Optimal Method for Disulfide Bond Closure in the Synthesis of Atosiban—Antagonist of Oxytocin Receptors

This work is devoted to the large-scale solid-phase synthesis (SPS) of Atosiban, Mpa 1 -D-Tyr(OEt)-Ile-Thr-Asn-Cys 6 -Pro-Orn-Gly-NH 2 cyclic 1,6 disulfide, the only clinically used oxytocin receptor antagonist. The conditions have been selected for the closure of the disulfide bond (S–S) in the Ato...

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Bibliographic Details
Published in:Russian journal of bioorganic chemistry 2021-11, Vol.47 (6), p.1241-1248
Main Authors: Avdeev, D. V., Ovchinnikov, M. V., Dudkina, Y. S., Molokoedov, A. S., Azmuko, A. A., Palkeeva, M. E., Sidorova, M. V.
Format: Article
Language:English
Subjects:
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
By products
Byproducts
Life Sciences
Organic Chemistry
Receptors
Solid phase synthesis
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Summary:This work is devoted to the large-scale solid-phase synthesis (SPS) of Atosiban, Mpa 1 -D-Tyr(OEt)-Ile-Thr-Asn-Cys 6 -Pro-Orn-Gly-NH 2 cyclic 1,6 disulfide, the only clinically used oxytocin receptor antagonist. The conditions have been selected for the closure of the disulfide bond (S–S) in the Atosiban molecule both in the solution and solid phase with the minimal formation of by-products. A comparative assessment of the formation of the S–S bond was carried out under various conditions. The formation of by-products during the closure of the disulfide bond has been studied both in solution and on the polymer support. The developed technique allows for the synthesis of Atosiban on an enlarged scale (10–20 mmol) involving the cyclization of a protected intermediate with the formation of the S–S bond during solid-phase synthesis with the minimal formation of by-products.
ISSN:1068-1620
1608-330X
DOI:10.1134/S1068162021060042