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Peter Wipf

Publications and source records attributed to Peter Wipf.

At least 37 records · Page 2Linked to original sources
PubMed2005

The chiroptical signature of achiral metal clusters induced by dissymmetric adsorbates.

Using a dissymmetrically-perturbed particle-in-a-box model, we demonstrate that the induced optical activity of chiral monolayer protected clusters, such as Whetten's Au28(SG)16 glutathione-passivated gold nanoclusters (J. Phys. Chem. B, 2000, 104, 2630-2641), could arise from symmetric metal cores perturbed by a dissymmetric or chiral field originating from the adsorbates. This finding implies that the electronic states of the nanocluster core are chiral, yet the lattice geometries of these cores need not be geometrically distorted by the chiral adsorbates. Based on simple chiral monolayer protected cluster models, we rationalize how the adsorption pattern of the tethering sulfur atoms has a substantial effect on the induced CD in the NIR spectral region, and we show how the chiral image charge produced in the core provides a convenient means of visualizing dissymmetric perturbations to the achiral gold nanocluster core.

Adsorption↗
PubMed2005

Systematic assignment of the configuration of flexible natural products by spectroscopic and computational methods: the bistramide C analysis.

[reaction: see text] The combination of NMR NOE, chemical shift, and J-coupling measurements with molar rotation and circular dichroism (CD) determinations, including RI-DFT BP86/aug-cc-pVDZ calculations, reduced a candidate pool of 1024 possible stereoisomers of (+)-bistramide C to a single absolute configuration assignment for the 10 stereogenic carbons of the marine natural product.

Biological Products↗
PubMed2005

Endo entry to the nortricyclyl-norbornenyl cation system: stereochemistry in the fragmentation of endo-5-norbornenyl-2-oxychlorocarbene.

Fragmentation of (S)-endo-5-norbornenyl-2-oxychlorocarbene [(S)-8] in cyclohexane-d12 gives approximately 20% (S)-endo-2-chloro-5-norbornene [(S)-7] with approximately 50% ee, 65-70% (R)-exo-2-chloro-5-norbornene [(R)-4] with >95% ee, and approximately 12% (R)-3-nortricyclyl chloride [(R)-5] with approximately 22% ee. (Analogous stereochemical results were also obtained starting with the enantiomeric carbene (R)-8.) The (S)-8 to (S)-7 and (S)-8 to (R)-4 conversions are ascribed mainly to retention and inversion S(N)i transition states, respectively. These have been located by computational methods and are nearly isoenergetic. In more polar solvents (CDCl3 and CD3CN), the fragmentation of (S)-8 increasingly occurs via competitive ion pair pathways in which steroselectivity is diminished, and escape to the norbornenyl-nortricyclyl cation directs the products away from endo-2-chloro-5-norbornene toward exo-chloride 4 and nortricyclyl chloride 5.

Journal Article↗
PubMed2005

Transition-metal-mediated cascade reactions: the water-accelerated carboalumination-Claisen rearrangement-carbonyl addition reaction.

[Chemical reaction: See text] A three-step cascade reaction involving a water-accelerated catalytic carboalumination, a Claisen rearrangement, and a nucleophilic carbonyl addition converts terminal alkynes and allyl vinyl ethers into allylic alcohols containing up to three contiguous asymmetric carbon centers. Stoichiometric quantities of water as an additive increase the rate of the [3,3] sigmatropic rearrangement as well as the diastereoselectivity of the carbonyl addition process. Reaction products contain 1,6-diene functionalities that are readily cyclized to substituted cyclopentenes. An extension of this methodology to a sequence involving a [1,3] sigmatropic shift was feasible with a cyclopropylmethyl vinyl ether substrate.

Acetylene↗
PubMed2005

A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach.

