Günter Wulff (1935 -2023): Father of Molecular Imprinting.

Günter Wulff, internationally well known for his invention of Molecular Imprinting, passed away on December 11, 2023 in Erkrath-Hochdahl, Germany, not far from the University of Düsseldorf, where he made his greatest discoveries. A passionate researcher and deep conceptual thinker, he greatly advanced our understanding of polymer chemistry.

Non-Immunosuppressive Cyclophilin Inhibitors.

Cyclophilins, enzymes with peptidyl-prolyl cis/trans isomerase activity, are relevant to a large variety of biological processes. The most abundant member of this enzyme family, cyclophilin A, is the cellular receptor of the immunosuppressive drug cyclosporine A (CsA). As a consequence of the pathophysiological role of cyclophilins, particularly in viral infections, there is a broad interest in cyclophilin inhibition devoid of immunosuppressive activity. This Review first gives an introduction into the physiological and pathophysiological roles of cyclophilins. The presentation of non-immunosuppressive cyclophilin inhibitors will commence with drugs based on chemical modifications of CsA. The naturally occurring macrocyclic sanglifehrins have become other lead structures for cyclophilin-inhibiting drugs. Finally, de novo designed compounds, whose structures are not derived from or inspired by natural products, will be presented. Relevant synthetic concepts will be discussed, but the focus will also be on biochemical studies, structure-activity relationships, and clinical studies.

Synthesis of the aglycon of scorzodihydrostilbenes B and D.

Benzyl- and methyl-protected 2,4-dihydroxyacetophenones are added under ruthenium catalysis to 4-methoxy- and 3,4-dimethoxystyrene in a completely regioselective manner. Thus, oxygenated dihydrostilbenes are obtained that feature the skeleton of scorzodihydrostilbenes - antioxidative agents that were recently isolated from Scorzonera radiata. Selective deprotection liberates the corresponding phenols, among them the aglycon of scorzodihydrostilbenes B and D.

Analysis of the inhibition potential of zosuquidar derivatives on selected bacterial and fungal ABC transporters.

The increasing number of multidrug-resistant pathogenic microorganisms is a serious public health issue. Among the multitude of mechanisms that lead to multidrug resistance, the active extrusion of toxic compounds, mediated by MDR efflux pumps, plays an important role. In our study we analyzed the inhibitory capability of 26 synthesized zosuquidar derivatives on three ABC-type MDR efflux pumps, namely Saccharomyces cerevisiae Pdr5 as well as Lactococcus lactis LmrA and LmrCD. For Pdr5, five compounds could be identified that inhibited rhodamine 6G transport more efficiently than zosuquidar. One of these is a compound with a new catechol acetal structure that might represent a new lead compound. Furthermore, the determination of IC(50) values for rhodamine 6G transport of Pdr5 with representative compounds reveals values between 0.3 and 0.9 µM. Thus the identified compounds are among the most potent inhibitors known for Pdr5. For the ABC-type efflux pumps LmrA and LmrCD from L. lactis, seven and three compounds, which inhibit the transport activity more than the lead compound zosuquidar, were found. Interestingly, transport inhibition for LmrCD was very specific, with a drastic reduction by one compound while its diastereomers showed hardly an effect. Thus, the present study reveals new potent inhibitors for the ABC-type MDR efflux pumps studied with the inhibitors of Pdr5 and LmrCD being of particular interest as these proteins are well known model systems for their homologs in pathogenic fungi and Gram-positive bacteria.

Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance.

The inhibition of ABC (ATP binding cassette) transporters is considered a powerful tool to reverse multidrug resistance. Zosuquidar featuring a difluorocyclopropyl-annulated dibenzosuberyl moiety has been found to be an inhibitor of the P-glycoprotein, one of the best-studied multidrug efflux pumps. Twelve 5-oxyisoquinoline derivatives, which are analogues of zosuquidar wherein the dibenzosuberyl-piperazine moiety is replaced by either a diarylaminopiperidine or a piperidone-derived acetal or thioacetal group, have been synthesized as pure enantiomers. Their inhibitory power has been evaluated for the bacterial multidrug-resistance ABC transporter LmrCD and fungal Pdr5. Four of the newly synthesized compounds reduced the transport activity to a higher degree than zosuquidar, being up to fourfold more efficient than the lead compound in the case of LmrCD and about two times better for Pdr5.

