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Biomedical subjects

Helen E Blackwell

Publications and source records attributed to Helen E Blackwell.

15 recordsLinked to original sources
PubMed2006

Tuning peptoid secondary structure with pentafluoroaromatic functionality: a new design paradigm for the construction of discretely folded peptoid structures.

Peptoids, or oligomers of N-substituted glycine, are an important class of non-native polymers whose close structural similarity to natural alpha-peptides and ease of synthesis offer significant advantages for the study of biomolecular interactions and the development of biomimetics. Peptoids that are N-substituted with alpha-chiral aromatic side chains have been shown to adopt either helical or "threaded loop" conformations, depending upon solvent and oligomer length. Elucidation of the factors that impact peptoid conformation is essential for the development of general rules for the design of peptoids with discrete and novel structures. Here, we report the first study of the effects of pentafluoroaromatic functionality on the conformational profiles of peptoids. This work was enabled by the synthesis of a new, alpha-chiral amine building block, (S)-1-(pentafluorophenyl)ethylamine (S-2), which was found to be highly compatible with peptoid synthesis (delivering (S)-N-(1-(pentafluorophenyl)ethyl)glycine oligomers). The incorporation of this fluorinated monomer unit allowed us to probe both the potential for pi-stacking interactions along the faces of peptoid helices and the role of side chain electrostatics in peptoid folding. A series of homo- and heteropeptoids derived from S-2 and non-fluorinated, alpha-chiral aromatic amide side chains were synthesized and characterized by circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. Enhancement of pi-stacking by quadrupolar interactions did not appear to play a significant role in stabilizing the conformations of heteropeptoids with alternating fluorinated and non-fluorinated side chains. However, incorporation of (S)-N-(1-(pentafluorophenyl)ethyl)glycine monomers enforced helicity in peptoids that typically exhibit threaded loop conformations. Moreover, we found that the incorporation of a single (S)-N-(1-(pentafluorophenyl)ethyl)glycine monomer could be used to selectively promote looped or helical structure in this important peptoid class by tuning the electronics of nearby heteroatoms. The strategic installation of this monomer unit represents a new approach for the manipulation of canonical peptoid structure and the construction of novel peptoid architectures.

Amides↗
PubMed2006

Hitting the SPOT: small-molecule macroarrays advance combinatorial synthesis.

The small-molecule macroarray represents a new tool to accelerate combinational library synthesis and screening. This array platform originates from the SPOT-synthesis technique, or the spatially addressed synthesis of peptides on cellulose supports. Recent advances in the field have expanded this technique beyond peptidic systems into the realm of complex small-molecule synthesis. Small-molecule macroarrays offer some significant advantages over traditional combinatorial synthesis platforms--these focused, 50-200 compound arrays are straightforward to synthesize, inexpensive, and amenable to numerous screening applications where the array compounds are either bound to or cleaved from the planar support. Critical advances in the small-molecule macroarray technique are highlighted herein, including the use of microwave-assisted organic reactions, multicomponent reactions, and automated spotting methods to further accelerate and broaden macroarray technology.

Combinatorial Chemistry Techniques↗
PubMed2006

N-[1-(Pentafluorophenyl)ethyl]acetamide.

The title compound, C10H8F5NO, crystallizes as a racemate with four symmetry-independent molecules in the asymmetric unit. The four molecules form two hydrogen-bonded pairs. Each pair is a building unit of an independent C4 chain propagating parallel to the ab plane.

Acetamides↗
PubMed2006

Discovery of fluorescent cyanopyridine and deazalumazine dyes using small molecule macroarrays.

[structure: see text] Small molecule macroarrays of cyanopyridines and deazalumazines were generated in high purities via spatially addressed synthesis on planar cellulose supports. Examination of the spectral properties of the heterocycles both on and off of the planar support revealed a set of promising new fluorescent dyes that exhibit high quantum yields, low pH dependence, and high sensitivity to solvent polarity.

Journal Article↗
PubMed2006

Interception of quorum sensing in Staphylococcus aureus: a new niche for peptidomimetics.

Pathogenesis in Staphylococcus aureus is dependent on local cell density and is regulated in part by small macrocyclic peptides. Natural and artificial peptide inhibitors of this quorum sensing response have been synthesized and evaluated in structure-activity relationship studies. These investigations have illuminated the quorum sensing mechanism and set the stage for the design of biostable, peptidomimetic inhibitors that could be developed ultimately as therapeutics.

Bacterial Proteins↗
PubMed2005

Small molecule macroarray construction via Ugi four-component reactions.

