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Biomedical subjects

P Wipf

Publications and source records attributed to P Wipf.

At least 19 recordsLinked to original sources
PubMed2001

Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase Cdc25.

The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signaling processes and cell proliferation, but potent and selective inhibitors are lacking. We experimentally examined the 1990 compound National Cancer Institute Diversity Set and then computationally selected from their 140 000 compound repository 30 quinolinediones of which 8 had in vitro mean inhibitory concentrations <1 microM. The most potent was 6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione (NSC 663284), which was 20- and 450-fold more selective against Cdc25B(2) as compared with VHR or PTP1B phosphatases, respectively. NSC 663284 exhibited mixed competitive kinetics against Cdc25A, Cdc25B(2), and Cdc25C with K(i) values of 29, 95, and 89 nM, respectively. As compared with NSC 663284, the regioisomer 7-chloro-6-(2-morpholin-4-ylethylamino)quinoline-5,8-dione was 3-fold less active against Cdc25B(2) in vitro and less potent as a growth inhibitor of human breast cancer cells. Computational electrostatic potential mapping suggested the need for an electron-deficient 7-position for maximal inhibitor activity. Using a chemical complementation assay, we found that NSC 663284 blocked cellular Erk dephosphorylation caused by ectopic Cdc25A expression.

Antineoplastic Agents↗
PubMed2001

New inhibitors of the thioredoxin-thioredoxin reductase system based on a naphthoquinone spiroketal natural product lead.

Natural products of the naphthoquinone spiroketal structural type served as lead structures for the development of novel inhibitors of the thioredoxin-thioredoxin reductase redox system. The most potent compound in this series inhibited thioredoxin with an IC(50) of 350 nM, and many derivatives showed low micromolar activities for growth inhibition against two breast cancer cell lines.

Antineoplastic Agents↗
PubMed2001

Determining absolute configuration in flexible molecules: a case study.

Assigning absolute configuration of molecules continues to be a major problem. Determining absolute configuration in conformationally flexible systems is challenging, even for experts. Here, we present a case study in which we use a combination of molecular modeling, solution NMR, and X-ray crystallography to illustrate why it is difficult to use solution methods alone for configuration assignment. For the case examined, a comparison of calculated and experimental optical rotatory dispersion (ORD) data provides the most straightforward way to assign the absolute configuration.

Benzoates↗
PubMed2001

Tandem zirconocene homologation-aldimine allylation.

[reaction: see text]. Hydrozirconation of internal and terminal alkynes followed by in situ transmetalation to dimethylzinc and treatment with diiodomethane leads to chain extended allylic organometallics. Addition to N-phosphinoyl or N-sulfonyl aldimines provides homoallylic amines in 48-87% yield and 3:2 to >20:1 diastereomeric ratios favoring anti-products.

Journal Article↗
PubMed2001

Water-accelerated tandem Claisen rearrangement-catalytic asymmetric carboalumination.

[reaction: see text] The addition of stoichiometric quantities of water accelerates both the trimethylaluminum-mediated aromatic Claisen reaction and the chiral zirconocene-catalyzed asymmetric carboalumination of terminal alkenes. The two reactions occur in a tandem sequence resulting in the selective formation of two new C-C and one C-O bond after oxidative quench of the intermediate trialkylalane.

Journal Article↗
PubMed2001

Enantioselective synthesis of the AB-ring system of the antitumor antibiotic tetrazomine.

The synthesis of the 1,2,3,4-tetrahydroisoquinoline moiety of tetrazomine was accomplished in 18 steps and in 3% overall yield from commercially available o-anisaldehyde. The reaction sequence utilizes a Sharpless asymmetric dihydroxylation to install the stereocenter and an intramolecular Friedel--Crafts hydroxyalkylation with an N-protected 2-oxo-acetamide to close the heterocyclic ring.

Alkylation↗
PubMed2001

Sulfonylated aminothiazoles as new small molecule inhibitors of protein phosphatases.

Based on a previously identified lead structure, SC-alphaalphadelta9, we have developed a versatile new chemical scaffold that can be readily modified to generate libraries of both Tyr and dual specificity phosphatase inhibitors with reduced molecular weight and lipophilicity. The most potent analogue identified to date, aminothiazole 8z, inhibits the dual specificity phosphatase Cdc25B with a Ki of 4.6+/-0.4 microM and a Hill coefficient of 2.

