Organic Chemistry

A new approach to trifluoromethyl substituted butenolides and their thioanalogues is described starting from 2-fluoro-3-trifluoromethylfurans and -thiophenes, respectively. The reaction sequence includes three steps -nucleophilic displacement reaction, Claisen, and finally Cope rearrangement -which can be run as domino reaction. A modification of the domino reaction (transesterification instead of Cope rearrangement) provides a concise access to -trifluoromethyl--ketoacids.

Hippocrates (the father of medicine) described the healing properties of St. Johns wort 2500 years ago and prescribed it for the treatment of depression. Hyperforin, which is considered to be responsible for this activity, also has anticancer, antibacterial, and woundhealing activity. A. Giannis et al. describe in their Communication on page 5219 ff. that hyperforin and two related compounds are inhibitors of sirtuins SIRT1 and SIRT2. This property could explain some of the pharmacological properties of hyperforin.

HUVE cells. To obtain proliferating cells, 3000-4000 HUVE cells were seeded into each well of a 96-well microplate 24 h prior to incubation with the natural products, which were then applied as described for the cell-viability assay. Cells were incubated with the natural products for 72 h and the proliferation status was determined according to the test instructions using an Orion Microplate Luminometer (Bertholt) to measure chemiluminescence.

Merocyanines are of widespread interest for different applications [5] and have attracted considerable attention owing to their intense absorption bands and the outstanding sensitivity of these bands to solvents. The solvent sensitivity of the absorption bands is discussed in terms of a simple valence bond (VB) model, which assumes that the electronic ground (S 0 ) and excited state (S 1 ) of merocyanines can be approximated as a linear combination of a non-charge-separated polyene-like and a charge-separated polyene-like limiting form. [5] The net balance is influenced by the nature of the solvent, passing through the "cyanine limit". Several parameters have been suggested for quantifying the contribution of the two limiting forms to the equilibrium structure of the ground state. The concepts of the average bond-length alternation (BLA), [7] and the closely related average p-bond order alternation (BOA), between adjacent bonds in the hydrocarbon chain are most popular. Surprisingly, within the same concept merocyanines have been described by two quite different models, namely Equations (1), [7a,c, 8b,c] and , [7b, 8a] in which A (electron acceptor) and D (electron donor) are capable of charge exchange. Polymethines are characterized by a chain of conjugated double bonds with an odd number n of p centers and (n + 1) p electrons, whereas polyenes are characterized by an even number of p centers and the same number of p electrons. Therefore, polyenes and polymethines differ considerably in electronic structure and light absorption, [5] and, consequently, polymethines cannot be viewed as acceptor/donor-substituted polyenes. Equation (1) describes two possible limiting forms of acceptor/ donor-substituted polyenes and, therefore, cannot be used for merocyanines. Equation represents polymethines; A = N (+) and D = N corresponds to a cyanine [Eq. (3)], A = O and D = O (À) to an oxonole, and A = N (+) and D = O (À) or A = N (+) and D = C (À) to merocyanines [Eqs. (4) and (5)]. The structure labeled b in Equations and do not represent polyene-like forms as often claimed, but are equivalent to structure b in Equation for cyanines and are polymethines.

A phytochemical investigation of the constituents of the aerial parts of Baccharis genistelloides has resulted in the isolation of the new piquerol derivative (E)-4-acetoxy-6-methylene-5-(prop-1en-2-yl)cyclohex-2-enyl 2-methylbut-2-enoate 4, along with two other compounds [foliasalacin A 4 5, and (E)-icosyl 3-(4-hydroxy-3-methoxyphenyl)-acrylate 6], which have not been reported as constituents of this plant until now.