[reaction: see text] We report the construction of small molecule macroarrays via Ugi four-component reactions on planar cellulose supports. Array synthesis was enabled by the development of a high efficiency photocleavable linker system and the strategic use of both water- and microwave-assisted organic reactions.

Cellulose↗
PubMed2005

Small molecule inhibitors of bacterial quorum sensing and biofilm formation.

Bacteria monitor their local population densities using small molecules (or autoinducers) in a process known as quorum sensing. Here, we report a new and efficient synthetic route to naturally occurring bacterial autoinducers [N-acyl l-homoserine lactones (AHLs)] that is readily amenable to the synthesis of analogues. This route has been applied in the first synthesis of a library of non-native AHLs. Evaluation of these compounds in bacterial reporter gene and biofilm assays has revealed a potent set of quorum sensing antagonists. These ligands will serve as valuable new tools to explore the role of quorum sensing in bacterial pathogenesis.

Bacterial Proteins↗
PubMed2005

Expedient synthesis and design strategies for new peptoid construction.

[reaction: see text] A range of peptoids can be prepared efficiently using microwave-assisted solid-phase chemistry in a commercial reactor. This method is most effective for the installation of electronically deactivated benzylic amines. The systematic incorporation of these amines into peptoids can deliver oligomers capable of displaying unique and stable structural motifs-microwave-assisted solid-phase synthesis will enable their future study and application.

Combinatorial Chemistry Techniques↗
PubMed2005

Bacterial crowd control with iron.

Bacterial biofilms account for more than 80% of human infections. Hergenrother and coworkers report in this issue that high concentrations of iron salts can block the formation of these bacterial communities; this represents an attractive new method for biofilm control.

Animals↗
PubMed2004

Microwave-accelerated SPOT-synthesis on cellulose supports.

[reaction: see text] We demonstrate that microwave irradiation can dramatically accelerate reaction rates for spatially addressable library synthesis on planar membrane supports. The development of a robust support/linker system, microwave-assisted synthesis of small molecule test libraries, and methods for solid-phase scale-up on cellulose are described.

Cellulose↗
PubMed2003

SIR1, an upstream component in auxin signaling identified by chemical genetics.

Auxin is a plant hormone that regulates many aspects of plant growth and development. We used a chemical genetics approach to identify SIR1, a regulator of many auxin-inducible genes. The sir1 mutant was resistant to sirtinol, a small molecule that activates many auxin-inducible genes and promotes auxin-related developmental phenotypes. SIR1 is predicted to encode a protein composed of a ubiquitin-activating enzyme E1-like domain and a Rhodanese-like domain homologous to that of prolyl isomerase. We suggest a molecular context for how the auxin signal is propagated to exert its biological effects.

Adenosine Triphosphate↗
PubMed2003

Out of the oil bath and into the oven--microwave-assisted combinatorial chemistry heats up.

The application of microwave irradiation to expedite solid-phase organic reactions could be the tool that allows combinatorial chemistry to deliver on its promise--providing rapid access to large collections of diverse small molecules. Herein, several different approaches to microwave (MW)-assisted solid-phase reactions and library synthesis are introduced, including the use of solid-supported reagents, multicomponent coupling reactions, solvent-free parallel library synthesis, and spatially addressable library synthesis on planar solid supports. The future impact of MW-assisted organic reactions on solid-phase and combinatorial chemistry could prove to be immense, and methods for further improvement of this strategic combination of technologies are highlighted.

Journal Article↗
PubMed2002

Diversity-oriented synthesis of biaryl-containing medium rings using a one bead/one stock solution platform.

Diversity-oriented synthesis of structurally complex and diverse small molecules can be used as the first step in a process to explore cellular and organismal pathways. The success of this process is likely going to be dependent on advances in the synthesis of small molecules having natural product-like structures in an efficient and stereoselective manner. The development, scope, and mechanism of the oxidation of organocuprates was investigated and exploited in the atropdiastereoselective synthesis of biaryl-containing medium rings (9-, 10-, and 11-membered rings). The methodology was performed on high-capacity, large polystyrene beads by metalating aryl bromides with i-PrBu(2)MgLi, followed by transmetalating with CuCN x 2LiBr and then oxidizing with 1,3-dinitrobenzene, and was used in a diversity-oriented synthesis of biaryl-containing medium rings (library total theoretical maximum 1412 members). The high capacity beads were arrayed into 384-well plates and, using a process optimized during the development of a one bead/one stock solution technology platform, converted into arrays of stock solutions, with each stock solution containing largely one compound. These stock solutions were used in numerous phenotypic and protein-binding assays. The process described outlines a pathway that we feel will contribute to a comprehensive and systematic chemical approach to exploring biology (chemical genetics).

Animals↗