Formation of a Disulfide Bridge on the Resin during Solid-Phase Synthesis of Terlipressin: Influence of the Boc-Protected and Free N-Terminal Amino Group

Formation of a Disulfide Bridge on the Resin during Solid-Phase Synthesis of Terlipressin: Influence of the Boc-Protected and Free N-Terminal Amino Group Full article

Journal

Organic Process Research & Development
ISSN: 1083-6160 , E-ISSN: 1520-586X

Output data

Year: 2023, Volume: 27, Number: 9, Pages: 1624-1630 Pages count : 7 DOI: 10.1021/acs.oprd.3c00142

Authors

Avdeev Dmitry ¹ , Ovchinnikov Michael V. ¹ , Medvedev Michael G. ² , Molokoedov Alexander S. ¹ , Sidorova Maria V. ¹

Affiliations

1	Chazov National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, Moscow 121552, Russia
2	N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow 119991, Russian Federation

An industry-ready approach for the synthesis of terlipressin is developed: the entire peptide chain assembly and subsequent disulfide bond closure are carried out on a polymeric carrier with a specific precaution for the protection of the N-terminal α-amino group. The effect of various factors on the purity of crude disulfide was studied, and the solid-phase cyclization process was optimized. The designed approach has high fidelity and reproducibility and is applicable for a large-scale peptide synthesis (we show it up to 15 g of the pure product). Using molecular modeling, we have found that the state of the N-terminal amino group (free or protected) has a significant influence on the ability of two cysteine side chains to reach each other, paving the way to a rational choice of protecting groups in peptide synthesis.

Avdeev D. , Ovchinnikov M.V. , Medvedev M.G. , Molokoedov A.S. , Sidorova M.V.
Formation of a Disulfide Bridge on the Resin during Solid-Phase Synthesis of Terlipressin: Influence of the Boc-Protected and Free N-Terminal Amino Group
Organic Process Research & Development. 2023. V.27. N9. P.1624-1630. DOI: 10.1021/acs.oprd.3c00142 WOS Scopus OpenAlex

≡ Web of science:	WOS:001065159200001
≡ Scopus:	2-s2.0-85171631765
≡ OpenAlex:	W4386274806