A still unknown low-molecular-mass cofactor essential for the activity of carnitine-metabolizing enzymes (e.g., L-carnitine dehydratase, crotonobetaine reductase) from E. coli has been purified to homogeneity from a cell-free extract of E. coli O44K74. The purity of the cofactor was confirmed by HPLC analysis. Biosynthesis of the unknown compound was only observed when bacteria were cultivated anaerobically in the presence of L-carnitine or crotonobetaine. The determined properties, together with results obtained from UV-visible, 1 H NMR, and mass spectrometry, indicate that the compound in question is a new CoA derivative. The esterified compound was suggested to be γ-butyrobetainesa metabolite of carnitine metabolism of E. coli. Proof of structure was performed by chemical synthesis. Besides γ-butyrobetainyl-CoA, a second new CoA derivative, crotonobetainyl-CoA, was also chemically synthesized. Both CoA derivatives were purified and their structures confirmed using NMR and mass spectrometry. Comparisons of structural data and of the chemical properties of γ-butyrobetainyl-CoA, crotonobetainyl-CoA, and the isolated cofactor verified that the unknown compound is γ-butyrobetainyl-CoA. The physical and chemical properties of γ-butyrobetainyl-CoA and crotonobetainyl-CoA are similar to known CoA derivatives. FIGURE 2: (A) Analysis of purified cofactor of carnitine-metabolizing enzymes from E. coli O44K74 by MALDI-TOF mass spectrometry. (B-D) Analysis of γ-butyrobetainyl-CoA and crotonobetainyl-CoA by MALDI-TOF-and ESI-MS. (B) MALDI-TOF mass spectrum of γ-butyrobetainyl-CoA. (C) MALDI-TOF mass spectrum of crotonobetainyl-CoA. (D) ESI mass spectrum of γ-butyrobetainyl-CoA. γ-Butyrobetainyl-CoA and Crotonobetainyl-CoA

The palladium(II) bis-chelate complexes of the type [Pd(TSC 1−5 ) 2 ] (6-10), with their corresponding ligands 4-phenyl-1-(acetone)thiosemicarbazone, HTSC 1 (1), 4-phenyl-1-(2 -chloro-benzaldehyde)-thiosemicarbazone, HTSC 2 (2), 4-phenyl-1-(3 -hydroxybenzaldehyde)-thiosemicarbazone, HTSC 3 (3), 4-phenyl-1-(2 -naphthaldehyde)-thiosemicarbazone, HTSC 4 (4), and 4-phenyl-1-(1 -nitro-2 -naphthaldehyde)-thiosemicarbazone, HTSC 5 (5), were synthesized and characterized by elemental analysis and spectroscopic techniques (IR and 1 H-and 13 C-NMR). The molecular structure of HTSC 3 , HTSC 4 , and [Pd(TSC 1 ) 2 ] (6) have been determined by single crystal X-ray crystallography. Complex 6 shows a square planar geometry with two deprotonated ligands coordinated to Pd II through the azomethine nitrogen and thione sulfur atoms in a cis arrangement. The in vitro cytotoxic activity measurements indicate that the palladium(II) complexes (IC 50 = 0.01-9.87 M) exhibited higher antiproliferative activity than their free ligands (IC 50 = 23.48-70.86 and >250 M) against different types of human tumor cell lines. Among all the studied palladium(II) complexes, the [Pd(TSC 3 ) 2 ] (8) complex exhibited high antitumor activity on the DU145 prostate carcinoma and K562 chronic myelogenous leukemia cells, with low values of the inhibitory concentration (0.01 and 0.02 M, resp.).

The synthesis, pharmacological evaluation, and structure-activity relationships (SARs) of a series of novel arylalkylpiperazines structurally related to BP897 (3) are described. In binding studies, the new derivatives were tested against a panel of dopamine, serotonin, and noradrenaline receptor subtypes. Focusing mainly on dopamine D 3 receptors, SAR studies brought to light a number of structural features required for high receptor affinity and selectivity. Several heteroaromatic systems were explored for their dopamine receptor affinities, and combinations of synthesis, biology, and molecular modeling, were used to identify novel structural leads for the development of potent and selective D 3 receptor ligands. Introduction of an indole ring linked to a dichlorophenylpiperazine system provided two of the most potent and selective ligands known to date (D 3 receptor affinity in the picomolar range). The intrinsic pharmacological properties of a subset of potent D 3 receptor ligands were also assessed in [ 35 S]-GTPγS binding assays. Evidence from animal studies, in particular, has highlighted the dopaminergic system's role in how environmental stimuli induce drug-seeking behavior. We therefore tested two novel D 3 receptor partial agonists and a potent D 3 -selective antagonist in vivo for their effect in the cocaine-seeking behavior induced by reintroduction of cocaineassociated stimuli after a long period of abstinence, and without any further cocaine. Compound 5g, a nonselective partial D 3 receptor agonist with a pharmacological profile similar to 3, and 5p, a potent and selective D 3 antagonist, reduced the number of active lever presses induced by reintroduction of cocaine-associated stimuli. However, 5q, a highly potent and selective D 3 partial agonist, did not have any effect on cocaine-seeking behavior. Although brain uptake studies are needed to establish whether the compounds achieve brain concentrations comparable to those active in vitro on the D 3 receptor, our experiments suggest that antagonism at D 2