WorldCat Identities

Hergenrother, Paul J.

Overview
Works: 71 works in 76 publications in 1 language and 92 library holdings
Roles: Author
Publication Timeline
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Most widely held works by Paul J Hergenrother
Introduction to chemical biology by Paul M Hergenrother( Book )

4 editions published between 2010 and 2011 in English and held by 11 WorldCat member libraries worldwide

Preparative and mechanistic aspects of palladium-catalyzed cross-coupling reactions of alkali-metal arylsilanolates by Russell C Smith( )

1 edition published in 2010 in English and held by 2 WorldCat member libraries worldwide

The development of alkali-metal arylsilanolates as notable organometallic reagents for the preparation of biaryls has been realized through in depth mechanistic and preparative studies. The alkali-metal salts (potassium and sodium) of a large number of arylsilanols undergo smooth cross-coupling with a wide range of aromatic bromides and chlorides. The critical feature for the success of these coupling reactions and their considerable scope is the use of bis(tri-tert-butylphosphine)palladium. Additionally, these studies have identified the use of phosphine oxides (e.g. triphenylphosphine oxide) as useful ligands for palladium-catalyzed cross-coupling reactions. This serendipitous discovery was founded on kinetic experiments which revealed a significant rate enhancement employing these species as ligands for palladium. Later, these ligands were implemented in the reaction of arylsilanolates for the preparation of biaryl products. The mechanism of palladium-catalyzed cross-coupling reactions of alkali-metal organosilanolates has also been investigated. Under catalysis by (t-Bu3P)2Pd, the coupling with aryl bromides displays the following rate equation: rate = kobs[R3SiOK]0[ArylBr]0, with kobs = k[(t-Bu3P)2Pd]0.98. An independent study of the individual steps of the catalytic cycle has revealed a dual mechanistic pathway. The transmetalation can occur by a thermal process via an 8-Si-4 intermediate without the need for anionic activation. Additionally, arylsilanolates can serve as activators for transmetalation via a hypervalent 10-Si-5 siliconate intermediate. The independent isolation of the putative arylpalladium(II) arylsilanolate intermediate has confirmed the generation of the Pd-O-Si linkage prior to transmetalation. The unique opportunity to isolate a pretransmetalation intermediate has allowed the transmetalation step to be further refined through a detailed Hammett analysis which has demonstrated that increased electron-density about the arylsilanolate nucleophile increases the rate of coupling. Furthermore, a number of alkenyl- and arylsilanolate pretransmetalation species have been isolated with various ligands in attempts to identify the critical features of the cross-coupling of this class of organonucleophiles
Complex botanical natural products: Synthesis of cephalotaxus esters and of the C19-diterpenoid skeleton of aconitum and delphinium alkaloids by Jeremy T Wilmot( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

Small Molecule Activation of Procaspase-2 for the Selective Induction of Apoptotic Death in Breast Cancer Cells( Book )

2 editions published in 2007 in English and held by 2 WorldCat member libraries worldwide

We have synthesized a library of compounds based on a previously identified procaspase-2 activator. These compounds were then tested for their ability to activate procaspase-2 in vitro. The results from these tests indicated that several of the compounds did indeed activate procaspase-2. Testing of these active compounds against a panel of enzymes then revealed, surprisingly, that the compounds are general enzyme activators. We have now explored this phenomena of general enzyme activation more thoroughly and have submitted a manuscript on the topic. The data and knowledge acquired through this work now allows us to move confidently to a high-throughput screen to identify truly specific procaspase-2 activators
Oxidative Heck Reactions with Terminal Olefins by Jared H Delcamp( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

Direct procaspase-3 activation as an anti-cancer strategy : compound discovery, mechanism of action, and a phase I canine clinical trial by Paul J Hergenrother( Visual )

1 edition published in 2010 in English and held by 2 WorldCat member libraries worldwide

Elucidation of the mycosamine dependent sterol binding and antifungal activities of amphotericin B by Daniel S Palacios( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

