PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (1355)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
more »
1.  A Nuclear Receptor Ligand-based Probe Enables Temporal Control of C. elegans Development 
C. elegans development and lifespan are controlled by the nuclear hormone receptor DAF-12, an important model for vertebrate vitamin D and liver-X receptors. Similar to its mammalian homologs, DAF-12 function is regulated by bile acid-like steroidal ligands, the dafachronic acids; however, tools for investigating their biosynthesis and function in vivo are lacking. We report a flexible synthesis for DAF-12 ligands and masked ligand derivatives that enable precise temporal control of DAF-12 function. For ligand masking, we introduce photocleavable amides of 5-methoxy-N-methyl-2-nitroaniline (MMNA). MMNA-masked ligands are bioavailable and after incorporation into the worm can be used to trigger expression of DAF-12 target genes and initiate development from dauer larvae to adults by brief, innocuous UV-irradiation. In-vivo release of DAF-12 ligands and other small-molecule signals using MMNA-based probes will enable functional studies with precise spatial and temporal resolution.
doi:10.1002/anie.201307465
PMCID: PMC4016105  PMID: 24453122
small-molecule signaling; synthesis; steroid hormones; photolysis
2.  Direct Observation of a Photoinduced Radical-Pair Intermediate in a Cryptochrome DASH Blue-Light Photoreceptor 
doi:10.1002/anie.200803102
PMCID: PMC4329312  PMID: 19058271
radicals; EPR spectroscopy; flavins; ET process; photophysics
3.  RhI-Catalyzed Decarbonylative Spirocyclization via C–C Cleavage of Benzocyclobutenones: An Efficient Approach to Access Functionalized Spirocycles 
We describe a rhodium-catalyzed all-carbon spirocenter formation through a decarbonylative coupling of trisubstituted cyclic olefins and benzocyclobutenones via C–C activation. A [Rh(CO)2Cl]2/P(C6F5)3 metal-ligand combination was found to catalyze this transformation most efficiently. A range of diverse spirocyclic rings were synthesized in good to excellent yields and many sensitive functional groups were tolerated. Mechanistic study supports the hydrogen-transfer process that occurs via a β-H elimination/decarbonylation pathway.
doi:10.1002/anie.201310149
PMCID: PMC3970409  PMID: 24446067
C–C activation; homogeneous catalysis; rhodium; spirocycle; decarbonylation
4.  Mismatches Improve the Performance of Strand-Displacement Nucleic Acid Circuits** 
Catalytic hairpin assembly (CHA) has previously proven useful as a transduction and amplification method for nucleic acid detection. However, the two hairpin substrates in a CHA circuit can potentially react non-specifically even in the absence of a singles-stranded catalyst, and this non-specific background degrades signal-to-noise. The introduction of mismatched base-pairs that impede uncatalyzed strand exchange reactions greatly decreased background signal while only partially damping signal in the presence of catalyst. Various types and lengths of mismatches were assayed by fluorimetry and in many instances our MismatCHA designs yielded 100-fold signal-to-background ratios compared to a similar ratio of 4 with the perfectly matched substrates. These observations may prove to be of general utility for the design of non-enzymatic nucleic acid circuits.
doi:10.1002/anie.201307418
PMCID: PMC3983710  PMID: 24402831
Catalyzed hairpin assembly; Mismatch; Signal: background ratio
5.  Nickel-Catalyzed Mizoroki–Heck Reaction of Aryl Sulfonates and Chlorides with Electronically Unbiased Terminal Olefins: High Selectivity for Branched Products** 
Achieving high selectivity in the Heck reaction of electronically unbiased alkenes has been a longstanding challenge. Using a nickel-catalyzed cationic Heck reaction, we were able to achieve excellent selectivity for branched products (≥19:1 in all cases) over a wide range of aryl electrophiles and aliphatic olefins. A bidentate ligand with a suitable bite angle and steric profile was key to obtaining high branched/linear selectivity, while the appropriate base suppressed alkene isomerization of the product. Though aryl triflates are traditionally used to access the cationic Heck pathway, we have shown that by using triethylsilyl trifluoromethanesulfonate (TESOTf), we can effect a counterion exchange of the catalytic nickel complex such that cheaper and more stable aryl chlorides, mesylates, tosylates, and sulfamates can be used to yield the same branched products with high selectivity.
