Vinylphosphonites for Staudinger-induced chemoselective peptide cyclization and functionalization

Kasper, Marc‐André; Glanz, Maria; Oder, Andreas; Schmieder, Peter; Kries, Jens Peter von; Hackenberger, Christian P. R.

doi:10.1039/c9sc01345h

Cited by 58 publications

(81 citation statements)

References 52 publications

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“…Recently, we introduced unsaturated phosphonamidates for the selective and irreversible modification of cysteine residues in proteins and antibodies . We described the synthesis of NHS‐modified ethynylphosphonamidate building block 2 and demonstrated that hydrophilic diethylene glycol substitution at the phosphonamidate ester residue could drastically increase the water solubility .…”

Section: Introductionmentioning

confidence: 99%

N‐Hydroxysuccinimide‐Modified Ethynylphosphonamidates Enable the Synthesis of Configurationally Defined Protein Conjugates

et al. 2020

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Herein, the application of N‐hydroxysuccinimide‐modified phosphonamidate building blocks for the incorporation of cysteine‐selective ethynylphosphonamidates into lysine residues of proteins, followed by thiol addition with small molecules and proteins, is reported. It is demonstrated that the building blocks significantly lower undesired homo‐crosslinking side products that can occur with commonly applied succinimidyl 4‐(N‐maleimidomethyl)cyclohexane‐1‐carboxylate (SMCC) under physiological pH. The previously demonstrated stability of the phosphonamidate moiety additionally solves the problem of premature maleimide hydrolysis, which can hamper the efficiency of subsequent thiol addition. Furthermore, a method to separate the phosphonamidate enantiomers to be able to synthesize protein conjugates in a defined configuration has been developed. Finally, the building blocks are applied to the construction of functional antibody–drug conjugates, analogously to FDA‐approved, SMCC‐linked Kadcyla, and to the synthesis of a functional antibody–protein conjugate.

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Section: Introductionmentioning

confidence: 99%

N‐Hydroxysuccinimide‐Modified Ethynylphosphonamidates Enable the Synthesis of Configurationally Defined Protein Conjugates

et al. 2020

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“…Phosphoramidates and other phosphate‐based constructs have become useful tools in chemical biology as probes for biochemical processes, such as membrane transport, protein phosphorylation and conjugation. [1a] In addition, these compounds can also be used as alternatives to phosphorothioate antisense oligonucleotides or as candidates for the development of smart materials, including biodegradable polymers, or sensors for medical applications such as diagnosis[1b], , and drug delivery…”

Section: Introductionmentioning

confidence: 99%

Sterically‐Controlled Self‐Immolation in Phosphoramidate Linkers Triggered by Light

et al. 2020

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Phosphoramidate prodrugs stand out for their applications as drug delivery systems. However, information on their activation remains limited to prodrug half‐live and metabolite structure, which hinders their development. Considering the lack of data on phosphoramidate self‐immolation, we studied light‐triggered self‐immolation of phosphoramidate‐based linkers bearing various amino acid arms by NMR spectroscopy with in situ irradiation, complemented with mathematical fitting, and by optical methods. By changing the alanine arm, we were able to systematically fine‐tune, slow down or speed up the cyclization rate. The cyclization rate of branched amino acid arms increased with the steric demands of their α‐substituents according to the Thorpe‐Ingold effect. The cyclization of β‐alanine and proline was very slow or did not proceed at all, but lactate may be a good alternative for the alanine arm because lactate exhibits a significantly slower cyclization rate than alanine (ca. 60 times). Overall, our study demonstrates that phosphoramidate self‐immolation strongly depends on the structure of the amino acid arm and on the conditions used (solvent, concentration and temperature), thereby providing a solid foundation for the rational design of new self‐immolative phosphoramidate systems with desired properties.

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“…Accordingly, a number of ''selfhydrolysing'' maleimides have now been developed, with ring-opening catalysed by adjacent functional groups such as primary amine, polyethylene glycol (PEG) and N-aryl amongst the most promising. [76][77][78][79] Other reagents including a-halocarbonyls, 80 palladium oxidative-addition complexes, 81 ethynylphosphonamidates, 82,83 vinylphosphonites 84 and ethynylbenziodoxolones 85 have also been used to synthesise ADCs with stable thioether bonds via modification of reduced interchain disulfides ( Fig. 5B).…”

Section: Stochastic Conjugation With Naturally Occurring Amino Acidsmentioning

confidence: 99%

Site-selective modification strategies in antibody–drug conjugates

et al. 2021

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Vinylphosphonites for Staudinger-induced chemoselective peptide cyclization and functionalization

Abstract: Vinylphosphonites react in chemoselective Staudinger-phosphonite reactions (SPhR) with azides to form vinylphosphonamidates for the subsequent modification of cysteine residues in peptides and proteins.

Cited by 58 publications

References 52 publications

N‐Hydroxysuccinimide‐Modified Ethynylphosphonamidates Enable the Synthesis of Configurationally Defined Protein Conjugates

N‐Hydroxysuccinimide‐Modified Ethynylphosphonamidates Enable the Synthesis of Configurationally Defined Protein Conjugates

Sterically‐Controlled Self‐Immolation in Phosphoramidate Linkers Triggered by Light

Site-selective modification strategies in antibody–drug conjugates

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