N-(4-[18F]fluorobenzyl)cholylglycine, a novel tracer for PET of enterohepatic circulation of bile acids: radiosynthesis and proof-of-concept studies in rats

Enterohepatic circulation (EHC) of conjugated bile acids is an important physiological process crucial for regulation of intracellular concentrations of bile acids and their function as detergents and signal carriers. Only few bile acid-derived imaging agents have been synthesized and hitherto none have been evaluated for studies of EHC. We hypothesized that N-(4-[F]fluorobenzyl)cholylglycine ([F]FBCGly), a novel fluorine-18 labeled derivative of endogenous cholylglycine, would be a suitable tracer for PET of the EHC of conjugated bile acids, and we report here a radiosynthesis of [F]FBCGly and a proof-of-concept study by PET/MR in rats.A radiosynthesis of [F]FBCGly was developed based on reductive alkylation of glycine with 4-[F]fluorobenzaldehyde followed by coupling to cholic acid. [F]FBCGly was investigated in vivo by dynamic PET/MR in anesthetized rats; untreated or treated with cholyltaurine or rifampicin. Possible in vivo metabolites of [F]FBCGly were investigated by analysis of blood and bile samples, and the stability of [F]FBCGly towards enzymatic de-conjugation by Cholylglycine Hydrolase was tested in vitro.[F]FBCGly was produced with a radiochemical purity of 96% ± 1% and a non-decay corrected radiochemical yield of 1.0% ± 0.3% (mean ± SD; n = 12). PET/MR studies showed that i.v.-administrated [F]FBCGly underwent EHC within 40-60 min with a rapid transhepatic transport from blood to bile. In untreated rats, the radioactivity concentration of [F]FBCGly was approximately 15 times higher in bile than in liver tissue. Cholyltaurine and rifampicin inhibited the biliary secretion of [F]FBCGly. No fluorine-18 metabolites of [F]FBCGly were observed.We have developed a radiosynthesis of a novel fluorine-18 labeled bile acid derivative, [F]FBCGly, and shown by PET/MR that [F]FBCGly undergoes continuous EHC in rats without metabolizing. This novel tracer may prove useful in PET studies on the effect of drugs or diseases on the EHC of conjugated bile acids

Synthesis, characterization and biological activities of semicarbazones and their copper complexes

Substituted semicarbazones/thiosemicarbazones and their copper complexes have been prepared and several single crystal structures examined. The copper complexes of these semicarbazone/thiosemicarbazones were prepared and several crystal structures examined. The single crystal X-ray structure of the pyridyl-substituted semicarbazone showed two types of copper complexes, a monomer and a dimer. We also found that the p-nitrophenyl semicarbazone formed a conventional 'magic lantern' acetate-bridged dimer. Electron Paramagnetic Resonance (EPR) of several of the copper complexes was consistent with the results of single crystal X-ray crystallography. The EPR spectra of the p-nitrophenyl semicarbazone copper complex in dimethylsulfoxide (DMSO) showed the presence of two species, confirming the structural information. Since thiosemicarbazones and semicarbazones have been reported to exhibit anticancer activity, we examined the anticancer activity of several of the derivatives reported in the present study and interestingly only the thiosemicarbazone showed activity while the semicarbazones were not active indicating that introduction of sulphur atom alters the biological profile of these thiosemicarbazones. (C) 2016 Elsevier Inc All rights reserved

Secondary metabolites of the sponge-derived fungus Acremonium persicinum

This study reports the isolation and characterization of six new acremine metabolites, 5-chloroacremine A (4), 5-chloroacremine H (5), and acremines 0 (6), P (7), Q(8), and R (9), together with the known acremines A (1), F (2), and N (3) from the fungus Acremonium persicinum cultured from the marine sponge Anomoianthella rubra. The relative configuration of acremine F (2) was determined by analyses of proton coupling constant values and NOESY data, and the absolute configuration confirmed as (IS, 4S, 6R) by X-ray crystallographic analysis of the borate ester derivative 15. Acremines O, P, and R were each shown to be of 8R configuration by H-1 NMR analyses of MPA esters. The relative configurations suggested for acremines P and Q were each deduced by molecular modeling together with NOESY and coupling constant data. The (3)J(H-C) values in acremine P were measured using the pulse sequence EXSIDE, and the observed (3)J(H8-C4) of 5.4 Hz and small (3)J(H-C) values

