Biomedical subjects
Publications and source records attributed to Peter Wipf.
[reaction: see text] 1,3-Azole derivatives of 2-aminocyclohexanecarboxylic acid represent a new class of bidentate ligands for metal-mediated catalytic asymmetric synthesis. N-[2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)cyclohexyl]methanesulfonamide (6) is particularly well suited for the addition of alkylzinc reagents to aliphatic aldehydes in high enantiomeric excess.
After the isolation of the bioactive polyether bistramide C from the marine ascidian Lissoclinum bistratum in 1988, NMR spectroscopic investigations over the next 12 years reduced the total number of possible stereoisomers of this compound from 1024 to 32. Based on the preparation of segments of the natural product as well as the total synthesis of a randomly selected stereoisomer of bistramide C, the stereochemical puzzle could be further simplified to eight possible stereoisomers. A convergent three-segment coupling strategy, the use of a common, D-glucose-derived intermediate for the preparation of pyran rings in two segments, a stereoselective photo-spiroketalization, and the use of azides to minimize protective group manipulations before segment couplings are highlights of the synthetic approach. The total synthesis also provided the key segments for a chiroptical analysis according to van't Hoff's principle of optical superposition, which was crucial for the assignment of a sole relative and absolute configuration of the natural product. Bistramide C represents therefore the first member of this class of structurally unusual marine polyethers whose configuration is known as a result of the combined use of synthetic and chiroptical tools.
Microbial and chemical transformation studies of the marine sesquiterpene phenols (S)-(+)-curcuphenol (1) and (S)-(+)-curcudiol (2), isolated from the Jamaican sponge Didiscus oxeata, were accomplished. Preparative-scale fermentation of 1 with Kluyveromyces marxianus var. lactis (ATCC 2628) has resulted in the isolation of six new metabolites: (S)-(+)-15-hydroxycurcuphenol (3), (S)-(+)-12-hydroxycurcuphenol (4), (S)-(+)-12,15-dihydroxycurcuphenol (5), (S)-(+)-15-hydroxycurcuphenol-12-al (6), (S)-(+)-12-carboxy-10,11-dihydrocurcuphenol (7), and (S)-(+)-12-hydroxy-10,11-dihydrocurcuphenol (8). Fourteen-days incubation of 1 with Aspergillus alliaceus (NRRL 315) afforded the new compounds (S)-(+)-10beta-hydroxycurcudiol (9), (S)-(+)-curcudiol-10-one (10), and (S)-(+)-4-[1-(2-hydroxy-4-methyl)phenyl)]pentanoic acid (11). Rhizopus arrhizus (ATCC 11145) and Rhodotorula glutinus (ATCC 15125) afforded (S)-curcuphenol-1alpha-D-glucopyranoside (12) and (S)-curcudiol-1alpha-D-glucopyranoside (13) when incubated for 6 and 8 days with 1 and 2, respectively. The absolute configuration of C(10) and C(11) of metabolites 7-9 was established by optical rotation computations. Reaction of 1 with NaNO(2) and HCl afforded (S)-(+)-4-nitrocurcuphenol (14) and (S)-(+)-2-nitrocurcuphenol (15) in a 2:1 ratio. Acylation of 1 and 2 with isonicotinoyl chloride afforded the expected esters (S)-(+)-curcuphenol-1-O-isonicotinate (16) and (S)-(+)-curcudiol-1-O-isonicotinate (17), respectively. Curcuphenol (1) shows potent antimicrobial activity against Candida albicans, Cryptococcus neoformans, methicillin-resistant Staphylococcus aureus, and S. aureus with MIC and MFC/MBC ranges of 7.5-25 and 12.5-50 microg/mL, respectively. Compounds 1 and 3 also display in vitro antimalarial activity against Palsmodium falciparium (D6 clone) with MIC values of 3600 and 3800 ng/mL, respectively (selectivity index >1.3). Both compounds were also active against P. falciparium (W2 clone) with MIC values of 1800 (S.I. >2.6) and 2900 (S.I. >1.6) ng/mL, respectively. Compound 14 shows anti-hepatitis B virus activity with an EC(50) of 61 microg/mL.
Dual-specificity protein phosphatases are a subclass of protein tyrosine phosphatases that are uniquely able to hydrolyse the phosphate ester bond on both a tyrosine and a threonine or serine residue on the same protein. Dual-specificity phosphatases have a central role in the complex regulation of signalling pathways that are involved in cell stress responses, proliferation and death. Although this enzyme family is increasingly the target of drug discovery efforts in pharmaceutical companies, a summary of the salient developments in the biology and medicinal chemistry of dual-specificity phosphatases has been lacking. We hope that this comprehensive overview will stimulate further progress in the development of small-molecule inhibitors that could form the basis for a new class of target-directed therapeutic agents.
Small molecules provide powerful tools to interrogate biological pathways but many important pathway participants remain refractory to inhibitors. For example, Cdc25 dual-specificity phosphatases regulate mammalian cell cycle progression and are implicated in oncogenesis, but potent and selective inhibitors are lacking for this enzyme class. Thus, we evaluated 10,070 compounds in a publicly available chemical repository of the National Cancer Institute for in vitro inhibitory activity against oncogenic, full-length, recombinant human Cdc25B. Twenty-one compounds had mean inhibitory concentrations of <1 microM; >75% were quinones and >40% were of the para-naphthoquinone structural type. Most notable was NSC 95397 (2,3-bis-[2-hydroxyethylsulfanyl]-[1,4]naphthoquinone), which displayed mixed inhibition kinetics with in vitro K(i) values for Cdc25A, -B, and -C of 32, 96, and 40 nM, respectively. NSC 95397 was more potent than any inhibitor of dual specificity phosphatases described previously and 125- to 180-fold more selective for Cdc25A than VH1-related dual-specificity phosphatase or protein tyrosine phosphatase 1b, respectively. Modification of the bis-thioethanol moiety markedly decreased enzyme inhibitory activity, indicating its importance for bioactivity. NSC 95397 showed significant growth inhibition against human and murine carcinoma cells and blocked G(2)/M phase transition. A potential Cdc25 site of interaction was postulated based on molecular modeling with these quinones. We propose that inhibitors based on this chemical structure could serve as useful tools to probe the biological function of Cdc25.
