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Biomedical subjects

Peter Wipf

Publications and source records attributed to Peter Wipf.

At least 73 records · Page 4Linked to original sources
PubMed2004

NAD(P)H:quinone oxidoreductase-1-dependent and -independent cytotoxicity of potent quinone Cdc25 phosphatase inhibitors.

Cdc25 dual-specificity phosphatases coordinate cell cycle progression and cellular signaling. Consequently, Cdc25 inhibitors represent potential anticancer agents. We evaluated >10,000 compounds for inhibition of human Cdc25 phosphatases and identified many potent and selective inhibitors, which all contained a quinone. Bioreductive enzymes frequently detoxify or activate quinones. Therefore, we evaluated the effect of NAD(P)H:quinone oxidoreductase-1 (NQO1) and reductase-rich microsomes on the activity of three quinone-containing Cdc25 inhibitors: 2-(2-hydroxyethylsulfanyl)-3-methyl-1,4-naphthoquinone (Cpd 5, compound 5; NSC 672121), 2,3-bis-(2-hydroxyethylsulfanyl)-1,4-naphthoquinone (NSC 95397), and 6-chloro-7-(2-morpholin-4-yl-ethylamino)quinoline-5,8-dione (NSC 663284). Each inhibitor was reduced by human NQO1 (K(m) of 0.3-0.5 microM) but none by microsomes. Compounds were evaluated with six cancer cell lines containing different amounts of NQO1: HT-29 (1056 nmol/mg/min), HCT116 (660 nmol/mg/min), sublines HCT116-R30A (28 nmol/mg/min) and HCT-116R30A/NQ5 (934 nmol/mg/min), MDA-MB-231/Q2 (null NQO1), and subline MDA-MB-231/Q6 (124 nmol/mg/min) but containing similar amounts of microsomal cytochrome P450 reductase and cytochrome b(5) reductase. Growth inhibition and G2/M arrest by Cpd 5 was proportional to NQO1 levels, requiring 4- to 5-fold more Cpd 5 to inhibit HCT-116 or HCT-116R30A/NQ5 compared with HCT-116R30A. In contrast, in all tested cell lines irrespective of NQO1 level, growth inhibition and G2/M arrest by NSC 95375 and NSC 663284 were similar (average IC(50) of 1.3 +/- 0.3 and 2.6 +/- 0.4 microM, respectively). NSC 95375 and NSC 663284 also caused similar Cdk1 hyperphosphorylation, indicating similar Cdc25 inhibition. However, lower Cpd 5 concentrations were needed to produce Cdk1 hyperphosphorylation in sublines with minimal NQO1. Thus, NQO1 detoxified Cpd 5, probably by reducing it to a less active hydroquinone, whereas NSC 95397- and NSC 663284-generated cytotoxicity was unaffected by NQO1.

CDC2 Protein Kinase↗
PubMed2004

Chemistry and biology of curacin A.

Many natural and synthetic compounds bind to tubulin, an ubiquitous globular protein that provides the building blocks for the cellular microtubule network that controls chromosome segregation during mitosis, vesicle movements, intracellular transport of organelles, ciliar and flagellar movement, and maintenance of cell shape. Since the isolation of the antimitotic marine natural product curacin A in 1994, synthetic work on this colchicine-site binding agent has been intense, but only recently have synthetic derivatives been identified that match its potency for tubulin polymerization inhibition and its high level of growth inhibition in cancer cell lines. In addition to several total synthesis efforts, combinatorial libraries were constructed using solution phase and fluorous scavenging approaches. Low water-solubility and lack of chemical stability represent strong detriments for the clinical development of curacin A, but synthetic analogs with improved bioavailability might ultimately probe the paradigm for anticancer efficacy of colchicine-site tubulin binding agents.

Animals↗
PubMed2004

Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling.

We have developed biologically stable semisynthetic viridins as inhibitors of phosphoinositide (PtdIns)-3-kinases. The most active compound was PX-866 (acetic acid (1S,4E,10R,11R,13S,14R)-[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7,17-trioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester), which inhibited purified PtdIns-3-kinase with an IC50 of 0.1 nmol/L and PtdIns-3-kinase signaling measured by phospho-Ser473-Akt levels in HT-29 colon cancer cells with an IC50 of 20 nmol/L. PX-866 administered to mice at 10 mg/kg inhibited phospho-Ser473-Akt in HT-29 colon tumor xenografts up to 80% with recovery taking >48 hours after p.o. administration but more rapidly after i.v. or i.p. administration. PX-866 was eliminated from mouse plasma with a half-life of 18 minutes and a clearance of 360 mL/min/kg following i.v. administration and, when administered i.p. or p.o., showed first-pass metabolism with sequential N-deallylation. Synthetic standards of the N-deallylated metabolites of PX-866 inhibited PtdIns-3-kinase at low nanomolar per liter concentrations. PX-866 exhibited in vivo antitumor activity against s.c. OvCar-3 human ovarian cancer and A-549 human lung cancer xenografts in immunodeficient mice with log cell kills up to 1.2. PX-866 also increased the antitumor activity of cisplatin against A-549 xenografts and radiation treatment against OvCar-3 xenografts. The results show that PX-866 is a biologically stable broad-spectrum PtdIns-3-kinase inhibitor with good pharmacokinetics that causes prolonged inhibition of PtdIns-3-kinase signaling in human tumor xenografts. PX-866 exhibits single agent in vivo antitumor activity and increases the antitumor effects of cisplatin and radiation treatment.