doi:10.1002/anie.201308391
PMCID: PMC4159703  PMID: 24402966
alkenes; Heck reaction; nickel; regioselectivity
6.  [No title available] 
PMCID: PMC4038264  PMID: 24458538
7.  [No title available] 
PMCID: PMC4083751  PMID: 24453187
8.  Covalent Modification of a Cysteine Residue in the XPB Subunit of the General Transcription Factor TFIIH Through Single Epoxide Cleavage of the Transcription Inhibitor Triptolide** 
Triptolide is a key component of the traditional Chinese medicinal plant Thunder God Vine and has potent anticancer and immunosuppressive activities. It is an irreversible inhibitor of eukaryotic transcription through covalent modification of XPB, a subunit of the general transcription factor TFIIH. Cys342 of XPB was identified as the residue that undergoes covalent modification by the 12,13-epoxide group of triptolide. Mutation of Cys342 of XPB to threonine conferred resistance to triptolide on the mutant protein. Replacement of the endogenous wild-type XPB with the Cys342Thr mutant in a HEK293T cell line rendered it completely resistant to triptolide, thus validating XPB as the physiologically relevant target of triptolide. Together, these results deepen our understanding of the interaction between triptolide and XPB and have implications for the future development of new analogues of triptolide as leads for anticancer and immunosuppressive drugs.
doi:10.1002/anie.201408817
PMCID: PMC4314353  PMID: 25504624
inhibitors; medicinal chemistry; natural products; target validation; transcription factors
9.  Spherical Nucleic Acid Nanoparticle Conjugates Enhance G-Quadruplex Formation and Increase Serum Protein Interactions** 
To understand the effect of three-dimensional oligonucleotide structure on protein corona formation, we studied the identity and quantity of human serum proteins that bind to spherical nucleic acid (SNA) nanoparticle conjugates. SNAs exhibit cellular uptake properties that are remarkably different from those of linear nucleic acids, which have been related to their interaction with certain classes of proteins. Through a proteomic analysis, this work shows that the protein binding properties of SNAs are sequence-specific and supports the conclusion that the oligonucleotide tertiary structure can significantly alter the chemical composition of the SNA protein corona. This knowledge will impact our understanding of how nucleic acid-based nanostructures, and SNAs in particular, function in complex biological milieu.
doi:10.1002/anie.201409211
PMCID: PMC4314381  PMID: 25393322
DNA; G-quadruplexes; nanoparticles; protein corona; proteomics
10.  Low Temperature N2 Binding to 2-coordinate L2Fe0 Enables Reductive Trapping of L2FeN2− and NH3 Generation.** 
The 2-coordinate (CAAC)2Fe complex [CAAC = cyclic (alkyl)(amino)carbene] binds dinitrogen at low temperature (T < −80 °C). The resulting putative 3-coordinate N2-complex, (CAAC)2Fe(N2), was trapped by one electron reduction to its corresponding anion [(CAAC)2FeN2]− at low temperature. This complex was structurally characterized and features an activated dinitrogen unit that can be silylated at the β-nitrogen. The redox linked complexes (CAAC)2FeIBArF24, (CAAC)2Fe0 and [(CAAC)2Fe−IN2]− were all found to be active for the reduction of dinitrogen to ammonia upon treatment with reductant (KC8) and acid (HBArF24·2Et2O) at −95 °C (up to 3.4 ±1.0 equivalent of ammonia per Fe center). The N2 reduction activity is highly temperature dependent, with significant N2 reduction to NH3 only occurring below −78 °C. This reactivity profile tracks with the low temperatures needed for N2 binding and an otherwise unavailable electron transfer step to generate reactive [(CAAC)2FeN2]−.