Cell Cycle Proteins↗
PubMed2001

Antimitotic actions of a novel analog of the fungal metabolite palmarumycin CP1.

The pentacyclic palmarumycins are structurally unique natural products with both antifungal and antibacterial activities but their antineoplastic effects are not well established. We have examined their antiproliferative actions against tumor cells using a temperature-sensitive tsFT210 mouse mammary carcinoma cell line and found that a novel palmarumycin analog, [8-(furan-3-ylmethoxy)-1-oxo-1,4-dihydronaphthalene-4-spiro-2'-naphtho[1",8"-de][1',3'][dioxin] or SR-7, prominently blocked mammalian cell cycle transition in G2/M but not in G1 phase. We found no evidence for inhibition of the critical mitosis-controlling cyclin-dependent kinase Cdk1, or its regulator, the dual specificity phosphatase Cdc25. Moreover, Cdk1 was hypophosphorylated and not directly inhibited by SR-7. SR-7 also failed in vitro to hypernucleate bovine tubulin, did not compete with colchicine for tubulin binding, and only modestly blocked GTP-induced assembly. In addition, SR-7 caused almost equal inhibition of paclitaxel-sensitive and -resistant cell growth. Moreover, unlike benchmark tubulin-disrupting agents, SR-7 did not cause hyperphosphorylation of the antiapoptotic protein Bcl-2. Thus, SR-7 represents a novel chemical structure that can inhibit G2/M transition by a mechanism that appears to be independent of marked tubulin disruption.

Animals↗
PubMed2000

Total synthesis and stereochemical revision of (+)-aeruginosin 298-A.

[structure:see text] Novel routes toward both enantiomers of the bicyclic proline surrogate 2-carboxy-6-hydroxyoctahydroindole, i.e., Choi, were developed on the basis of the oxidative cyclization of L-tyrosine. Synthesis of the proposed sequence of (+)-aeruginosin 298-A did not provide the natural product. Incorporation of a D-leucine residue, in contrast, led to the total synthesis of this thrombin inhibitor.

Antithrombins↗
PubMed2000

Small molecule inhibitors of dual specificity protein phosphatases.

One hallmark of neoplasia is the deregulation of cell cycle control mechanisms, which is secondary to altered protein phosphorylation. Dual specificity protein phosphatases uniquely dephosphorylate both phosphoserines/threonines and phosphotyrosines on the same protein substrate. As a class they regulate intracellular signaling through the mitogen activated and stress activated kinases and govern cellular movement through G1/S and G2/M cell cycle checkpoints by affecting the activity of cyclin-dependent kinases. In particular, the Cdc25 phosphatases, which dephosphorylate cyclin-dependent kinases, are overexpressed in many human tumors and this increased expression is associated with a poor prognosis. In addition to expression levels, the intracellular activity of Cdc25 phosphatases is determined by their subcellular distribution and physical proximity to substrates. Small molecules that either inhibit the catalytic activity or alter the subcellular distribution of these dual specificity protein phosphatases could provide effective tools to interrogate the role of phosphorylation pathways and may afford new approaches to the management of cancer.

Animals↗
PubMed2000

Formal total synthesis of (+)-diepoxin sigma.

The highly oxygenated antifungal anticancer natural product (+/-)-diepoxin sigma was prepared in 10 steps and in 15% overall yield from O-methylnaphthazarin. Highlights of the synthetic work include an Ullmann coupling and a possibly biomimetic oxidative spirocyclization for the introduction of the naphthalene ketal as well as the use of a retro-Diels-Alder reaction to unmask the reactive enone moiety in the naphthoquinone bisepoxide ring system. A novel highly bulky chiral binaphthol ligand was developed for a boron-mediated Diels-Alder reaction that constitutes a formal asymmetric total synthesis of (+)-diepoxin sigma.

Africa↗
PubMed2000

Chiral action at a distance: remote substituent effects on the optical activity of calyculins A and B.

[structure--see text] Calyculins A and B differ only by the (E)- vs (Z)-configuration at C(2). Yet, they show a large difference in optical rotations. We demonstrate a new strategy that provides a physical analysis of this long-range chiro-optical effect by Boltzmann-averaged atomic contribution mapping. The polarizability characteristics of the CN substituent rather than the perturbation of the stereogenic centers or the introduction of asymmetry into the polyene chain give rise to the remarkable difference in rotation angles.

Biological Factors↗