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Synlett
DOI: 10.1055/s-0043-1775499
DOI: 10.1055/s-0043-1775499
letter
Small Molecules in Medicinal Chemistry
Hydrophilic α-Aryl-α-Diazoamides for Protein Esterification
A.O. was supported by postdoctoral fellowship F32 CA247259 (National Institutes of Health, NIH). A.M. was supported by the Undergraduate Research Opportunities Program at the Massachusetts Institute of Technology. Y.D.P. was supported by a National Science Foundation (NSF) Graduate Research Fellowship. This work was supported by grants R35 GM148220, R35 GM149532, and P30 CA014051 (NIH).
Abstract
Bioreversible protein esterification is a simple, customizable, and traceless strategy for the exogenous delivery of proteins into mammalian cells. Enabling this protein delivery strategy are α-aryl-α-diazoamides bearing a tolyl moiety. The aqueous solubility of the ensuing esterified protein is, however, often compromised, which can result in the loss of soluble esterified protein for downstream applications. Here, we undertook a structure–activity relationship campaign to generate hydrophilic diazoamides for use as protein esterification and cellular delivery agents. We find that the careful adjustment of the hydrogen-bond basicity of α-aryl-α-diazoamides is sufficient to engender soluble esterified proteins, as high hydrogen-bond basicity correlates with high aqueous solubility. Importantly, enhancing aqueous solubility of diazoamides should proceed pari passu with preserving their lipophilicity and reactivity towards esterification of carboxylic acids, as the best-performing diazoamide from our study contains an N-acetyl piperazine while retaining the tolyl moiety. Our efforts can inspire new generations of esterified proteins with better solubility.
Key words
cell - delivery - diazo compounds - esterification - hydrophilicity - hydrophobicity - proteins - solubilitySupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0043-1775499.
- Supporting Information
Publikationsverlauf
Eingereicht: 02. März 2025
Angenommen nach Revision: 17. Juni 2025
Artikel online veröffentlicht:
15. Juli 2025
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