Late-stage diversification strategy for the synthesis of peptide acids and amides using hydrazides
Aim: Modification of the C-terminus of a peptide to improve its properties, particularly after constructing the peptide chain, has great promise in the development of peptide therapeutics. This study discusses the development of a late-stage diversification method for synthesizing peptide acids and...
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Open Exploration
2023-10-01
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| Series: | Exploration of Drug Science |
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| Online Access: | https://www.explorationpub.com/uploads/Article/A100823/100823.pdf |
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| author | Shoko Tanaka Mizuki Kanno Yosuke Tashiro Tetsuo Narumi Nobuyuki Mase Kohei Sato |
| author_facet | Shoko Tanaka Mizuki Kanno Yosuke Tashiro Tetsuo Narumi Nobuyuki Mase Kohei Sato |
| author_sort | Shoko Tanaka |
| collection | DOAJ |
| description | Aim: Modification of the C-terminus of a peptide to improve its properties, particularly after constructing the peptide chain, has great promise in the development of peptide therapeutics. This study discusses the development of a late-stage diversification method for synthesizing peptide acids and amides from hydrazides which can serve as a common precursor. Methods: Peptide hydrazides were synthesized solely by using conventional solid-phase peptide synthesis (SPPS). Hydrazides were subjected to oxidation by potassium peroxymonosulfate (Oxone) to afford carboxylic acids. Azidation of hydrazides using sodium nitrite (NaNO2) under acidic conditions, followed by the addition of β-mercaptoethanol (BME), could also be used to generate carboxylic acids. For the preparation of peptide amides, azides that can be prepared from hydrazides were reacted with ammonium acetate (NH4OAc) or tris(2-carboxyethyl)phosphine (TCEP)∙hydrochloride (HCl) to develop the products through ammonolysis or a Staudinger reaction, which produces iminophosphorane from an azide and a phosphine. The antimicrobial activity of modelin-5 derivatives synthesized from the corresponding hydrazides was evaluated by the colony count of Escherichia coli (E. coli) after treatment with the peptides. Results: Oxone oxidation yielded the corresponding acids rapidly although oxidation-prone amino acids were incompatible. Azidation and subsequent treatment with BME afforded peptide acids an acceptable yield even in sequences containing amino acids that are prone to oxidation. Both methods for conversion of hydrazides to amides were found to afford the desired products in good yield and compatibility. The conditions that were developed were adapted to the synthesis of modelin-5 derivatives from the corresponding hydrazides, yielding late-stage production of the desired peptides. The amides of the resulting peptide showed more potent activity against E. coli than the acid form, and the most potent activity was observed from the hydrazide. Conclusions: The developed protocols allow hydrazides to be converted to acids or amides, enabling late-stage diversification of peptide C-terminal residues. |
| format | Article |
| id | doaj-art-d85ca7bb5e2f486c8c77386175bba64b |
| institution | Kabale University |
| issn | 2836-7677 |
| language | English |
| publishDate | 2023-10-01 |
| publisher | Open Exploration |
| record_format | Article |
| series | Exploration of Drug Science |
| spelling | doaj-art-d85ca7bb5e2f486c8c77386175bba64b2025-02-08T03:49:04ZengOpen ExplorationExploration of Drug Science2836-76772023-10-011532233510.37349/eds.2023.00023Late-stage diversification strategy for the synthesis of peptide acids and amides using hydrazidesShoko Tanaka0Mizuki Kanno1Yosuke Tashiro2https://orcid.org/0000-0002-2619-0493Tetsuo Narumi3https://orcid.org/0000-0003-2412-4035Nobuyuki Mase4https://orcid.org/0000-0001-6244-4916Kohei Sato5https://orcid.org/0000-0001-6877-9223Graduate School of Science and Technology, Shizuoka University, Hamamatsu 432-8561, JapanGraduate School of Science and Technology, Shizuoka University, Hamamatsu 432-8561, JapanGraduate School of Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan; Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan; Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, JapanGraduate School of Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan; Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan; Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan; Research Institute of Green Science and Technology, Shizuoka University, Hamamatsu 432-8561, JapanGraduate School of Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan; Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan; Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan; Research Institute of Green Science and Technology, Shizuoka University, Hamamatsu 432-8561, JapanGraduate School of Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan; Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan; Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan; Research Institute of Green Science and Technology, Shizuoka University, Hamamatsu 432-8561, JapanAim: Modification of the C-terminus of a peptide to improve its properties, particularly after constructing the peptide chain, has great promise in the development of peptide therapeutics. This study discusses the development of a late-stage diversification method for synthesizing peptide acids and amides from hydrazides which can serve as a common precursor. Methods: Peptide hydrazides were synthesized solely by using conventional solid-phase peptide synthesis (SPPS). Hydrazides were subjected to oxidation by potassium peroxymonosulfate (Oxone) to afford carboxylic acids. Azidation of hydrazides using sodium nitrite (NaNO2) under acidic conditions, followed by the addition of β-mercaptoethanol (BME), could also be used to generate carboxylic acids. For the preparation of peptide amides, azides that can be prepared from hydrazides were reacted with ammonium acetate (NH4OAc) or tris(2-carboxyethyl)phosphine (TCEP)∙hydrochloride (HCl) to develop the products through ammonolysis or a Staudinger reaction, which produces iminophosphorane from an azide and a phosphine. The antimicrobial activity of modelin-5 derivatives synthesized from the corresponding hydrazides was evaluated by the colony count of Escherichia coli (E. coli) after treatment with the peptides. Results: Oxone oxidation yielded the corresponding acids rapidly although oxidation-prone amino acids were incompatible. Azidation and subsequent treatment with BME afforded peptide acids an acceptable yield even in sequences containing amino acids that are prone to oxidation. Both methods for conversion of hydrazides to amides were found to afford the desired products in good yield and compatibility. The conditions that were developed were adapted to the synthesis of modelin-5 derivatives from the corresponding hydrazides, yielding late-stage production of the desired peptides. The amides of the resulting peptide showed more potent activity against E. coli than the acid form, and the most potent activity was observed from the hydrazide. Conclusions: The developed protocols allow hydrazides to be converted to acids or amides, enabling late-stage diversification of peptide C-terminal residues.https://www.explorationpub.com/uploads/Article/A100823/100823.pdflate-stage diversificationpeptide hydrazidepeptide acidpeptide amideantimicrobial peptide |
| spellingShingle | Shoko Tanaka Mizuki Kanno Yosuke Tashiro Tetsuo Narumi Nobuyuki Mase Kohei Sato Late-stage diversification strategy for the synthesis of peptide acids and amides using hydrazides Exploration of Drug Science late-stage diversification peptide hydrazide peptide acid peptide amide antimicrobial peptide |
| title | Late-stage diversification strategy for the synthesis of peptide acids and amides using hydrazides |
| title_full | Late-stage diversification strategy for the synthesis of peptide acids and amides using hydrazides |
| title_fullStr | Late-stage diversification strategy for the synthesis of peptide acids and amides using hydrazides |
| title_full_unstemmed | Late-stage diversification strategy for the synthesis of peptide acids and amides using hydrazides |
| title_short | Late-stage diversification strategy for the synthesis of peptide acids and amides using hydrazides |
| title_sort | late stage diversification strategy for the synthesis of peptide acids and amides using hydrazides |
| topic | late-stage diversification peptide hydrazide peptide acid peptide amide antimicrobial peptide |
| url | https://www.explorationpub.com/uploads/Article/A100823/100823.pdf |
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