Efficient synthesis of CN2097 using in situ activation of sulfhydryl group |
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| Authors: | Shaban Darwish Keykavous Parang John Marshall Dennis J. Goebel Rakesh Tiwari |
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| Affiliation: | 1. Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA;2. Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, USA;3. Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI, USA;4. Organometallic and Organometalloid Chemistry Department, National Research Centre, El Bohouth St., Dokki, Giza, Egypt |
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| Abstract: | ![]()
CN2097 (R7Cs-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-sCR7 and CYK[KTE(β-Ala)]V) were synthesized, followed by solution phase coupling in water. Activation of the polyarginine (CR7) 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:H2O (95:2.5:2.5, v/v/v) for 4 h. The disulfide coupling was efficient which provided a 60% yield. |
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| Keywords: | CN2097 Disulfide Fmoc/tBu Polyarginine PDZ domain Solid-phase chemistry |
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