Aryl hetaryl ketones and thioketones as efficient inhibitors of peptidyl-prolyl cis-trans isomerases.

A series of 18 differently substituted new aryl hetaryl ketones and thioketones were synthesized in four to six steps from commercial starting materials. The new ketones were evaluated as inhibitors of the peptidyl-prolyl cis-trans isomerase hPin1 with K(i) values ranging in the one-digit micromolar to sub-micromolar numbers. A crystal structure revealed the non-planar arrangement of the aryl residues at the carbonyl compound and supports the hypothesis that the new compounds might mimic the transition state of the enzymatic conversion.

The diaryl(oxy)methyl group: more than an innocent bystander in chiral auxiliaries, catalysts, and dopants.

Either as the free alcohol or deprotonated, a carbinol residue bearing gemial, identical aryl residues can at first sight be recognized as an achiral structural unit. When incorporated, however, into a chiral molecule, the two aryl groups become diastereotopic. Thus, they might contribute to an enhancement in stereoselectivity and do so in a variety of reactions. This Minireview highlights developments in stereochemistry when the diaryl(oxy)methyl group is involved, with emphasis given to the beneficial effect of this moiety. Of particular focus are auxiliaries, the stoichiometric use of metal complexes, metal and organocatalysts, and finally chiral dopants for liquid crystals, all featuring the diaryl(oxy)methyl group.

Enantioselective and diastereoselective Tsuji-Trost allylic alkylation of lactones: an experimental and computational study.

The Tsuji-Trost protocol has been successfully employed for the allylic alkylation of preformed lactone enolates. It has been demonstrated that this Pd-catalyzed reaction can be carried out in an enantio- and diastereoselective manner. The use of additives, such as LiCl, was found to be crucial for reaching high levels of product selectivity. For one particular pair of reactants, density functional theory was used to investigate the mechanism of the nucleophilic addition. Among the five pathways considered, the reaction between an (allyl)Pd(BINAP) complex and a LiCl-lithium enolate adduct is predicted to be the most likely route for C-C bond formation. LiCl plays a key role as the connecting link between the noble metal and the enolate in the kinetically favored transition state. The computed diastereoselectivity ratio is in good agreement with the experimentally observed value.

Stereogenic boron in 2-amino-1,1-diphenylethanol-based boronate-imine and amine complexes.

Racemic boronate-imine and boronate-amine complexes 8 and 10, both featuring a stereogenic boron atom were synthesized from 2-amino-1,1-diphenylethanol (5) and characterized by crystal structure analyses. Proof of enantiomerism at the boron center for the novel boronate-amine complex 10 was established by separation of the enantiomers. Racemization barriers were found to be in the same range for both amine and imine complexes (100-110 kJ/mol).

A calcineurin-independent mechanism of angiogenesis inhibition by a nonimmunosuppressive cyclosporin A analog.

Cyclosporin A (CsA) is a widely used immunosuppressant drug. Its immunosuppressive activity occurs through the inhibition of the protein phosphatase calcineurin via formation of a ternary complex with cyclophilin A (CypA). CsA also inhibits endothelial cell proliferation and angiogenesis. This has been thought to occur through calcineurin inhibition as well. However, CsA is also a potent inhibitor of cyclophilins, a class of prolyl isomerases. Because calcineurin inhibition requires binding, and therefore inhibition of CypA, the relative contributions of calcineurin and cyclophilin inhibition in antiangiogenesis have not been addressed. We have taken a chemical biology approach to explore this question by dissociating the two activities of CsA at the molecular level. We have identified a nonimmunosuppressive analog of CsA that does not inhibit calcineurin but maintains inhibition of endothelial cell proliferation and in vivo angiogenesis. The same analog also maintains inhibition of all cyclophilin isoforms tested. We also show that a second, structurally distinct, cyclophilin inhibitor is sufficient to block endothelial cell proliferation. These results suggest that the inhibition of cyclophilins may play a larger role in the antiangiogenic activity of CsA than previously believed, and that cyclophilins may be potential antiangiogenic drug targets.