Modulating the structure and function of tubulin and microtubules is an important route to anticancer therapeutics, and therefore, small molecules that bind to tubulin and cause mitotic arrest are of immense interest. A large number of synthetic and natural compounds with diverse structures have been shown to bind at the colchicine site, one of the major binding sites on tubulin, and inhibit tubulin assembly. Using the recently determined X-ray structure of the tubulin:colchicinoid complex as the template, we employed docking studies to determine the binding modes of a set of structurally diverse colchicine site inhibitors. These binding models were subsequently used to construct a comprehensive, structure-based pharmacophore that in combination with molecular dynamics simulations confirms and extends our understanding of binding interactions at the colchicine site.

2-Methoxyestradiol↗
PubMed2005

Mitochondrial targeting of selective electron scavengers: synthesis and biological analysis of hemigramicidin-TEMPO conjugates.

Synthetic hemigramicidin S-peptidyl TEMPO conjugates are effectively delivered into cells and mitochondria, where they act as electron scavengers and exert protection against apoptosis. Our delivery approach is based on the use of specific structural signaling features recognizable by cells as mitochondria targeting sequences and offers considerable therapeutic anti-apoptotic potential.

Animals↗
PubMed2005

Redox regulation of Cdc25B by cell-active quinolinediones.

Intracellular reduction and oxidation pathways regulate protein functionality through both reversible and irreversible mechanisms. The Cdc25 phosphatases, which control cell cycle progression, are potential subjects of oxidative regulation. Many of the more potent Cdc25 phosphatase inhibitors reported to date are quinones, which are capable of redox cycling. Therefore, we used the previously characterized quinolinedione Cdc25 inhibitor DA3003-1 [NSC 663284 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] and a newly synthesized congener JUN1111 [7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] to test the hypothesis that quinone inhibitors of Cdc25 regulate phosphatase activity through redox mechanisms. Like DA3003-1, JUN1111 selectively inhibited Cdc25 phosphatases in vitro in an irreversible, time-dependent manner and arrested cells in the G1 and G2/M phases of the cell cycle. It is noteworthy that both DA3003-1 and JUN1111 directly inhibited Cdc25B activity in cells. Depletion of glutathione increased cellular sensitivity to DA3003-1 and JUN1111, and in vitro Cdc25B inhibition by these compounds was sensitive to pH, catalase, and reductants (dithiothreitol and glutathione), consistent with oxidative inactivation. In addition, both DA3003-1 and JUN1111 rapidly generated intracellular reactive oxygen species. Analysis of Cdc25B by mass spectrometry revealed sulfonic acid formation on the catalytic cysteine of Cdc25B after in vitro treatment with DA3003-1. These results indicate that irreversible oxidation of the catalytic cysteine of Cdc25B is indeed a mechanism by which these quinolinediones inactivate this protein phosphatase.

Cell Cycle Proteins↗
PubMed2005

Total synthesis and structure validation of (+)-bistramide C.

The convergent total synthesis of the marine natural product (+)-bistramide C confirms the a priori assignments of its relative and absolute configurations, which were originally based on the combined application of [alpha]D analysis, NMR, and synthesis.

Ethers, Cyclic↗
PubMed2005

A pregnane X receptor agonist with unique species-dependent stereoselectivity and its implications in drug development.

Pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of genes encoding drug-metabolizing enzymes and transporters. In addition to affecting drug metabolism, potent and selective PXR agonists may also have therapeutic potential by removing endogenous and exogenous toxins. In this article, we report the synthesis and identification of novel PXR agonists from a library of peptide isosteres. Compound S20, a C-cyclopropylalkylamide, was found to be a PXR agonist with both enantiomer- and species-specific selectivity. S20 has three chiral carbons and was resolved into its two enantiomers. The individual S20 enantiomers exhibited striking mouse/human-specific PXR activation, whereby enantiomer (+)-S20 preferentially activated hPXR, and enantiomer (-)-S20 was a better activator for mPXR. As a human PXR (hPXR) agonist, (+)-S20 was more potent and efficacious than rifampicin. Mutagenesis studies revealed that the ligand binding domain residue Phe305 is critical for the preference for the (-)-S20 enantiomer by the rodent PXR. Treatment of S20 induced the expression of drug-metabolizing enzymes and transporters in reporter gene assays, in primary human hepatocytes, and in "humanized" hPXR transgenic mice. To our knowledge, S20 represents the first compound whose enantiomers have opposite species preference in activating a xenobiotic receptor. The stereoselectivity may be used to guide the development of safer drugs to avoid drug-drug interactions or to achieve human-specific therapeutic effects when a xenobiotic receptor is being used as a drug target.

