Solvent effects on coupling yields during rapid solid-phase synthesis of CGRP(8-37) employing in situ neutralization

C. K. Taylor, Peter W. Abel, Martin Hulce, D. D. Smith

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The success of solid-phase peptide synthesis is often dependent upon solvation of the resin and the growing resin-bound peptide chain. We investigated the relationship between solvent properties and solvation of the resin and peptide-resin in order to obtain satisfactory coupling yields for the rapid solid-phase peptide synthesis, using butyloxycarbonyl-(Boc)-amino acid derivatives, of human-α-calcitonin gene-related peptide(8-37) (CGRP(8-37)). Solvation of (p-methylbenzhydrylamine)copoly(styrene-1% divinylbenzene (DVB) (resin) and resin covalently bound to the fully protected amino acid sequence of CGRP(8-37) (peptide-resin) was correlated to solvent Hildebrand solubility (6) and hydrogen-bonding (δh) parameters. Contour solvation plots of δh vs. δ revealed maximum solvation regions of resin and peptide-resin. Maximum resin solvation occurred with N-methylpyrrolidinone (NMP), NMP:dimethylsulfoxide (DMSO) (8:2) and DMSO. Inefficient solvation of the peptide-resin occurred with these solvents and resulted in poor syntheses with average coupling yields of 78.1, 88.9 and 91.8%, respectively. Superior peptide-resin solvation was obtained using dimethylacetamide (DMA) and dimethylformamide (DMF), resulting in significantly higher average coupling yields of 98.0 and 99.5%, respectively. Thus, the region of maximum peptide-resin solvation shifts to solvents with higher δh values. DMF provided the most effective peptide-resin solvation and was the only solvent from which CGRP(8-37) was obtained as a single major product in the crude cleaved material.

Original languageEnglish
Pages (from-to)84-89
Number of pages6
JournalJournal of Peptide Research
Volume65
Issue number1
DOIs
StatePublished - Jan 2005

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Solid-Phase Synthesis Techniques
Solvation
Resins
Peptides
1-methyl-2-pyrrolidinone
Dimethylformamide
Dimethyl Sulfoxide
divinyl benzene
calcitonin gene-related peptide (8-37)
Hydrogen Bonding
Solubility
Amino Acid Sequence
Amino Acids
Styrene

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology

Cite this

Solvent effects on coupling yields during rapid solid-phase synthesis of CGRP(8-37) employing in situ neutralization. / Taylor, C. K.; Abel, Peter W.; Hulce, Martin; Smith, D. D.

In: Journal of Peptide Research, Vol. 65, No. 1, 01.2005, p. 84-89.

Research output: Contribution to journalArticle

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AB - The success of solid-phase peptide synthesis is often dependent upon solvation of the resin and the growing resin-bound peptide chain. We investigated the relationship between solvent properties and solvation of the resin and peptide-resin in order to obtain satisfactory coupling yields for the rapid solid-phase peptide synthesis, using butyloxycarbonyl-(Boc)-amino acid derivatives, of human-α-calcitonin gene-related peptide(8-37) (CGRP(8-37)). Solvation of (p-methylbenzhydrylamine)copoly(styrene-1% divinylbenzene (DVB) (resin) and resin covalently bound to the fully protected amino acid sequence of CGRP(8-37) (peptide-resin) was correlated to solvent Hildebrand solubility (6) and hydrogen-bonding (δh) parameters. Contour solvation plots of δh vs. δ revealed maximum solvation regions of resin and peptide-resin. Maximum resin solvation occurred with N-methylpyrrolidinone (NMP), NMP:dimethylsulfoxide (DMSO) (8:2) and DMSO. Inefficient solvation of the peptide-resin occurred with these solvents and resulted in poor syntheses with average coupling yields of 78.1, 88.9 and 91.8%, respectively. Superior peptide-resin solvation was obtained using dimethylacetamide (DMA) and dimethylformamide (DMF), resulting in significantly higher average coupling yields of 98.0 and 99.5%, respectively. Thus, the region of maximum peptide-resin solvation shifts to solvents with higher δh values. DMF provided the most effective peptide-resin solvation and was the only solvent from which CGRP(8-37) was obtained as a single major product in the crude cleaved material.

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