Amphotericin B (AmB) is a clinically vital, yet highly toxic antifungal agent that is dependent on the presence of membrane sterols to exert its biological activity. This natural product has been shown to form ion channels in model membrane systems and therefore represents a molecule with the capacity to perform protein-like function, i.e. the formation of a transmembrane ion channel. Efforts to improve the therapeutic index of AmB or harness its potential to act as a molecular prosthetic to treat diseases that arise from a lack of protein function would benefit from an atomistic understanding of the mechanism of action. To elucidate this poorly understood mechanism, we developed a strategy focused upon the synthesis-enabled deletion of functional groups from the macrolide skeleton followed by determination of the biological and biophysical consequences. The first functional groups we targeted for deletion were the carboxylic acid and the mycosamine sugar appendages. Both of these functional groups had been predicted to be critical for the following roles: 1) stabilizing ion channel formation via an intermolecular salt-bridge interaction, 2) anchoring AmB to phospholipid bilayers and 3) binding to sterols. However, an alternative hypothesis states that AmB does not directly bind sterols but rather that sterol-induced global membrane properties are the source of the sterol dependency of AmB. This debate has been ongoing since the early 1970⁰́₉s and had yet to be resolved at the time this work began. The functional group deletion strategy proved to be remarkably effective. Ultimately, we found that polar interactions between the acid and mycosamine are not required for ion channel formation or antifungal activity. In addition, we found that electrostatic interactions between the acid and/or mycosamine and the zwitterionic phospholipid headgroup are not required for AmB to partition into phospholipid bilayers. Finally, it was discovered that AmB directly binds ergosterol and cholesterol and that the mycosamine appendage is strictly required for this binding interaction. Furthermore, this binding interaction was shown to be absolutely required for forming ion channels and killing yeast cells. Consequently, the long contentious theory that AmB and membrane sterols participate in a functionally vital small molecule-small molecule interaction was finally confirmed. Based upon these results, and related studies with another natural product, natamycin, we proposed a novel, potentially general, two mechanism model to account for AmB⁰́₉s potent antifungal activity. These discoveries provide a foundation for the more effective utilization of AmB and demonstrate the capacity of synthetic organic chemistry to illuminate even the most elusive aspects of small molecule function
Development and Mechanistic Characterization of Novel Small Molecules as Cancer Therapeutics by Rahul Palchaudhuri( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

The discovery and development of novel small molecules as anti-cancer agents plays an integral role in the fight against cancer. Such efforts will lead to the development of the therapies of tomorrow. Potentially useful molecules may be discovered through cell-based toxicity screens, enzyme-based in vitro screens or developed from computational design against proteins of interest. The elucidation of the mechanism of action of small molecules discovered in cell-based screens remains a challenging endeavor. Whole genome transcript profiling and genome-wide shRNA screens are tools that have recently become available to the researcher and their use in aiding mechanism elucidation is reviewed in Chapter 1. Also presented herein is the development and investigation of the mechanism of action of several novel small molecules that exhibit anti-cancer activity. Genome-wide technologies are employed to characterize the mechanism of several of these molecules. Chapter 2 focuses on the mechanism of a rapid inducer of caspase-dependent apoptosis. Chapters 3 and 4 investigate novel triphenylmethyl containing anticancer agents and compare their mechanisms of action to known agents. The development of lactate dehydrogenase-A (LDH-A) inhibitors as a novel anticancer strategy is discussed in Chapter 5. In Chapter 6, the mode of action of anti-cancer quinones is described. And finally, the discovery of triazole-containing small molecules as tubulin-targeting agents is narrated in Chapter 7
Cross-modulatory Actions of Cell Cycle Machinery on Estrogen Receptor-alpha Level and Transcriptional Activity in Breast Cancer Cells by Shweta Bhatt( )

1 edition published in 2010 in English and held by 2 WorldCat member libraries worldwide

Computational and synthetic approaches in the design and development of chemical probes for estrogen receptor function by Christopher G Mayne( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

Development, characterization and applications of a direct, general method to photochemically generate patterns and gradients on planar glass substrates, corrugated substrates and in highly porous collagen-GAG scaffolds by Teresa A Martin( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

Recent surface chemical approaches to physically modeling the extra-cellular matrix (ECM) have provided invaluable insight into the molecular nature of cell adhesion and have clearly established the contributions of altered cell adhesion to disease onset and progression. In order to better understand the complex relationships between the many molecules involved in cell adhesion, we have developed a general method to create multi-component biological surface gradients that present multiple, distinct adhesive molecules onto planar substrates, corrugated substrates and the surface of collagen-GAG scaffolds at varied concentrations, and in defined geometric patterns. In our approach the generation of a light density gradient across a photo-active benzophenone monolayer will form covalent linkages between a solution phase biomolecule and the surface, resulting in the transfer of the photon gradient to a biomolecular gradient. The method is promising for the direct generation of complex, multi-component patterns or gradients of biomolecules, which may serve as biomolecularly relevant models of the ECM. Future work will focus on applying multi-component biomolecular patterns and gradients to investigations of cell adhesion, migration, proliferation, and differentiation
RNA recognition: controlling RNA-protein complexes with small molecules by Sreenivasa Rao Ramisetty( )

1 edition published in 2010 in English and held by 2 WorldCat member libraries worldwide

