Multiple simultaneous synthesis of phenolic libraries

Meyers, Harold V.; Dilley, Garrett J.; Durgin, Tracy; Powers, Timothy S.; Winssinger, Nicolas; Zhu, Haifei; Pavia, Michael R.

doi:10.1007/bf01715805

“…Chain assembly of S100A12 38 -53 (KELANTIKNIKDKAVI) and its alanine scan mutants (24) was performed manually as described (25). Endotoxin levels in all preparations were Ͻ10 pg/10 g using the chromogenic limulus amebocyte lysate assay (Cape Cod Associates, Woods Hole, MA).…”

Section: Methodsmentioning

confidence: 99%

Mast Cell and Monocyte Recruitment by S100A12 and Its Hinge Domain

Yan

¹

,

Armishaw

²

,

Goyette

³

et al. 2008

Journal of Biological Chemistry

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S100A12 is expressed at sites of acute, chronic, and allergic inflammation. S100 proteins have regions of high sequence homology, but the "hinge" region between the conserved calcium binding domains is structurally and functionally divergent. Because the murine S100A8 hinge domain (mS100A8 [42][43][44][45][46][47][48][49][50][51][52][53][54][55] ) is a monocyte chemoattractant whereas the human sequence (hS100A8 [43][44][45][46][47][48][49][50][51][52][53][54][55][56] ) is inactive, we postulated that common hydrophobic amino acids within the S100A12 hinge sequence may be functional. The hinge domain, S100A12 38 -53 , was chemotactic for human monocytes and murine mast cells in vitro. S100A12 38 -53 provoked an acute inflammatory response similar to that elicited by S100A12 in vivo and caused edema and leukocyte and mast cell recruitment. Circular dichroism studies showed that S100A12 38 -53 had increased helical structure in hydrophobic environments. Mutations in S100A12 38 -53 produced using an alanine scan confirmed that specific hydrophobic residues (I44A, I47A, and I53A) on the same face of the helix were critical for monocyte chemotaxis in vitro and generation of edema in vivo. In a hydrophobic environment such as the cell membrane, these critical residues would likely align on one face of an ␣-helix to facilitate receptor interaction. Interaction is unlikely to occur via the receptor for advanced glycation end products but, rather, via a G-protein-coupled mechanism.

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“…Cycloaddition [2 + 2] of 27 with ketene was carried out in dichloromethane at À78 C. The ketene was generated in situ from corresponding phenoxyacetyl chloride in the presence of triethylamine. In all cases, cis-b-lactams [86]. Under the reaction conditions, the b-lactam ring underwent rearrangement to produce trans-3,4-dihydro-2(1H)-quinolinones 30, through an intramolecular nucleophilic attack of the bÀlactam amide moiety by newly generated amino groups.…”

Section: Solid-phase Techniques For B-lactam Synthesismentioning

confidence: 99%

Recent Approaches Toward Solid Phase Synthesis of β-Lactams

Mandal

¹

,

Ghosh

²

,

Basu

³

2010

Heterocyclic Scaffolds I

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Since the discovery of penicillin in 1929, b-lactam antibiotics have been recognized as potentially chemotherapeutic drugs of incomparable effectiveness, conjugating a broad spectrum of activity with very low toxicity. The primary motif azetidin-2-one ring (b-lactam) has been considered as specific pharmacophores and scaffolds. With the advent of combinatorial chemistry and automated parallel synthesis coupled with ample interests from the pharmaceutical industries, recent trends have been driven mostly by adopting solid phase techniques and polymersupported synthesis of b-lactams. The present survey will present an overview of the developments on the polymer-supported and solid phase techniques for the preparation of b-lactam ring or b-lactam containing antibiotics published over the last decade. Both unsubstituted and substitutions with different functional groups at various positions of b-lactams have been synthesized using solid phase technology. However, Wang resin and application of Staudinger [2+2] cycloaddition reaction have remained hitherto the major choice. It may be expected that other solid phase approaches involving different resins would be developed in the coming years.

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“…Various reaction apparatus [36] have been developed for parallel synthesis on the basis of a 96-deep-well polypropylene microtiter plate (e.g., the Flexchem Solid Phase Chemistry System, a modular system of hardware designed for highthroughput parallel synthesis marked by Robbin Scientific Corporation.). The resin beads and reaction solutions are placed into each well of the plate.…”

Section: Reaction Apparatus Using Resin Beadsmentioning

confidence: 99%

Combinatorial Chemistry

Tiebes

¹

,

Peters

²

2000

Ullmann's Encyclopedia of Industrial Chemistry

0

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The article contains sections titled: 1. Introduction 2. Concept of Combinatorial Chemistry 3. Methods and Techniques of Combinatorial Synthesis 3.1. Synthetic Strategies Towards Combinatorial Libraries 3.1.1. Split ‐ Pool Synthesis Towards Combinatorial Libraries 3.1.1.1. Techniques using Resin Beads 3.1.1.2. Tea‐Bag Method 3.1.2. Parallel Synthesis Towards Combinatorial Libraries 3.1.2.1. Reaction Apparatus using Resin Beads 3.1.2.2. Multipin Technique 3.1.2.3. Spatially Addressable Parallel Synthesis on Silica Wafer 3.1.3. Reagent Mixture Synthesis Towards Combinatorial Libraries 3.2. Synthetic Methodology for Organic Library Construction 3.2.1. Solid‐Phase Organic Synthesis 3.2.1.1. Solid Support, Linker, and Cleavage Strategies 3.2.1.2. Reaction Portfolio 3.2.2. Synthesis in Solution and Liquid‐Phase Synthesis 4. Characterization of Combinatorial Libraries 4.1. Analytical Characterization 4.2. Hit Identification in Combinatorial Libraries by High‐Throughput Screening 4.2.1. Strategies for Libraries of Compound Mixtures 4.2.1.1. On‐Bead Screening 4.2.1.2. Deconvolution 4.2.1.2.1. Iterative Deconvolution 4.2.1.2.2. Deconvolution by Positional Scanning 4.2.1.2.3. Deconvolution by Orthogonal Libraries 4.2.1.3. Encoding 4.2.1.4. Multiple Cleavable Linkers 4.2.2. Strategies for Libraries of Separate Single Compounds 4.2.3. Conclusion 5. Automation and Data Processing 5.1. Synthesis Automation and Data Processing 5.2. Automated Purification 6. Library Design and Diversity Assessment 6.1. Diversity Assessment for Selection of Building Blocks or Compound 6.2. Iterative Optimization Methods 7. Economic Aspects and Industrial Case Studies 8. Further Developments 8.1. Combinatorial Chemistry and Catalysis 8.2. Combinatorial Chemistry and Material Science

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Multiple simultaneous synthesis of phenolic libraries

Cited by 101 publications

References 26 publications

Mast Cell and Monocyte Recruitment by S100A12 and Its Hinge Domain

Mast Cell and Monocyte Recruitment by S100A12 and Its Hinge Domain

Recent Approaches Toward Solid Phase Synthesis of β-Lactams

Combinatorial Chemistry

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