Eng und persönlich: Eng zusammenstehende Retinoidpolyene, wie sie auf dem rechten Sessel abgebildet sind, reagieren leicht mit Sauerstoff (rot) zu polyoxygenierten Verbindungen. Getrennte Polyene dagegen, wie sie auf dem linken Sofa zu sehen sind, werden nur eingeschränkt oxidiert.

A combined chemical/chiroptical microscale protocol for the determination of absolute configurations of cyclic α-hydroxyketones is described. The hydroxyl group in cyclic α-hydroxyketones is converted into (3-aminopropylamino)acetate (NH₂CH₂CH₂CH₂NHCH₂COOR), or more generally, according to a newly developed protocol, into (3-hydroxypropylamino)acetate group (HOCH₂CH₂CH₂NHCH₂COOR). The resultant conjugated compound forms a 1:1 host–guest complex with a dimeric zinc porphyrin tweezer, which exhibits exciton-coupled bisignate CD spectrum centered around the 420-nm porphyrin Soret band due to induced helicity between the two porphyrins in the complex. The absolute configurations of the α-stereogenic center is then determined by comparison of the sign of the observed CD exciton couplet of the complex with that of the preferred porphyrin twist predicted by the Merck Molecular Force Field (MMFFs) method. Chirality 17:305–315, 2005. © 2005 Wiley-Liss, Inc.

An all-trans-retinal (ATR) dimer (1) isolated from photoreceptor outer segments was found to have a stereogenic center at C13′ flanked by tetraene (295 nm) and hexaenal (438 nm) chromophores. Analytical chiral HPLC (Chiralcel OD) revealed that the isolated retinoid had formed in 13% enantiomeric excess. Using a combination of ¹H-¹H NOESY constraints, molecular modeling, and CD exciton coupling analysis, it was determined that the favored enantiomer was 13′(R). Three low-energy conformers of the 13′(S) model were found with MMFF/DFT and were used to calculate the CD spectrum of the ATR dimer (DeVoe method). The Boltzmann weighted spectrum was found to exhibit a positive exciton couplet, in excellent agreement with the experimental spectrum for the first eluted enantiomer. This further suggested that despite the large energy difference between the two interacting chromophores, the dominant source of optical activity in the CD spectrum is the nondegenerate exciton mechanism. Chirality 16:637–641, 2004. © 2004 Wiley-Liss, Inc.

Ginkgo biloba – der Ginkgobaum – ist die älteste lebende Baumart der Welt. Ginkgo-Präparate sind ein wichtiger Bestandteil in der traditionellen chinesischen Medizin, und in den letzten Jahren haben die Blattextrakte als Phytopräparat in Europa und als Nahrungsergänzungsmittel weltweit breiten Absatz gefunden. Zu den postulierten Wirkungen des Ginkgo-biloba-Extrakts gehören die Verbesserung der Gedächtnisleistung, die Steigerung der Blutzirkulation und eine Verzögerung der Alzheimer-Demenz. Was den Extrakt so einzigartig macht, sind die Terpentrilactone – Ginkgolide und Bilobalid –, die als strukturell komplexe Moleküle attraktive Zielstrukturen für Totalsynthesen waren. Es wird angenommen, dass Terpentrilactone für die neuroregulatorischen Eigenschaften der Ginkgo-biloba-Extrakte mit ausschlaggebend sind. Eine Reihe biologischer Wirkungen der in den letzten Jahren entdeckten Terpentrilactone macht diese zu aussichtsreichen pharmakologischen Substanzen.

Ginkgo biloba, the ginkgo tree, is the oldest living tree, with a long history of use in traditional Chinese medicine. In recent years, the leaf extracts have been widely sold as phytomedicine in Europe and as a dietary supplement worldwide. Effects of Ginkgo biloba extracts have been postulated to include improvement of memory, increased blood circulation, as well as beneficial effects to sufferers of Alzheimer's disease. The most unique components of the extracts are the terpene trilactones, that is, ginkgolides and bilobalide. These structurally complex molecules have been attractive targets for total synthesis. Terpene trilactones are believed to be partly responsible for the neuromodulatory properties of Ginkgo biloba extracts, and several biological effects of the terpene trilactones have been discovered in recent years, making them attractive pharmacological tools that could provide insight into the effects of Ginkgo biloba extracts.

The visual pigment rhodopsin (bovine) is a 40 kDa protein consisting of 348 amino acids, and is a prototypical member of the subfamily A of G protein-coupled receptors (GPCRs). This remarkably efficient light-activated protein (quantum yield = 0.67) binds the chromophore 11-cis-retinal covalently by attachment to Lys296 through a protonated Schiff base. The 11-cis geometry of the retinylidene chromophore keeps the partially active opsin protein locked in its inactive state (inverse agonist). Several retinal analogs with defined configurations and stereochemistry have been incorporated into the apoprotein to give rhodopsin analogs. These incorporation results along with the spectroscopic properties of the rhodopsin analogs clarify the mode of entry of the chromophore into the apoprotein and the biologically relevant conformation of the chromophore in the rhodopsin binding site. In addition, difference UV, CD, and photoaffinity labeling studies with a 3-diazo-4-oxo analog of 11-cis-retinal have been used to chart the movement of the retinylidene chromophore through the various intermediate stages of visual transduction. © 2004 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 4: 120–135; 2004: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20000