doi:10.1002/anie.201409454
PMCID: PMC4314396  PMID: 25394570
Iron; Nitrogen fixation; Low-coordinate; Carbenes
11.  An Alkoxide-Directed Intermolecular [2+2+1] Annulation: A Three-Component Coupling Reaction for the Synthesis of Tetrasubstituted α,β-Unsaturated γ-Lactams** 
A regio- and stereoselective cross-coupling reaction is described between internal alkynes and imines that provides selective access to allylic amines and γ-lactams.
doi:10.1002/anie.200605060
PMCID: PMC4313383  PMID: 17427164
imines; alkynes; cross coupling; carbometalation; titanium
12.  Ru(II)-Catalyzed Mild [3+2] Carbocyclization with Aromatic N-H Ketimines and Internal Alkynes Using N-Heterocyclic Carbene (NHC) Ligands 
A convenient and highly efficient synthesis of indenamines has been developed via ruthenium-catalyzed [3+2] carbocyclization under very mild conditions. A catalyst system of Ru(II) π-allyl precursor and N-heterocyclic carbene (NHC) ligand promotes facile coupling between aromatic N–H ketimines with internal alkynes at mild temperatures, without added oxidants or other metal salts, and in non-polar solvents. A proposed mechanism involves imine-directed activation of aromatic C–H bond, alkyne insertion, and carbocyclization by intramolecular imine insertion into Ru–alkenyl linkages.
doi:10.1002/anie.201209031
PMCID: PMC4310470  PMID: 23696055
N-H ketimine; indenamine; C-H bond activation; ruthenium; N-heterocyclic carbene
13.  Through-Bond/Through-Space Anion Relay Chemistry (ARC) Exploiting Vinylepoxides as Bifunctional Linchpins** 
The development of new bifunctional linchpins that permits the union of diverse building blocks is essential for the synthetic utility of Anion Relay Chemistry (ARC). Herein, we report the design, synthesis and validation of three vinylepoxide linchpins for through-bond/through-space ARC. For negative charge migration, this class of bifunctional linchpins employs initial through-bond ARC via an SN2′ reaction, followed by through-space ARC exploiting a 1,4-Brook rearrangement. Trans-Disubstituted vinylepoxide linchpin yields a mixture of E/Z-isomers, while cis-disubstituted and trans-trisubstituted vinylepoxide linchpins proceed to deliver three-component adducts with excellent E-selectivity.
doi:10.1002/anie.201309270
PMCID: PMC3969824  PMID: 24375870
through-bond/through-space; anion relay chemistry; vinylepoxides; SN2’ addition; Brook rearrangement
14.  Translocation of Platinum Anticancer Drugs by Human Copper ATPases ATP7A and ATP7B** 
Cisplatin, carboplatin, and oxaliplatin are widely used anticancer drugs. Their efficacy is strongly reduced by development of cell resistance, a phenomenon not entirely understood, with contribution of drug detoxification, defective accumulation, and efflux from the cell. Down-regulation of CTR1, responsible for Cu uptake by the cell, and up-regulation of the Cu-ATPases, ATP7A and ATP7B, which accept Cu from the cytosolic chaperone Atox1 and transfer the metal ion into the secretory pathway where it is incorporated into cuproenzymes, have been associated to augmented drug resistance. To gain information on translocation of Pt drugs by human Cu-ATPases, we performed electrical measurements on COS-1 cell microsomal fraction, enriched with recombinant ATP7A, ATP7B, and selected mutants, adsorbed on a solid supported membrane (SSM). The experimental results demonstrate that Pt drugs activate Cu-ATPases and undergo ATP-dependent translocation with a mechanism identical to that of Cu. We then used NMR spectroscopy and ESI-MS to determine the binding mode of these drugs to the first N-terminal metal binding domain of ATP7A (Mnk1).