ABSTRACT PART I. Investigation of Small Molecule Binding to an RNA Hairpin Loop Containing a Dangling End PART II. Unraveling the Interaction of Pathogenic RNAs with the MBNL1 Protein and Complex Inhibition by Small Molecules PART I. RNA plays important and versatile roles in gene expression by both carrying and regulating the information used to direct protein synthesis. Therefore, small molecules able to bind to RNA and alter these biological processes would be of great utility. This part of my thesis describes the virtual screening and identification of a quinoline derivative binding cooperatively to a GCAA RNA tetraloop containing a 3⁰́₉ dangling end (tGCAA). The compound NSC5485 (QD2) was identified by performing a similarity search of the NCI database of 250,000 compounds and using the program AutoDock 3. Fluorescence and ITC experiments revealed that QD2 binds cooperatively to four identical binding sites on tGCAA RNA hairpin. The equilibrium binding dissociation constant of the four identical binding sites is 8.2 (±0.4) ℗æM. CD spectroscopy and UV titration experiments suggested that binding of QD2 changes the conformation of RNA and perturbs the QD2 chromophore. PART II. Trinucleotide repeat expansions are the genetic cause of numerous human diseases, including Huntington⁰́₉s disease, Fragile X mental retardation, and myotonic dystrophy type 1. Myotonic dystrophy (DM1 and DM2) is an autosomal dominant neuromuscular disorder associated with a (CTG)n and (CCTG)n expansion in the 3⁰́₉-untranslated region of the Dystrophia Myotonica protein kinase (DMPK) gene. The disease is characterized by a waning of the muscles (muscular dystrophy), eye-lens opacity and myotonia. The pathogenic poly(CUG)RNA and poly(CCUG)RNA binds to and sequesters key proteins, such as MBNL1 (muscleblind-like protein 1), preventing them from regulating proper splicing of different pre-mRNAs. The severity of disease correlates with the length of the repeat tract in peripheral blood. The first part of this project is about investigating the interaction of the MBNL1N protein with poly(CUG)RNA. We are interested in identifying important amino acids or zinc finger domains involved in recognition of MBNL1N protein to poly(CUG)RNA. To address this question we did alanine scanning for six amino acids and expressed truncated versions of the protein and studied their interaction with MBNL1N protein by gel-shift assays. In the second part, the inhibition of complexes formed between the toxic poly(CUG)RNA or poly(CCUG) RNA with MBNL1 protein by a small molecules has been shown by gel-shift assays. We identified small molecules containing triaminotriazine-acridine and triaminopyrimidine-acridine conjugates which can specifically inhibit (CUG)12 and (CCUG)6 complexes with MBN1N protein, respectively. Thus the compounds triaminotriazine-acridine and triaminopyrimidine-acridine conjugates are potential lead compounds for targeting DM1 and DM2, respectively
Chemical diversification and anticancer activity of natural products by Karen Morrison( )

1 edition published in 2013 in English and held by 1 WorldCat member library worldwide

Linear allylic C-H oxidation: methods and utility by Nicolaas Vermeulen( )

1 edition published in 2012 in English and held by 1 WorldCat member library worldwide

A comparison of resultant fibrils upon environmental and sequential manipulations of [alpha]-synuclein, a Parkinson's disease associated protein by Luisel Lemkau( )

1 edition published in 2012 in English and held by 1 WorldCat member library worldwide

Deoxyribozymes for peptide substrates: exploring the landscape of nucleophiles and electrophiles by Amit Sachdeva( )

1 edition published in 2012 in English and held by 1 WorldCat member library worldwide

Small molecule activators of procaspase-3 as an anticancer strategy by Quinn P Peterson( )

1 edition published in 2012 in English and held by 1 WorldCat member library worldwide

Unraveling the interactions between MBNL1 protein and its RNA targets by Yuan Fu( )

1 edition published in 2012 in English and held by 1 WorldCat member library worldwide

Improving the process synthesis, potency, and pharmacokinetics of the anticancer compound PAC-1 by Howard Steven Roth( )

1 edition published in 2015 in English and held by 1 WorldCat member library worldwide

Chemical diversification of the natural products quinine, abietic acid and pleuromutilin by ring distortion by Robert W Hicklin( )

1 edition published in 2015 in English and held by 1 WorldCat member library worldwide

Ring distortion reactions directly alter the core ring systems of small molecules and can lead to striking changes in molecular structure. Strategic application of ring distortion reactions to complex molecules, such as natural products, is an effective method for the generation of compounds that exhibit significant molecular complexity, but possess vastly different molecular structures. The compounds produced by this complexity to diversity approach are advantageous starting points for the discovery of new biologically active compounds, as they possess a level of molecular complexity found in approved drugs but lacking in other screening collections used in drug discovery. The chapters herein emphasize the utility of ring distortion reactions for modifying complex molecules and assert the potential of ring distortion as strategy for the synthesis of complex and diverse small molecules. Chapter 1 defines the different methods of ring distortion and demonstrates how these reactions can be employed for the selective modification of complex molecules. Chapter 2 focuses on the application of ring distortion reactions to the cinchona alkaloid natural product quinine towards the creation of a collection of complex and diverse small molecules. Chapter 3 details the ring distortion of the terpene natural product abietic acid and details strategies for the synthesis of derivative libraries from the products of ring distortion. Chapter 4 describes on the ring distortion of the terpene natural product pleuromutilin and the discovery of a pleuromutilin-derived compound with anticancer activity
 
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English (24)