Synthesis of benzofuran, benzothiophene, and benzothiazole-based thioamides and their evaluation as K(ATP) channel openers.

Several series of benzofurans, benzothiophenes, and benzothiazoles, all featuring the thioamide group, were synthesized and tested as novel K(ATP) channel openers in artificial cell systems: CHO cells transfected with SUR1/Kir6.2, and HEK 293 cells transfected with SUR2B/Kir6.1; these served as model systems for insulin-secreting pancreatic ß cells and smooth muscle cells, respectively. All compounds were investigated with respect to their binding affinity for the SUR2B-type K(ATP) channels using [(3)H]P1075 as radioligand. Selected compounds were also tested as agonists in intact cells using DiBAC(4)(3) and DyeB (R7260) as membrane potential dyes. Remarkable affinity for SUR2B/Kir6.1 channels in the single-digit micromolar range was observed. In addition, benzothiazole-derived thioamides with sterically demanding, lipophilic substituents showed >100-fold selectivity in favor of SUR2B/Kir6.1. A one-carbon spacer between the heterocyclic skeleton and the thioamide moiety was observed to be crucial for affinity and selectivity. Two of the most potent and selective compounds were studied by crystal structure analyses.

Synthesis of the fluorescent amino acid rac-(7-hydroxycoumarin-4-yl)ethylglycine.

The hydrochloride of the racemic amino acid (7-hydroxycoumarin-4-yl)ethylglycine, a versatile fluorescent probe in proteins, has been synthesized in five steps from commercially available (7-hydroxycoumarin-4-yl)acetic acid. The key step involves the alkylation of a glycine-enolate equivalent.

Synthesis of modified 4H-1,2,4-benzothiadiazine-1,1-dioxides and determination of their affinity and selectivity for different types of K(ATP) channels.

4H-1,2,4-Benzothiadiazine-1,1-dioxides with various substituents in positions 3, 5, and 7 were synthesized and tested as K(ATP) channel agonists in artificial cell systems (CHO cells transfected with SUR1/Kir6.2, and HEK 293 transfected with SUR2B/Kir6.1) as model systems for insulin-secreting pancreatic beta-cells and for smooth muscle cells, respectively. The effects of agonists were tested in intact cells using DiBAC4(3) [bis-(1,3-dibarbituric acid)trimethine oxanol] as a membrane potential dye, and the results compared with their binding affinity for the SUR2B-type K(ATP) channels using the radioligand [(3)H]P1075. Compounds with cycloalkyl and (cycloalkyl)methyl side chains in position 3 had higher affinities towards the SUR2B/Kir6.1 receptor compared with the parent compound diazoxide (1 a). Compounds with bulky, nonpolar residues in position 3 exhibited remarkable selectivity for SUR2B-type K(ATP) channels. The compound substituted with a bulky (1-adamantyl)methyl residue exhibited micromolar affinity and activity on SUR2B-type K(ATP) channels without being able to activate the SUR1-type K(ATP) channels.

Isoform-specific inhibition of cyclophilins.

Cyclophilins belong to the enzyme class of peptidyl prolyl cis-trans isomerases which catalyze the cis-trans isomerization of prolyl bonds in peptides and proteins in different folding states. Cyclophilins have been shown to be involved in a multitude of cellular functions like cell growth, proliferation, and motility. Among the 20 human cyclophilin isoenzymes, the two most abundant members of the cyclophilin family, CypA and CypB, exhibit specific cellular functions in several inflammatory diseases, cancer development, and HCV replication. A small-molecule inhibitor on the basis of aryl 1-indanylketones has now been shown to discriminate between CypA and CypB in vitro. CypA binding of this inhibitor has been characterized by fluorescence anisotropy- and isothermal titration calorimetry-based cyclosporin competition assays. Inhibition of CypA- but not CypB-mediated chemotaxis of mouse CD4(+) T cells by the inhibitor provided biological proof of discrimination in vivo.

