. Construct HMBS-1 also had the highest hepatic HMB-synthase activity following hydrodynamic delivery into HMB-synthase deficient mice, with a approximately 6-fold increase over saline-treated mice. CONCLUSIONS: These studies support the use of a gene therapy vector containing the alpha1Me/alpha1ATp combination for preclinical studies of the efficacy and safety of liver-targeted gene therapy for AIP.