Ginkgolides from the Ginkgo biloba tree are diterpenes with a cage structure consisting of six five-membered rings and a unique tBu group. They exert a variety of biological properties. In addition to being antagonists of the platelet activating factor receptor (PAFR), it has recently been shown that native ginkgolides are potent and selective antagonists of the inhibitory glycine receptor. Forty new ginkgolide derivatives have been prepared in good to high yields on milligram scales and investigated for their antagonistic properties at homomeric α1 glycine receptors, thus providing the first structure–activity relationship study of ginkgolides at glycine receptors. A high-throughput screening assay showed that native ginkgolide C was the most potent ligand, and that manipulation of any of the hydroxyl groups led to loss of activity at α1 glycine receptors.

Microphysiometry was used to evaluate the effects of terpene trilactone and flavonoid constituents of Ginkgo biloba on human platelet-activating-factor receptor (PAFR). Inhibition of the platelet-activating factor response by terpene trilactones was confirmed using this functional assay. Ginkgolide B (GB) and 10-O-benzyl-GB showed the strongest inhibition (81 and 93%, resp.) of the PAFR response, while the flavonoids rutin, quercetin, and kaempferol showed negligible response inhibition. G. biloba extract mixtures were also tested, and results indicate possible synergistic effects among various components.

Both enantiomers of 13-(E) and 13-(Z) isomers of 11-cis-locked bicyclo[5.1.0]octanyl retinal were prepared by an improved synthesis and incubated with bovine opsin. The synthesis also establishes the absolute configuration of the enantiomers. Only one of the enantiomers binds to opsin, thus showing the steric restrictions regarding the middle polyene moiety of the retinoid molecule; this is in sharp contrast to the known leniency of the ring moiety binding site of retinoids. However, although one enantiomer is incorporated into the pigment, the circular dichroic spectrum of the pigment incorporating the bound enantiomer yields only a very weak Cotton effect, showing that, once incorporated, the bicyclo[5.1.0]octanyl chromophore is flattened by the opsin binding site. The titled retinoid was synthesized for study of the absolute conformation of the retinal pigment in rhodopsin. Chirality 14:340–346, 2002. © 2002 Wiley-Liss, Inc.

Neun Epoxidringe entstehen nacheinander, wenn A2E mit blauem Licht in Gegenwart von Sauerstoff bestrahlt wird [Gl. (1)]. Mechanistisch gesehen erzeugt A2E Singulettsauerstoff und reagiert mit diesem zu den Polyoxiranen. Das Verständnis der Reaktion von A2E mit Sauerstoff ist wichtig, weil blaues Licht die Apoptose von A2E-beladenen Zellen des retinalen Pigmentepithels auslöst, die typisch für die altersabhängige Makuladegeneration ist.

Nine epoxide rings are formed sequentially when A2E is irradiated with blue light in the presence of oxygen [Eq. (1)]. Mechanistically, A2E generates singlet oxygen and reacts with it to give the polyoxiranes. An understanding of the reaction of A2E with oxygen is important as blue light induces the apoptotic death of A2E-laden retinal pigment epithelium cells, which are typical of age-related macular degeneration.

Incubation of opsin with synthetic 6-s-locked retinoids 2 a and 2 b only led to pigment formation from the alpha-locked 2 a, the CD spectrum of which was similar to that of native rhodopsin (Rh). This establishes that the 6-s-bond of the chromophore in rhodopsin is cis, and that its helicity is negative. Earlier cross-linking studies showed that the 11-cis to all-trans photoisomerization occurring in the batho-Rh to lumi-Rh conversion induces a flip over of the side carrying the ring moiety. The GTP-binding assay of pigment Rh-(2 a), incorporating retinal analogue 2 a, has shown that its activity is 80 % that of the native pigment. That is, the overall conformation around the 6-s bond is retained in the steps leading to G-protein activation.

With ¹³C-labeled samples, it is possible to measure internuclear distances up to 7 Å by solid-state NMR, thus providing a powerful tool for probing ligand—receptor interactions. However, limitations in measurable distances and appreciable natural abundant ¹³C background signals present problems in solid-state ¹³C NMR. In order to overcome these disadvantages, a set of reference compounds with known F—F distances, namely, quinolinol, p-biphenyl, and p-terphenyl-bearing trifluoromethyl and trifluoromethylthio groups, have been synthesized. The preparation of these reference compounds and means for diluting these references in solid-state NMR are described.

Synthesis of 11-cis-retinal analogues, of great importance in bioorganic studies of the photoreceptor of the visual transduction pathway, has been hampered by unusual difficulties in establishing the 11-cis geometry. However, a general and mild preparation of 11-cis-retinoids in high yield has been achieved by reduction of 11-yne precursors to 11-cis-enes with Cu/Ag-activated zinc dust (below). The ready availability of the 11-yne precursors makes this strategy applicable for general use.