doi:10.1002/anie.201307718
PMCID: PMC3937162  PMID: 24375922
platinum drugs; copper ATPases; NMR spectroscopy; charge measurements
15.  [No title available] 
PMCID: PMC3927463  PMID: 24376039
16.  Detection of Protein S-Sulfhydration by a Tag-Switch Technique** 
Protein S-sulfhydration (forming -S-SH adducts from cysteine residues) is a newly defined oxidative posttranslational modification and plays an important role in H2S-mediated signaling pathways. In this study we report the first selective, “tag-switch” method which can directly label protein S-sulfhydrated residues by forming stable thioether conjugates. Furthermore we demonstrate that H2S alone cannot lead to S-sulfhydration and that the two possible physiological mechanisms include reaction with protein sulfenic acids (P-SOH) or the involvement of metal centers which would facilitate the oxidation of H2S to HSC.
doi:10.1002/anie.201305876
PMCID: PMC4306352  PMID: 24288186
hydrogen sulfide; protein S-sulfhydration; signal transduction; tag-switch; thiols
17.  Activation and Retention: MR Probe for Detection of Acute Thrombosis 
doi:10.1002/anie.201308607
PMCID: PMC4041297  PMID: 24338877
disulfide; enzymatic activation; imaging agent; isomerase; thrombus
18.  Investigation of the Structure and Dynamics of the Capsid-Spacer Peptide 1-Nucleocapsid fragment of the HIV-1 Gag Polyprotein by solution NMR spectroscopy** 
Structural studies of HIV-1 Gag, the primary structural polyprotein involved in retroviral assembly, have been challenging owing to its flexibility and conformational heterogeneity. Using residual dipolar couplings we show that the four structural units of the capsid (CA)-spacer peptide 1 (SP1)-nucleocapsid (NC) fragment of HIV-1 Gag (namely, the N- and C-terminal domains of capsid, and the N- and C-terminal Zn-knuckles of nucleocapsid) have the same structures as their individually isolated counterparts, and tumble semi-independently of one another in the absence of nucleic acids. Nucleic acids bind exclusively to the nucleocapsid domain and fix the orientation of the two Zn-knuckles relative to one another so that the nucleocapsid domain-nucleic acid complex behaves as a single structural unit. The low 15N-{1H} heteronuclear NOE values (≤ 0.4), the close to zero values for the backbone amide residual dipolar couplings, and minimal deviations from random coil shifts for the C-terminal tail of capsid and SP1, both in the absence and presence of nucleic acids, indicate that these regions are intrinsically disordered in the context of CA-SP1-NC.
doi:10.1002/anie.201309127
PMCID: PMC4049115  PMID: 24338988
HIV-1; NMR Spectroscopy; Gag; Capsid; nucleocapsid; spacer peptide 1; intrinsically disordered proteins; residual dipolar couplings; conformational dynamics
19.  Visible Light Sensitization of Vinyl Azides by Transition Metal Photocatalysis 
Irradiation of vinyl and aryl azides with visible light in the presence of Ru photocatalysts results in the formation of reactive nitrenes, which can undergo a variety of C–N bond-forming reactions. The ability to use low-energy visible light instead of UV in the photochemical activation of azides avoids competitive photodecomposition processes that have long been a significant limitation on the synthetic utility of these reactions.
doi:10.1002/anie.201308820
PMCID: PMC3905105  PMID: 24281908
azides; nitrenes; nitrogen heterocycles; photocatalysis; visible light
20.  Crowdsourcing Natural Products Discovery to Access Uncharted Dimensions of Fungal Metabolite Diversity** 
A new Tolypocladium sp. was obtained through a crowdsourcing initiative. Triggering the expression of a silent biosynthetic pathway in this fungus was achieved through chemical epigenetics, culture medium manipulation, and co–culture to yield the unique polyketide–shikimate–NRPS–hybrid compound, maximiscin, which demonstrated in vivo antitumor activity.
