The aspartimide problem in Fmoc‐based SPPS. Part II

Mergler, M.; Dick, Fritz; Sax, B.; Stähelin, Christian; Vorherr, Thomas

doi:10.1002/psc.473

Cited by 60 publications

(61 citation statements)

References 10 publications

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“…The aspartimide formation is one the best documented side reactions in peptide synthesis. [49] This sequence-dependent cyclization is catalyzed both by acids and bases and frequently occurs during the solidphase synthesis of peptides bearing the Asp-Gly motif. Furthermore, it was shown that the use of harsh Fmoc cleavage conditions (i.e., use of DBU instead of piperidine) promoted the aspartimide formation even for Asp-AA motifs where Gly is replaced by more sterically hindered amino acids (e.g., Ala, HisA C H T U N G T R E N N U N G (Trt), TyrA C H T U N G T R E N N U N G (tBu)).…”

Section: Fluorescent Labeling Of Ardec-protected Peptidesmentioning

confidence: 99%

Aryldithioethyloxycarbonyl (Ardec): A New Family of Amine Protecting Groups Removable under Mild Reducing Conditions and Their Applications to Peptide Synthesis

Lapeyre

Leprince

Massonneau

et al. 2006

Chemistry A European J

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The development of phenyldithioethyloxycarbonyl (Phdec) and 2-pyridyldithioethyloxycarbonyl (Pydec) protecting groups, which are thiol-labile urethanes, is described. These new disulfide-based protecting groups were introduced onto the epsilon-amino group of L-lysine; the resulting amino acid derivatives were easily converted into N alpha-Fmoc building blocks suitable for both solid- and solution-phase peptide synthesis. Model dipeptide(Ardec)s were prepared by using classical peptide couplings followed by standard deprotection protocols. They were used to optimize the conditions for complete thiolytic removal of the Ardec groups both in aqueous and organic media. Phdec and Pydec were found to be cleaved within 15 to 30 min under mild reducing conditions: i) by treatment with dithiothreitol or beta-mercaptoethanol in Tris.HCl buffer (pH 8.5-9.0) for deprotection in water and ii) by treatment with beta-mercaptoethanol and 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) in N-methylpyrrolidinone for deprotection in an organic medium. Successful solid-phase synthesis of hexapeptides Ac-Lys-Asp-Glu-Val-Asp-Lys(Ardec)-NH2 has clearly demonstrated the full orthogonality of these new amino protecting groups with Fmoc and Boc protections. The utility of the Ardec orthogonal deprotection strategy for site-specific chemical modification of peptides bearing several amino groups was illustrated firstly by the preparation of a fluorogenic substrate for caspase-3 protease containing the cyanine dyes Cy 3.0 and Cy 5.0 as FRET donor/acceptor pair, and by solid-phase synthesis of an hexapeptide bearing a single biotin reporter group.

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Section: Fluorescent Labeling Of Ardec-protected Peptidesmentioning

confidence: 99%

Aryldithioethyloxycarbonyl (Ardec): A New Family of Amine Protecting Groups Removable under Mild Reducing Conditions and Their Applications to Peptide Synthesis

Lapeyre

Leprince

Massonneau

et al. 2006

Chemistry A European J

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“…The importance of the aspartyl side‐chain protection has been demonstrated in many studies . Aspartimide formation was exacerbated by the use of less bulky protecting groups: ODie 1 (Figure ) > OMpe > OtBu > O‐1‐adamantyl , trityl‐based > OBzl, OAll and O ‐phenacyl .…”

Section: Introductionmentioning

confidence: 99%

Advances in Fmoc solid‐phase peptide synthesis

Behrendt

White

Offer

2016

Journal of Peptide Science

570

426

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Today, Fmoc SPPS is the method of choice for peptide synthesis. Very‐high‐quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

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“…The extent of aspartimide formation is largely dependent on the nature of the amino acid preceding the aspartyl residue. Sequences containing the following dipeptide motifs are particularly susceptible: Asp‐Gly‐, ‐Asp‐Asp‐, ‐Asp‐Asn‐, ‐Asp‐Arg‐, ‐Asp‐Cys(Acm)‐ , ‐Asp‐Ser‐ and –Asp‐Thr‐ , (Table ). Peptide conformation can also play a role in promoting aspartimide formation, meaning, this side reaction is not just limited to peptides containing those sequences listed previously .…”

Section: Introductionmentioning

confidence: 99%

New t‐butyl based aspartate protecting groups preventing aspartimide formation in Fmoc SPPS

Behrendt

Huber

Martí

et al. 2015

Journal of Peptide Science

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Obtaining homogenous aspartyl-containing peptides via Fmoc/tBu chemistry is often an insurmountable obstacle. A generic solution for this issue utilising an optimised side-chain protection strategy that minimises aspartimide formation would therefore be most desirable. To this end, we developed the following new derivatives: Fmoc-Asp(OEpe)-OH (Epe = 3-ethyl-3-pentyl), Fmoc-Asp(OPhp)-OH (Php = 4-n-propyl-4-heptyl) and Fmoc-Asp(OBno)-OH (Bno = 5-n-butyl-5-nonyl). We have compared their effectiveness against that of Fmoc-Asp(OtBu)-OH and Fmoc-Asp(OMpe)-OH in the well-established scorpion toxin II model peptide variants H-Val-Lys-Asp-Asn/Arg-Tyr-Ile-OH by treatments of the peptidyl resins with the Fmoc removal reagents containing piperidine and DBU at both room and elevated temperatures. The new derivatives proved to be extremely effective in minimising aspartimide by-products in each application.

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The aspartimide problem in Fmoc‐based SPPS. Part II

Cited by 60 publications

References 10 publications

Aryldithioethyloxycarbonyl (Ardec): A New Family of Amine Protecting Groups Removable under Mild Reducing Conditions and Their Applications to Peptide Synthesis

Aryldithioethyloxycarbonyl (Ardec): A New Family of Amine Protecting Groups Removable under Mild Reducing Conditions and Their Applications to Peptide Synthesis

Advances in Fmoc solid‐phase peptide synthesis

New t‐butyl based aspartate protecting groups preventing aspartimide formation in Fmoc SPPS

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