Androstadienes↗
PubMed2003

Optical rotation of noncovalent aggregates.

Dilute solutions of (R)-(-)-pantolactone in CCl4 were studied by polarimetry in conjunction with theoretical calculations of [alpha]D. Our data demonstrate that the self-association of a chiral solute results in a change in [alpha]D that can be accounted for by the presence of hydrogen-bonded dimeric species. The theoretical analysis predicts a concentration-dependent specific rotation in good agreement with experiment. Further exploration of monomer and dimer [alpha]D differences, through atomic map analysis, reveals large contributions to [alpha]D from the hydrogen-bonded hydroxyl groups in the tightly-coupled dimer. This study extends the computation of chiroptical properties to the accurate concentration-dependent prediction of [alpha]D for noncovalently interacting self-associating species.

4-Butyrolactone↗
PubMed2003

Transition-metal-mediated cascade reactions: C,C-dicyclopropylmethylamines by way of double C,C-sigma-bond insertion into bicyclobutanes.

The organometallic multicomponent reaction of alkenyl zirconocene, alkynyl imine, and zinc carbenoid in the presence of dimethylzinc leads to novel C,C-dicyclopropylmethylamines. The formation of intermediate bicyclo[1.1.0]butanes represents the first synthetically useful example of a double C,C-sigma-bond insertion, and the increase in structural complexity from starting materials is highlighted by the formation of nine new C,C-bonds in the final product.

Journal Article↗
PubMed2003

Photoactivated tungsten hexacarbonyl-catalyzed conversion of alkynols to glycals.

The photoactivated W(CO)(6)/DABCO/THF system has been used for the formal endo-cyclization of alkynes to pyran rings. We found that the regioselectivity of ring closure depends on the relative configuration of the 3,5-dihydroxy-1-alkynes, as well as, more decisively, on the type of O-protective group. Oxygen substitution at the propargylic carbon slows the rate of alkyne insertion and allows for dihydrofuran formation through exo-cyclization. In contrast, the use of bulky silyl ethers or carbon substituents leads to dihydropyrans through endo-cyclization. Substrates bearing leaving groups such as esters, phenols, or thiophenols at the propargylic site eliminate and thus represent a limitation to the cycloisomerization methodology. Propargyl vinyl ethers will rearrange to give dienals instead of glycals. 1,2-Wittig rearrangement products of dihydropyrans are readily prepared and converted to complex bicyclic building blocks for organic synthesis.

Alcohols↗
PubMed2003

Dimethylzinc-mediated addition of alkenylzirconocenes to alpha-keto and alpha-imino esters.

[reaction: see text] Hydrozirconation of alkynes followed by in situ transmetalation to dimethylzinc and 1,2-addition to activated ketones and N-diphenylphosphinoylimines leads to tertiary allylic alcohols and amines in high overall yield. With 8-phenylmenthol as the chiral auxiliary, si-face attack proceeds in good to excellent diastereoselectivities.

Journal Article↗
PubMed2003

Dimethylzinc-mediated additions of alkenylzirconocenes to aldimines. New methodologies for allylic amine and C-cyclopropylalkylamine syntheses.

Hydrozirconation of alkynes with zirconocene hydrochloride followed by in situ transmetalation to dimethylzinc provides access to reactive alkenyl organometallic reagents from readily available precursors. Upon addition of imines, 1,2-attack leads to synthetically useful allylic amine building blocks. In the presence of CH(2)I(2) or CH(2)Cl(2), the N-metalated allylic amide intermediate is cyclopropanated and C-cyclopropylalkylamines are formed in high yield and excellent diastereoselectivities favoring the anti products. The use of enynes as starting materials for this domino reaction provides conjugated biscyclopropanes and thus allows the stereoselective formation of five new carbon-carbon bonds. A transition state that explains the need for both zirconocene complex and alkyl zinc in the cyclopropanation reaction is proposed.

Journal Article↗
PubMed2003

On the role of chiral catalysts in the alkenyl zirconocene/zinc addition to aldehydes: a study of ligand loading and asymmetric amplification.