Amides↗
PubMed2005

Electrostatic versus steric effects in peptidomimicry: synthesis and secondary structure analysis of gramicidin S analogues with (E)-alkene peptide isosteres.

A concise synthetic strategy was used for the first preparation of GS analogues with trisubstituted (E)-alkene peptide bond replacements. Solution and solid state conformational analysis demonstrated that the bistrifluoromethylated analogue was a superior mimic of the natural product, whereas the incorporation of methyl groups into the alkene peptide isostere led to a far greater perturbation of the secondary structure features of GS. The difference between CF3- and CH3-substitution can be explained by the superior electrostatic carbonyl group mimicry of the former function.

Alkenes↗
PubMed2005

Chemistry and biology of wortmannin.

Recent synthetic and biological studies of the viridin class of steroidal furans have revealed multiple opportunities for fundamental discoveries as well as advanced drug design. Wortmannin is a potent enzyme inhibitor that binds to the ATP site of important regulatory kinases such as PI-3 kinase and Polo-like kinase. The natural product shares a unique mechanism-based biological activation pathway with other viridins. Furthermore, while there have been several encouraging approaches toward the total synthesis of these compounds, there is still ample room for improvements in synthetic strategies and tactics, and the development of structurally simplified analogs that exert more specific biological effects and are devoid of toxicity issues that have thwarted the clinical development of the parent compounds.

Adenosine Triphosphate↗
PubMed2005

Stereochemistry of oxachlorocarbene S(N)i reactions.

[reaction: see text] 3-Nortricyclyloxychlorocarbene and trans-4-methylcyclohexyloxychlorocarbene both fragment in hydrocarbon solvents with extensive loss of stereochemical integrity to the corresponding chlorides via competitive and nearly isoenergetic S(N)i-like transition states.

Journal Article↗
PubMed2005

Three-component synthesis of alpha,beta-cyclopropyl-gamma-amino acids.

[reaction: see text] The multicomponent coupling of alkenylzirconocenes with N-diphenylphosphinoyl imines provides rapid access to functionalized C-cyclopropylalkylamides which have been readily transformed into alpha,beta-cyclopropyl-gamma-amino acids. These novel scaffolds are thus accessible in ca. 8 steps from commercially available alkynes.

Alkynes↗
PubMed2005

Asymmetric total syntheses of tuberostemonine, didehydrotuberostemonine, and 13-epituberostemonine.

Detailed experimental approaches toward the pentacyclic Stemona alkaloids tuberostemonine and didehydrotuberostemonine and the close analogue 13-epituberostemonine are described. The syntheses originate with a hydroindolinone derivative that can be obtained on a large scale in a single step from carbobenzoxy-protected l-tyrosine. Highlights of the conversion of this hydroindolinone to the target structures are the three-fold use of ruthenium catalysts, first in azepine ring-closing metathesis and then in alkene isomerization and cross-metathesis propenyl-vinyl exchange, as well as the stereoselective attachment of a gamma-butyrolactone ring to a tetracycle core structure by use of a lithiated asymmetric bicyclo[3.2.1]octane (ABO) ortho ester. Structural analysis by density functional theory (DFT) methods revealed that the ease of oxidation of the natural product is likely due to the conformational preferences of the pyrrolidine and the fused cyclohexane rings.

Alkaloids↗