Challenges with the Synthesis of a Macrocyclic Thioether Peptide: From Milligram to Multigram Using Solid Phase Peptide Synthesis (SPPS).

Autor:	Kempson J; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Zhao R; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Pawluczyk J; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Wang B; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Zhang H; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Hou X; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Allen MP; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Wu DR; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Li P; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Yip S; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Smith A; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Traeger SC; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Huang S; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Cutrone J; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Mukherjee S; Chemical and Process Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903, United States., Sfouggatakis C; Chemical and Process Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903, United States., Poss M; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Scola PM; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Meanwell NA; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Carter PH; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Mathur A; Research and Early Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
Jazyk:	angličtina
Zdroj:	The Journal of organic chemistry [J Org Chem] 2024 May 17; Vol. 89 (10), pp. 6639-6650. Date of Electronic Publication: 2024 Apr 23.
DOI:	10.1021/acs.joc.4c00429
Abstrakt:	We describe an optimization and scale-up of the 45-membered macrocyclic thioether peptide BMS-986189 utilizing solid-phase peptide synthesis (SPPS). Improvements to linear peptide isolation, macrocyclization, and peptide purification were demonstrated to increase the throughput and purification of material on scale and enabled the synthesis and purification of >60 g of target peptide. Taken together, not only these improvements resulted in a 28-fold yield increase from the original SPPS approach, but also the generality of this newly developed SPPS purification sequence has found application in the synthesis and purification of other macrocyclic thioether peptides.
Databáze:	MEDLINE
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