Phospholipids and lipid second messengers mediate mitogenic signal transduction and oncogenesis, but there have been few successful examples of small molecules that affect biologically important phospholipid metabolism. Here we investigated the actions of a previously described antitumor agent, 4-(benzyl-(2-[(2,5-diphenyloxazole-4-carbonyl)amino]ethyl)carbamoyl)- 2-decanoylaminobutyric acid (SC-alpha alpha delta 9), which has antisignaling properties, on phospholipases. Although SC-alpha alpha delta 9 had been shown to be a potent and selective inhibitor of the Cdc25 family of dual-specificity phosphatases, many of its cellular effects are not readily reconciled with phosphatase inhibition. Molecular modeling studies suggested that SC-alpha alpha delta 9 shared several structural features with membrane phospholipids. Enzyme inhibition studies in vitro revealed that SC-alpha alpha delta 9 was a potent inhibitor of phospholipase C (PLC; IC50 = 25 microM) but did not inhibit phospholipase D activity at concentrations up to 100 microM. In H-ras (Q61L)-transformed Rat-1 fibroblasts with constitutively elevated levels of phosphorylated extracellular signal-regulated kinase (Erk), SC-alpha alpha delta 9 inhibited both proliferation and oncogenic Erk activation at concentrations that inhibited PLC in vitro. A SC-alpha alpha delta 9 congener that lacked antiproliferative activity also did not inhibit PLC in vitro. In the PLC-dependent scratch wound healing model, SC-alpha alpha delta 9 was 10-fold more potent than the phosphatidylcholine-specific PLC inhibitor D-609. We propose that the structural resemblance of SC-alpha alpha delta 9 to phospholipids allows it to inhibit cellular PLC, thereby providing a possible molecular mechanism for SC-alpha alpha delta 9's effects on oncogenic Erk activation.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
A new protocol for multicomponent condensation reactions that uses fluorous (highly fluorinated) substrates is introduced. This method takes advantage of the ease of purification of fluorous compounds by liquid-liquid extractions between fluorous and organic solvents. The application of this method to the Ugi and Biginelli reactions is described. The condensation products of these two reactions, amino acid amides and dihydropyrimidines, are easily obtained without chromatography in high purities, even though the other reagents are used in very large excesses. This is the first demonstration of the suitability of fluorous phase methods for combinatorial synthesis of "druglike" organic molecules.
Explore the source record for details and available documents.
The structurally novel antimitotic agent curacin A was prepared in 15 steps and in 2.6% yield for the longest linear sequence. Key steps in our synthesis are the use of a hydrozirconation-transmetalation protocol for the preparation of divinyl alcohol 8, the stereoselective formation of the acyclic triene segment 11 via enol triflate chemistry, and a second hydrozirconation of the conjugated triene followed by an isocyanide insertion. For the preparation of the heterocyclic moiety of curacin A, the oxazoline --> thiazoline conversion offered an efficient access to the sensitive marine natural product.
The recently isolated cyanobacterium metabolite muscoride A was synthesized in 15 steps and in 4.3% overall yield. Novel structural features of this peptide antibiotic include the presence of a threonine-derived bioxazole core and an N-(1,1-dimethyl)allyl ("reverse prenyl") valine residue. In the context of our synthesis, efficient new strategies for the preparation of these segments were developed. The synthesis of two epimers of muscoride A allowed the unambiguous assignment of the relative and absolute configuration of the natural product by NMR and optical rotation analyses.
A combinatorial library of oxazolines and thiazolines was synthesized in moderate to excellent yields using a newly developed methodology. Free carboxylic acids were directly condensed with amino alcohols and aminothiols in the presence of 3-nitrophenylboronic acid as a dehydration catalyst. The library synthesis illustrates the scope of this process: After traditional reaction optimization, a total of 17 oxazolines and 6 thiazolines were successfully prepared in a 24-reaction setup in a Radleys GreenHouse parallel synthesizer. The yields of the parallel reactions ranged from moderate to excellent, depending largely on carboxylate reactivity and functionalization, and generally exceeded those of the traditional reaction setup. The target compounds were isolated in high purities (average purity is 96% according to GC analysis) after passing reaction mixtures through short PrepSep SPE Florisil cartridges.
Cascade reactions of internal and terminal alkynes, zirconocene hydrochloride, dimethylzinc, and phosphinoyl imines (prepared in one step from aldehydes and diphenylphosphinoyl amide) lead to allylic phosphinoyl amides after aqueous workup. Microwave acceleration allows the completion of this one-pot reaction sequence in 10 min. These allylic amides can be converted into a variety of derivatives, including carbamates and sulfonamides, or reacted prior to workup with diiodomethane to give novel C-cyclopropylalkylamides. A solution-phase "libraries from libraries" approach was used to generate an intermediate 20-member library which was subsequently expanded to a 100-member library by a series of N-functionalizations. The biological activity was evaluated in an assay for competitive binding to the estrogen receptor (ERalpha), revealing three potent lead compounds of a new structural type.