A Fascinating Journey into History: Exploration of the World of Isonitriles En Route to Complex Amides

Wilson, Rebecca M.; Stockdill, Jennifer L.; Wu, Xiangyang; Li, Xuechen; Vadola, Paul A.; Park, Peter K.; Wang, Ping; Danishefsky, Samuel J.

doi:10.1002/anie.201106628

Cited by 107 publications

(56 citation statements)

References 51 publications

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“…22 Our synthetic approach toward KRas(G12V) relies on the use of Fmoc-based SPPS to generate five peptidyl sequences, which are subsequently assembled via combined NCL and isonitrile-mediated activation strategies to access a biotinylated variant of KRas(G12V). 23, 24 Peptide thioesters were synthesized via Sakakibara elongation of protected peptides with pre-formed C-terminal residue thioesters following SPPS or alternatively by C-terminal hydrazide oxidation. 25,26 In a retrosynthetic fashion, taking primary advantage of the native cysteine residues within the full sequence reduces the synthetic challenge to three NCLs at assembly points Cys51, Cys80, and Cys118.…”

Section: Resultsmentioning

confidence: 99%

Total Chemical Synthesis and Folding of All-l and All-d Variants of Oncogenic KRas(G12V)

Levinson

McGee

Roberts³

et al. 2017

J. Am. Chem. Soc.

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The Ras proteins are essential GTPases involved in the regulation of cell proliferation and survival. Mutated oncogenic forms of Ras alter effector binding and innate GTPase activity, leading to deregulation of downstream signal transduction. Mutated forms of Ras are involved in approximately 30% of human cancers. Despite decades of effort to develop direct Ras inhibitors, Ras has long been considered ‘undruggable’ due to its high affinity for GTP and its lack of hydrophobic binding pockets. Herein, we report a total chemical synthesis of all L- and all D-amino acid biotinylated variants of oncogenic mutant KRas(G12V). The protein is synthesized using Fmoc-based solid-phase peptide synthesis and assembled using combined native chemical ligation and isonitrile-mediated activation strategies. We demonstrate that both KRas(G12V) enantiomers can successfully fold and bind nucleotide substrates and binding partners with observable enantiodiscrimination. By demonstrating the functional competency of a mirror-image form of KRas bound to its corresponding enantiomeric nucleotide triphosphate, this study sets the stage for further biochemical studies with this material. In particular, this protein will enable mirror-image yeast surface display experiments to identify all-D peptide ligands for oncogenic KRas, providing a useful tool in the search for new therapeutics against this challenging disease target.

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Section: Resultsmentioning

confidence: 99%

Total Chemical Synthesis and Folding of All-l and All-d Variants of Oncogenic KRas(G12V)

Levinson

McGee

Roberts³

et al. 2017

J. Am. Chem. Soc.

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“…ix,x Finally, Danishefsky and coworkers recently showed that isonitriles and carboxylic acids react to form N -formyl amides, with application for the synthesis of complex peptidic structures. xi …”

Section: Introductionmentioning

confidence: 99%

Syntheses and biological studies of marine terpenoids derived from inorganic cyanide

Schnermann

Shenvi

2015

Nat. Prod. Rep.

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Isocyanoterpenes (ICTs) are marine natural products biosynthesized through an unusual pathway that adorns terpene scaffolds with nitrogenous functionality derived from cyanide. The appendage of nitrogen functional groups–isonitriles in particular–onto stereochemically-rich carbocyclic ring systems provides enigmatic, bioactive molecules that have required innovative chemical syntheses. This review discusses the challenges inherent to the synthesis of this diverse family and details the development of the field. We also present recent progress in isolation and discuss key aspects of the remarkable biological activity of these compounds.

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“…9 The reaction of particular interest for us, drawn from our menu of new isonitrile chemistry, involves coupling of a thioacid ( 3 ) with an amine ( 5 ) in the presence of a hindered isonitrile ( 4 ). As we have shown, 10,11 this three-component reaction gives rise to an amide linkage under remarkably mild conditions .…”

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confidence: 99%

Revisiting Oxytocin through the Medium of Isonitriles

Wang

2012

J. Am. Chem. Soc.

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The reaction of thioamino acids and N-terminal peptides, mediated by hindered isonitriles and HOBt, gives rise to peptide bonds. In one pathway, oxytocin was synthesized by eight such reiterative amidations. In another stereospecific track, oxytocin was constructed by native chemical ligation, wherein the two building blocks were assembled by thioacid amine amidation. The NMR spectra of oxytocin and dihydro-oxytoxin suggest a high level of pre-organization in the latter, perhaps favoring oxidative folding.

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A Fascinating Journey into History: Exploration of the World of Isonitriles En Route to Complex Amides

Cited by 107 publications

References 51 publications

Total Chemical Synthesis and Folding of All-l and All-d Variants of Oncogenic KRas(G12V)

Total Chemical Synthesis and Folding of All-l and All-d Variants of Oncogenic KRas(G12V)

Syntheses and biological studies of marine terpenoids derived from inorganic cyanide

Revisiting Oxytocin through the Medium of Isonitriles

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