Time-Reduced N-Methylation: Exploring a Faster Synthesis Technique

Helbik-Maciejewska, Aleksandra; Gitlin-Domagalska, Agata; Glavaš, Mladena; Ptaszyńska, Natalia; Dębowski, Dawid; Łęgowska, Anna; Rolka, Krzysztof (2025) Time-Reduced N-Methylation: Exploring a Faster Synthesis Technique. The Journal of Organic Chemistry, 90 (22). pp. 7182-7190. ISSN 1520-6904

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Abstract

Backbone N-methylation is a pivotal peptide modification that enhances lipophilicity, metabolic stability, and binding affinity or specificity, thereby improving bioactive peptides’ bioavailability. Substitution of a backbone amide hydrogen with a methyl group is a three-step procedure which is fully integrated with solid-phase peptide synthesis strategy and usually takes about 4 h. We have revolutionized this process by optimizing the method and slashing the total N-methylation procedure time from 4 h to just 40 min. Moreover, we demonstrate that N-methylation can be equally efficient regardless of the laboratory equipment used, such as a standard laboratory shaker, microwave synthesizer, or common ultrasonic bath. Our study not only results in acceleration of the N-methylation process during solid-phase peptide synthesis but also offers a flexible choice of laboratory equipment, making peptide modifications more efficient and achievable.

Item Type:	Article
Uncontrolled Keywords:	High-performance liquid chromatography; Monomers; Organic polymers; Organic reactions; Peptides and proteins
Subjects:	NATURAL SCIENCES > Chemistry > Organic Chemistry
Divisions:	NMR Center Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type National Science Centre projekt: Lipophilic Prodrug Charge Masking (LPCM) as a novel strategy to enhance oral bioavailability of charged active peptides. Optimization and generalization of the method Agata Gitlin-Domagalska UMO-2019/35/D/NZ7/00174 UNSPECIFIED
Depositing User:	Mladena Glavaš
Date Deposited:	17 Dec 2025 08:41
URI:	http://fulir.irb.hr/id/eprint/10530
DOI:	10.1021/acs.joc.5c00083

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