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Thioester deprotection using a biomimetic NCL approach
Valentina Villamil1,2, Cecilia Saiz1, Graciela Mahler1
1Laboratorio de Química Farmacéutica (DQO), Facultad de Química, Universidad de la República, Montevideo, Uruguay.
Frontiers in Chemistry
|September 8, 2022
Summary
This study introduces a biomimetic deprotection method using 2-aminothiols for acyl groups, offering a faster, cheaper, and higher-yielding alternative to existing techniques for synthesizing important biological molecules.
Area of Science:
- Biochemistry
- Organic Chemistry
- Medicinal Chemistry
Background:
- The thiol-thioester linkage is crucial in biochemistry and chemistry.
- Native Chemical Ligation (NCL) utilizes this linkage for peptide synthesis.
- Previous methods for thioester deprotection using thioglycolic acid (TGA) have limitations.
Purpose of the Study:
- To explore 2-aminothiols for deprotecting acyl-bearing thiols, inspired by NCL.
- To develop a more efficient and cost-effective deprotection method.
- To synthesize novel analogs of mercaptomethyl bisthiazolidine, inhibitors of Metallo-β-Lactamases (MBLs).
Main Methods:
- Utilized cysteamine or L-cysteine as 2-aminothiols for deprotection.
- Conducted reactions in an aqueous buffer at pH 8 and room temperature.
- Applied the method for S-acetyl, S-butyryl, and S-benzoyl heterocycles deprotection.
- Synthesized six new analogs of mercaptomethyl bisthiazolidine.
Main Results:
- Achieved high yields (up to 84%) for heterocycle deprotection.
- Demonstrated efficient deprotection within 30 minutes.
- The biomimetic deprotection showed superior performance compared to TGA-based methods.
- Successfully synthesized novel MBL inhibitor analogs.
Conclusions:
- The novel biomimetic deprotection using 2-aminothiols is efficient, mild, and cost-effective.
- This method offers significant advantages over existing thioester deprotection techniques.
- The synthesized analogs represent potential new therapeutic agents against MBLs.
