An Alkylsilyl-Tethered, High-Capacity Solid Support Amenable to Diversity-Oriented Synthesis for One-Bead, One-Stock Solution Chemical Genetics

Tallarico, John A.; Depew, Kris M.; Pelish, Henry E.; Westwood, Nicholas J.; Lindsley, Craig W.; Shair, Matthew D.; Schreiber, Stuart L.; Foley, Michael A.

doi:10.1021/cc000107i

Cited by 109 publications

(110 citation statements)

References 29 publications

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“…We replaced the isopropoxy group of 534F6 with a hydroxyethyl group as a point of attachment to solid phase synthesis resin. 8 Approximately 35 mg of resin were employed in Irori tm kans and the synthesis was tracked using 2D-barcoding. 9 The first step of the synthesis was a reductive amination with a protected amine that would later be functionalized.…”

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confidence: 99%

N-Benzyl-3-sulfonamidopyrrolidines as novel inhibitors of cell division in E. coli

Mukherjee

Robinson

Howe

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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A new small molecule inhibitor of bacterial cell division has been discovered using a highthroughput screen in E. coli. Although the lead screening hit (534F6) exhibited modest inhibition of the GTPase activity of FtsZ (20±5% at 100 μM primary target for bacterial cell division inhibitors, several analogs caused potent bacterial growth inhibition with negligible antagonism of FtsZ GTPase activity. A library of analogs has been prepared and several alkyne-tagged photoaffinity probes have been synthesized for use in experiments to elucidate the primary target of this compound.The emergence of antibiotic-resistant strains of bacteria has prompted a worldwide effort to seek new avenues for fighting infectious disease. 1 Most antibiotics discovered to date target a narrow range of biochemical processes in bacteria. 2 FtsZ, the prokaryotic analog of tubulin, 3 has been examined as a potential new target for antimicrobial chemotherapy. Although FtsZ has been the primary target for small molecules that inhibit bacterial cell division, 4 it is likely that other proteins essential for bacterial cytokinesis can also be targeted. 5 A high-throughput screen has recently been developed to identify compounds that cause lethal cell filamentation in E. coli. 6,7 This screen revealed new inhibitors of FtsZ and at the same time yielded several compounds that caused cell filamentation without inducing the SOS response or without significantly inhibiting the GTPase activity of FtsZ. Herein we describe our preliminary SAR studies of 534F6, an N-benzyl-3-sulfonamidopyrrrolidine Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Figure 1) and our initial preparation of photoaffinity reagents for the identification of this compound's protein target(s). NIH Public Access534F6 displayed weak inhibition of FtsZ GTPase (20±5% at 100 μM), did not affect steadystate FtsZ polymerization as assayed by high-speed sedimentation, and induced SOSindependent E. coli cell filamentation (data not shown). Despite a certain degree of similarity to sulfonamide antibiotics, such as sulfamethoxazole, compound 534F6 exhibited markedly different effects on E. coli. Sulfamethoxazole showed modest lethality (MIC > 80μM) and did not cause E. coli (AcrAB efflux pump knockout strain DRC 39 4d ) to filament. Based on these observations, we set out to develop a library synthesis of 534F6 in an effort to optimize potency and eventually determine the protein target of this compound.We began by investigating the SAR of 534F6. Since the configuration of this compound was unknown, we prepared each of the two enantiomers as ...

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mentioning

confidence: 99%

N-Benzyl-3-sulfonamidopyrrolidines as novel inhibitors of cell division in E. coli

Mukherjee

Robinson

Howe

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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“…Direct resin loading of 11 gave a small amount of undesired attachment through the phenol hydroxyl, so the phenol was selectively protected as the acetate (12) prior to resin loading. 23 Protodesilylation of the resin 19 with triflic acid, addition of 12, and deprotection of the resulting resin-bound methyl ester with piperidine yielded the loaded resin 13 (loading level = 1.05 mmol/g resin).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of a 10,000-Membered Library of Molecules Resembling Carpanone and Discovery of Vesicular Traffic Inhibitors

et al. 2006

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Split-and-pool synthesis of a 10,000-membered library of molecules resembling the natural product carpanone has been achieved. The synthesis features development of solid-phase multicomponent reactions between nitrogen nucleophiles, enones, and hydroxylamines, and a solid-phase application of the Huisgen cycloaddition affording substituted triazoles. The synthesis was performed in highcapacity (500 μm) polystyrene beads using a one bead-one stock solution strategy that enabled phenotypic screens of the resulting library. Using whole-cell fluorescence imaging, we discovered a series of molecules from the carpanone-based library that inhibit exocytosis from the Golgi apparatus. The most potent member of this series has an IC 50 of 14 μM. We also report structureactivity relationships for the molecules exhibiting this interesting phenotype. These inhibitors of exocytosis may be useful reagents for the study of vesicular traffic.

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“…Cell microarrays may also become a powerful tool in the emerging field of chemical genomics (Chan et al 2000;Giaever et al 1999). With high-capacity diversity-oriented synthesis of small molecules (Tallarico et al 2001) it is feasible to assay one compound (from one bead) against the cell microarrays containing the genome-wide collection of gene deletion or overexpression strains.…”

Section: Discussionmentioning

confidence: 99%

High-Density Cell Microarrays for Parallel Functional Determinations

Xu¹

2002

Genome Res.

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Whole-genome sequencing projects have generated a wealth of gene sequences from a variety of organisms. A major challenge is to rapidly uncover gene regulatory circuits and their functional manifestations at the cellular level. Here we report the coupled fabrication of nanocraters ranging in size from 100 pL to 1.5 nL on permeable membranes for culturing cells. Using this approach, we developed bacterial and yeast cell microarrays that allowed phenotypic determinations of gene activities and drug targets on a large scale. Cell microarrays will therefore be a particularly useful tool for studying phenotypes of gene activities on a genome-wide scale.

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An Alkylsilyl-Tethered, High-Capacity Solid Support Amenable to Diversity-Oriented Synthesis for One-Bead, One-Stock Solution Chemical Genetics

Cited by 109 publications

References 29 publications

N-Benzyl-3-sulfonamidopyrrolidines as novel inhibitors of cell division in E. coli

N-Benzyl-3-sulfonamidopyrrolidines as novel inhibitors of cell division in E. coli

Synthesis of a 10,000-Membered Library of Molecules Resembling Carpanone and Discovery of Vesicular Traffic Inhibitors

High-Density Cell Microarrays for Parallel Functional Determinations

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