Synthesis and characterization of anils exhibiting thermochromism

Several Schiff bases containing a hydroxy naphthyl moiety and substituted pyridyl groups were synthesized. The pyridyl substituted Schiff bases were isolated as a single stable tautomer at room temperature. High-resolution proton and carbon NMR spectroscopy showed that these compounds exist as keto tautomers. The Schiff bases showed extraordinary stability and did not convert to the enol tautomer, even at high temperatures. Most of the compounds exhibited thermochromic properties

NMR and DFT investigations of structure of colchicine in various solvents including density functional theory calculations

A detailed NMR investigation of the chemical shifts of hydrogen and carbon atoms associated with the structure of the naturally occurring alkaloid colchicine was conducted using high field NMR. Initially, the experimental chemical shifts for colchicine in chloroform and DMSO were compared to the values calculated using density functional theory (DFT). There were significant deviations observed for the chloroform solvent, but these were only slight in the DMSO solution. Dilution of the chloroform solution changed the experimental chemical shifts and improved agreement with the DFT calculations, suggesting self-aggregation at higher concentrations. A dimeric model was proposed for which agreement with the DFT calculated chemical shifts was better than for corresponding monomeric structures. Three further solvents were studied to evaluate changes in chemical shift values at different dilutions. Chloroform, benzene and water showed significant chemical shift changes implying self-aggregation, whereas DMSO and acetone did not show significant change upon dilution

A variant of differential evolution for discrete optimization problems requiring mutually distinct parameters

A large number of real world problems are formulated in terms of a set of discrete or integer variables for which an optimal set is obtained through appropriate optimization of a function. These problems are best represented using a set of discrete numbers over bounded or unbounded discrete spaces, in order to limit the search domain of the algorithm. In this work, Differential Evolution (DE) is used for the discrete prob- lem, where the search space is augmented to improve the performance of the technique. Although in principal DE is used to nd the optimal solution, the manner in which the space is stated and then searched is altered to improve the overall performance. Both unique and non-unique discrete sets of variables are investigated as control variables of the functions, and the algorithm for each is outlined accordingly. A number of established test functions are used to state the performance of the proposed DE discrete variable op- timization technique, when compared to real space DE optimization

Investigation of two- and three-bond carbon-hydrogen coupling constants in cinnamic acid based compounds

Two- and three-bond coupling constants (2 JHC and 3 JHC ) were determined for a series of 12 substituted cinnamic acids using a selective 2D inphase/antiphase (IPAP)-single quantum multiple bond correlation (HSQMBC) and 1D proton coupled 13 C NMR experiments. The coupling constants from two methods were compared and found to give very similar values. The results showed coupling constant values ranging from 1.7 to 9.7 Hz and 1.0 to 9.6 Hz for the IPAP-HSQMBC and the direct 13 C NMR experiments, respectively. The experimental values of the coupling constants were compared with discrete density functional theory (DFT) calculated values and were found to be in good agreement for the 3 JHC . However, the DFT method under estimated the 2 JHC coupling constants. Knowing the limitations of the measurement and calculation of these multibond coupling constants will add confidence to the assignment of conformation or stereochemical aspects of complex molecules like natural products. Copyright © 2016 John Wiley & Sons, Ltd

Multiple quantum nuclear magnetic resonance spectra of partially oriented styrene in a nematic phase

Proton multiple-quantum nuclear magnetic resonance (MQNMR) spectra of styrene partially oriented in a nematic liquid crystal were acquired using the magnetic field gradient method. Six-, seven- and eight-quantum spectra were iteratively solved to yield all intramolecular dipolar couplings (Dij) which were used to determine the molecular shape of styrene. The dipolar couplings were fitted to a model averaging between four equivalent non-planar conformations of the molecule. Ignoring vibrational corrections, the analysis was consistent with a non-planar molecular geometry with a dihedral angle of approximately 16 degrees between the olefinic fragment and the aromatic ring

Revision of the structure of acremine P from a marine-derived strain of Acremonium persicinum

The previously published structure of the fungal metabolite acremine P is revised by re-evaluation of chemical shift values and NOESY data, and by DFT calculations