Showing papers by "Peter Wipf published in 2001"

Discovery and Biological Evaluation of a New Family of Potent Inhibitors of the Dual Specificity Protein Phosphatase CDC25.

Abstract: 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.

Determining absolute configuration in flexible molecules: a case study.

Abstract: 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.

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

Abstract: 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.

Enantioselective Synthesis of the AB-Ring System of the Antitumor Antibiotic Tetrazomine

Abstract: 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.

Syntheses and methods of use of new antimitotic agents

Abstract: Oxidative cyclization of bis-naphthyl ethers allows concise total syntheses of palmarumycin CP, and deoxypreussomerin A in 8-9 steps and 15-35% overall yield from 5-hydroxy-8-methoxy-1 -tetralone. A small library of palmarumycin analogs was created. Biological evaluation of these naphthoquinone spiroketals against MCF-7 and MDA-MB-23 1 human breast cancer cells revealed several low-micromolar growth inhibitors. A number of the analogs inhibit the thioredoxin -thioredoxin reductase system.

Synthesis and Biological Evaluation of Deoxypreussomerin A and Palmarumycin CP1 and Related Naphthoquinone Spiroketals.

Abstract: Oxidative cyclization of bis-hydroxynaphthyl ethers allows concise total syntheses of palmarumycin CP 1 and deoxypreussomerin A in 8-9 steps and 15–35% overall yield from 5-hydroxy-8-methoxy-1-tetralone ( 8 ). Polymer-bound triphenyl phosphine was found to be a superior reagent for the rapid preparation of a small library of palmarumycin analogs. Preliminary biological evaluation of naphthoquinone spiroketals against MCF-7 and MDA-MB-231 human breast cancer cells revealed several low-micromolar growth inhibitors.

Synthetic Studies Toward Diazonamide A. A Novel Approach for Polyoxazole Synthesis.

Abstract: [Reaction in text]The indole-bisoxazole fragment of diazonamide A was prepared by a Chan-type rearrangement of a tertiary amide. This approach represents a remarkably direct strategy for polyoxazole synthesis.

Sulfonylated Aminothiazoles as New Small Molecule Inhibitors of Protein Phosphatases.

Abstract: 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.

Total Synthesis and Stereochemical Revision of (+)‐Aeruginosin 298‐A.

Abstract: [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.

Methylketene Bis(trimethylsilyl) Acetal

Abstract: [31469-22-4] C9H22O2Si2 (MW 218.44) InChI = 1S/C9H22O2Si2/c1-8-9(10-12(2,3)4)11-13(5,6)7/h8H,1-7H3 InChIKey = IUFWLBQYLXTUFY-UHFFFAOYSA-N (reactive nucleophile in Mukaiyama-type aldol reactions;1, 2 additions to imines7 and enones;8 alkylations with α-halo sulfides;9 α-hydroxylations10) Alternate Name: 1,1-bis(trimethylsilyloxy)propene. Physical Data: bp 63–68 °C/12 mmHg. Solubility: highly sol organic solvents. Preparative Methods: ketene bis(trialkylsilyl) acetals are prepared by silylation of lithium trialkylsilyl carboxylates or treatment of the dianions of carboxylic acids with Chlorotrimethylsilane at −78 °C (eq 1).3 Alternatively, silyl carboxylates are silylated by trialkylsilyl triflates in the presence of Triethylamine.4 (1) Handling, Storage, and Precautions: easily hydrolyzed and oxidized by exposure to air. Storage possible in sealed tubes at rt.

Enantioselective Synthesis of the AB-Ring System of the Antitumor Antibiotic Tetrazomine.

Abstract: 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.

Tandem Zirconocene Homologation—Aldimine Allylation.

Abstract: [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.