Unusual nonlinear asymmetric amplification and chiral ligand loading effects were discovered for the use of catalytic quantities of chiral aminoalcohols in the in situ hydrozirconation-transmetalation-aldehyde addition processes. While the stereochemically most efficient aminothiol ligands demonstrated mechanistically conventional reaction parameters in excellent agreement with Kagan's ML(2) system, the asymmetric induction in the presence of a chiral aminoalcohol was found to vary greatly with loading and %ee of the ligand. Aminothiols remain the ligands of choice for the highly enantioselective formation of allylic alcohols and provide experimentally more predictable reaction variables. However, new, optimized conditions lead to a synthetically useful product %ee using the readily available and scalable aminoalcohol 2a.

Journal Article↗
PubMed2003

Cell-active dual specificity phosphatase inhibitors identified by high-content screening.

Phosphorylation of extracellular signal-regulated kinase (Erk) is tightly controlled by dual specificity phosphatases (DSPases), but few inhibitors of Erk dephosphorylation have been identified. Using a high-content, fluorescence-based cellular assay and the National Cancer Institute's 1990 agent Diversity Set, we identified ten compounds (0.5%) that significantly increased phospho-Erk cytonuclear differences in intact cells. Three of the ten positive compounds inhibited the mitogen-activated protein kinase phosphatase-3 (MKP-3/PYST-1) in vitro without affecting VHR or PTP1B phosphatases. The most potent inhibitor of MKP-3 had an IC(50) of <10 microM and inhibited MKP-3 in a novel, fluorescence-based multiparameter chemical complementation assay. These results suggest that the phospho-Erk nuclear accumulation assay may be a useful tool to discover DSPase inhibitors with biological activity.

Animals↗
PubMed2003

Structure reassignment of the fungal metabolite TAEMC161 as the phytotoxin viridiol.

Two-dimensional NMR analyses including HMBC, NOESY, and ROESY as well as 1D NOE experiments led to a reassignment of the structure of the recently identified Trichoderma hamatum metabolite TAEMC161 (1) as the previously known viridiol (2). In addition, GIAO-calculated (13)C NMR chemical shifts of 1 and 2 provided strong support for the revised structure.

Androstenediols↗
PubMed2003

Small molecule regulation of phosphatase-dependent cell signaling pathways.

Small molecules provide exceptionally useful tools for probing signaling targets relevant for cancer and stem cell differentiation. In contrast to genetic approaches, the application of small molecules generally offers a graded and reversible disruption of a particular pathway. The vast array of theoretical chemical entities that exist in the chemical universe are now becoming available through the production and distribution of chemical libraries generated by both traditional and combinatorial methods, which are suitable for pharmacological use. Convenient and inexpensive cell-free and cell-based assays can be used to identify chemicals that exhibit desirable antisignaling properties. We illustrate a model of how agents targeted against signaling macromolecules involved in cancer, namely dual specificity protein phosphatases, can be identified.

Antineoplastic Agents↗
PubMed2002

Total synthesis of (-)-tuberostemonine.

The first total synthesis of the complex pentacyclic Stemona alkaloid tuberostemonine was accomplished in 24 steps and in 1.4% overall yield from a hydroindole intermediate which is readily obtained in three steps from Cbz-l-tyrosine. An innovative synthetic strategy was applied that relays the single stereocenter of the amino acid precursor into nine of the ten stereogenic carbons of the target molecule. Among the highlights of the synthetic methodology are the 3-fold use of ruthenium catalysis, first in an azepine ring-closing metathesis and then in an alkene isomerization followed by a cross-metathesis propenyl-vinyl exchange, as well as the stereoselective attachment of the gamma-butyrolactone moiety to the core tetracycle by use of a lithiated ortho ester.

Alkaloids↗
PubMed2002

Synthesis and biological evaluation of structurally highly modified analogues of the antimitotic natural product curacin A.

Structure-activity relationship analysis of synthetic analogues of curacin A revealed the lack of activity of traditional heterocyclic replacements of the thiazoline ring or cyclopropyl analogues of the core diene segment. The significance of the C(3)-C(4)-(Z)-alkene geometry was established, and a novel oxime analogue was designed that displays biological properties that are a close match of the natural product lead. The much less lipophilic, structurally simplified oxime 50 was only slightly weaker at inhibiting the growth of cultured human tumor cells than the natural product and was found to be more potent than curacin A at inhibiting the assembly of purified tubulin. Accordingly, the oxime moiety is likely to serve as a novel bioisostere of the (Z)-alkene group.

Antineoplastic Agents↗
PubMed2002

Novel applications of alkenyl zirconocenes.

Alkenyl zirconocene complexes are readily obtained by diverse processes including hydrozirconation, carbozirconation, and cyclozirconation of alkynes, transmetalations, and bond insertions. In combination with other metals, novel reaction manifolds can emerge and provide access to useful synthetic building blocks. Both catalytic asymmetric processes and highly diastereoselective multicomponent transformations that involve the formation of three or more new carbon-carbon bonds are feasible. This Concept paper summarizes the current state of the art and opportunities for future reaction discovery in this field of research, with particular emphasis on synergistic effects of bimetallic combinations of zirconocenes and zinc.

Journal Article↗