doi:10.1002/anie.201306549
PMCID: PMC4028707  PMID: 24285637
epigenetics; shikimate-PKS-NRPS; crowdsourcing; Pgp; xenograft cancer
21.  Tunable Visible and Near IR Photoactivation of Light-Responsive Compounds 
doi:10.1002/anie.201308816
PMCID: PMC4036634  PMID: 24285381
Photochemistry; Energy transfer; Drug delivery; Vitamins; Fluorescence
22.  SpyTag/SpyCatcher Cyclization Confers Resilience to Boiling on a Mesophilic Enzyme** 
SpyTag is a peptide which spontaneously forms an amide bond to its protein partner SpyCatcher. Here we fused SpyTag at the N-terminus of β-lactamase and SpyCatcher at the C-terminus, so the partners could cyclize to lock together the termini of the enzyme. Wild-type enzyme aggregates above 37 °C, with irreversible loss of activity. Cyclized β-lactamase was soluble even after heating at 100 °C; after cooling, the catalytic activity was restored. SpyTag/SpyCatcher-cyclization achieved > 60 °C increase in stability, much larger than from point mutation or alternative approaches to cyclization. Cyclized dihydrofolate reductase was similarly resilient. Analyzing unfolding calorimetrically and via mutants, cyclization did not increase the unfolding temperature of β-lactamase, but facilitated refolding after thermal stress. SpyTag and SpyCatcher sandwiching represents a simple and efficient route for enzyme cyclization, with potential to greatly enhance the robustness of biocatalysts.
doi:10.1002/anie.201402519
PMCID: PMC4286826  PMID: 24817566
synthetic biology; protein engineering; enzymes; protein modifications; peptides
23.  Asymmetric Ion-Pairing Catalysis 
Charged intermediates and reagents are ubiquitous in organic transformations. The interaction of these ionic species with chiral neutral, anionic, or cationic small molecules has emerged as a powerful strategy for catalytic, enantioselective synthesis. This review describes developments in the burgeoning field of asymmetric ion-pairing catalysis with an emphasis on the insights that have been gleaned into the structural and mechanistic features that contribute to high asymmetric induction.
doi:10.1002/anie.201205449
PMCID: PMC4284951  PMID: 23192886
anion-binding catalysis; asymmetric catalysis; chiral anions; ion pairs; phase-transfer catalysis
24.  Non-Invasive and in situ Characterization of the Degradation of Biomaterial Scaffolds by Volumetric Photoacoustic Microscopy 
Degradation is among the most important properties of biomaterial scaffolds, which are indispensable for regenerative medicine. The currently used method relies on the measurement of mass loss across different samples and cannot track the degradation of an individual scaffold in situ. Here we report, for the first time, the use of multiscale photoacoustic microscopy to non-invasively monitor the degradation of an individual scaffold. We could observe alterations to the morphology and structure of a scaffold at high spatial resolution and deep penetration, and more significantly, quantify the degradation of an individual scaffold as a function of time, both in vitro and in vivo. In addition, the remodeling of vasculature inside a scaffold can be visualized simultaneously using a dual-wavelength scanning mode in a label-free manner. This optoacoustic method can be used to monitor the degradation of individual scaffolds, offering a new approach to non-invasively analyze and quantify biomaterial-tissue interactions in conjunction with the assessment of in vivo vascular parameters.
doi:10.1002/anie.201306282
PMCID: PMC3894115  PMID: 24130155
inverse opal scaffolds; regenerative medicine; MTT formazan; erosion; blood vessels; photoacoustic imaging
25.  Therapeutic Targeting of Oncogenic K-Ras by a Covalent Catalytic Site Inhibitor** 
We report the synthesis of a GDP analogue, SML-8-73-1, and a prodrug derivative, SML-10-70-1, which are selective, direct-acting covalent inhibitors of the K-Ras G12C mutant relative to wild-type Ras. Biochemical and biophysical measurements suggest that modification of K-Ras with SML-8-73-1 renders the protein in an inactive state. These first-in-class covalent K-Ras inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.
doi:10.1002/anie.201307387
PMCID: PMC3914205  PMID: 24259466
Cancer; Covalent inhibitor; Drug design; K-Ras

Results 1-25 (1355)