Dihydrostilbene derivatives from the Mongolian medicinal plant Scorzonera radiata.

Chromatographic separation of a crude extract obtained from aerial parts of the Mongolian medicinal plant Scorzonera radiata yielded five new dihydrostilbenes, scorzodihydrostilbenes A-E (1-5). The structures were unambiguously elucidated on the basis of one- and two-dimensional NMR ((1)H, (13)C, COSY, HMBC, HMQC, and ROESY) and mass spectrometric data. Compounds 1-5 exhibited antioxidative activity when analyzed in the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay. For 1 and 5 the antioxidant activities were stronger than that of the well-known naturally occurring stilbene antioxidant resveratrol.

Weekly vinorelbine versus docetaxel for metastatic breast cancer after failing anthracycline treatment.

BACKGROUND: Vinorelbine and docetaxel are active in anthracycline-pretreated, metastatic breast cancer. We compared their efficacy. PATIENTS AND METHODS: Patients were randomized to receive weekly vinorelbine (VIN) or weekly docetaxel (DOC), 6 weekly doses per 8-week cycle, with optional crossover (X-DOC vs. X-VIN. The primary end point was time to progression (TTP) on initial treatment. Remission induction, survival, and quality of life were secondary end points. RESULTS: Among 122 poor risk patients, a non-significant trend for better TTP was seen for DOC, both on initial and on crossover treatment. Responses were seen on either treatment, but progression was more common with VIN than with DOC, while more patients had a response with X-DOC than with X-VIN. Survival was identical in those receiving only the initial VIN vs. DOC and in the subgroups receiving crossover treatments. Grade 3-4 toxicity, especially hematological toxicity resulting in treatment delay, was more common with VIN. Non-graded toxicity contributed to abandoning DOC. Quality of life scores reflected worse results in patients crossing treatment arms, in either direction. CONCLUSIONS: DOC showed marginally better activity but did not improve TTP or other endpoints over VIN in this poor risk population.

Novel spiroannulated 3-benzofuranones. Synthesis and inhibition of the human peptidyl prolyl cis/trans isomerase Pin1.

The novel 3H-spiro[1-benzofuran-2-cyclopentan]-3-one skeleton has been made accessible by different routes. One- and two-step protocols lead to tricyclic and tetracyclic benzofuranones 2 and 3, respectively. A four-step synthesis to spirocompound 4 is described. The novel spirocyclic benzofuranones display modest to no inhibition of the human peptidyl prolyl cis/trans isomerase Pin1.

Bis-chelated imine-alkoxytitanium complexes: novel chiral dopants with high helical twisting power in liquid crystals.

Enantiomerically and diastereomerically pure bis-chelated imine-alkoxytitanium complexes 6 and 7 have been synthesized and used as chiral dopants for converting nematic into cholesteric phases. The dopants were tested in mainly commercially available nematic liquid crystalline compounds or mixtures: LC1 (BASF), ZLI-1695 and ZLI-1840 (Merck), as well as N-(4-methoxybenzylidene)-4'-butylaniline (MBBA). The values of the helical twisting power (HTP) were determined by the Grandjean-Cano method. Exceptionally high helical twisting powers were obtained. Thus, the titanium complex 6 h displayed a HTP value of 740 microm(-1) in MBBA, the highest HTP value reported. The helical twisting power has been found to depend strongly on the structure of the nematic phase and the substitution pattern of the chiral ligand in the titanium complexes 6 and 7. Crystal structure analysis of 6 f confirmed the A,R,R configuration of the metal complex. The chiral imine ligands 4 and 5 were derived from the regioisomeric amino alcohols 1 and 2.