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Efficient synthesis of CN2097 using in situ activation of sulfhydryl group.

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Title: Efficient synthesis of CN2097 using in situ activation of sulfhydryl group.
Authors: Darwish, Shaban1,2, Parang, Keykavous1, Marshall, John3, Goebel, Dennis J.4, Tiwari, Rakesh1 tiwari@chapman.edu
Source: Tetrahedron Letters: International Organ for the Rapid Publication of Preliminary Communications in Organic Chemistry. Aug2017, Vol. 58 Issue 31, p3053-3056. 4p.
Subjects: Sulfhydryl group, Peptidomimetics, Brain injuries, Angelman syndrome, Disulfides
Abstract: CN2097 (R 7 Cs-sCYK[KTE(β-Ala)]V) is a rationally designed peptidomimetic that shows effectiveness in preclinical models for the treatment of neurological disorders, such as Angelman syndrome, traumatic brain injury (TBI), and stroke. Because of its potential therapeutic activity for the treatment of human CNS disorders, there was an urgent need to develop an efficient strategy for large-scale synthesis of CN2097. The synthesis of CN2097 was accomplished using Fmoc/tBu solid phase chemistry in multiple steps. Two different peptide fragments (activated polyarginine peptide Npys-sCR 7 and CYK[KTE(β-Ala)]V) were synthesized, followed by solution phase coupling in water. Activation of the polyarginine (CR 7 ) was achieved in situ during cleavage of protected peptide (C(Trt)R(Pbf) 7 ) from the Rink amide resin using 5 equiv. of 2,2-dithopyridine in TFA:TIS:H 2 O (95:2.5:2.5, v/v/v) for 4 h. The disulfide coupling was efficient which provided a 60% yield. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
Description
Abstract:CN2097 (R 7 Cs-sCYK[KTE(β-Ala)]V) is a rationally designed peptidomimetic that shows effectiveness in preclinical models for the treatment of neurological disorders, such as Angelman syndrome, traumatic brain injury (TBI), and stroke. Because of its potential therapeutic activity for the treatment of human CNS disorders, there was an urgent need to develop an efficient strategy for large-scale synthesis of CN2097. The synthesis of CN2097 was accomplished using Fmoc/tBu solid phase chemistry in multiple steps. Two different peptide fragments (activated polyarginine peptide Npys-sCR 7 and CYK[KTE(β-Ala)]V) were synthesized, followed by solution phase coupling in water. Activation of the polyarginine (CR 7 ) was achieved in situ during cleavage of protected peptide (C(Trt)R(Pbf) 7 ) from the Rink amide resin using 5 equiv. of 2,2-dithopyridine in TFA:TIS:H 2 O (95:2.5:2.5, v/v/v) for 4 h. The disulfide coupling was efficient which provided a 60% yield. [ABSTRACT FROM AUTHOR]
ISSN:00404039
DOI:10.1016/j.tetlet.2017.06.066