Synthesis of Constrained Tetracyclic Peptides by Consecutive CEPS, CLIPS, and Oxime Ligation

Dieuwertje E. Streefkerk; Marcel Schmidt; Johannes H. Ippel; Tilman M. Hackeng; Timo Nuijens; Peter Timmerman; Jan H. van Maarseveen

doi:10.1021/acs.orglett.9b00378

Synthesis of Constrained Tetracyclic Peptides by Consecutive CEPS, CLIPS, and Oxime Ligation

Dieuwertje E. Streefkerk, Marcel Schmidt, Johannes H. Ippel, Tilman M. Hackeng, Timo Nuijens, Peter Timmerman, Jan H. van Maarseveen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

In Nature, multicyclic peptides constitute a versatile molecule class with various biological functions. For their pharmaceutical exploitation, chemical methodologies that enable selective consecutive macrocyclizations are required. We disclose a combination of enzymatic macrocyclization, CLIPS alkylation, and oxime ligation to prepare tetracyclic peptides. Five new small molecular scaffolds and differently sized model peptides featuring noncanonical amino acids were synthesized. Enzymatic macrocyclization, followed by one-pot scaffold-assisted cyclizations, yielded 21 tetracyclic peptides in a facile and robust manner.

Original language	English
Pages (from-to)	2095-2100
Number of pages	6
Journal	Organic Letters
Volume	21
Issue number	7
DOIs	https://doi.org/10.1021/acs.orglett.9b00378
Publication status	Published - 5 Apr 2019

Keywords

DISULFIDE-RICH PEPTIDES
MACROCYCLIZATION
CYCLIZATION
SYSTEM
SCAFFOLDS
HYBRIDS
SITE

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10.1021/acs.orglett.9b00378Licence: CC BY-NC-ND

Cite this

@article{8384c830139d4a3f8e940df19a4bd072,

title = "Synthesis of Constrained Tetracyclic Peptides by Consecutive CEPS, CLIPS, and Oxime Ligation",

abstract = "In Nature, multicyclic peptides constitute a versatile molecule class with various biological functions. For their pharmaceutical exploitation, chemical methodologies that enable selective consecutive macrocyclizations are required. We disclose a combination of enzymatic macrocyclization, CLIPS alkylation, and oxime ligation to prepare tetracyclic peptides. Five new small molecular scaffolds and differently sized model peptides featuring noncanonical amino acids were synthesized. Enzymatic macrocyclization, followed by one-pot scaffold-assisted cyclizations, yielded 21 tetracyclic peptides in a facile and robust manner.",

keywords = "DISULFIDE-RICH PEPTIDES, MACROCYCLIZATION, CYCLIZATION, SYSTEM, SCAFFOLDS, HYBRIDS, SITE",

author = "Streefkerk, {Dieuwertje E.} and Marcel Schmidt and Ippel, {Johannes H.} and Hackeng, {Tilman M.} and Timo Nuijens and Peter Timmerman and {van Maarseveen}, {Jan H.}",

note = "Funding Information: This project was financed by The Netherlands Organization for Scientific Research (NWO-TTW, Project No. 12557). The authors wish to thank Dr. Rodney Lax (EnzyPep B.V.) for useful discussions and providing corrections to this manuscript. Ed Zuidinga (UvA) and Dennis Suylen (Maastricht) are kindly acknowledged for exact mass analysis. Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

year = "2019",

month = apr,

day = "5",

doi = "10.1021/acs.orglett.9b00378",

language = "English",

volume = "21",

pages = "2095--2100",

journal = "Organic Letters",

issn = "1523-7060",

publisher = "American Chemical Society",

number = "7",

}

TY - JOUR

T1 - Synthesis of Constrained Tetracyclic Peptides by Consecutive CEPS, CLIPS, and Oxime Ligation

AU - Streefkerk, Dieuwertje E.

AU - Schmidt, Marcel

AU - Ippel, Johannes H.

AU - Hackeng, Tilman M.

AU - Nuijens, Timo

AU - Timmerman, Peter

AU - van Maarseveen, Jan H.

N1 - Funding Information: This project was financed by The Netherlands Organization for Scientific Research (NWO-TTW, Project No. 12557). The authors wish to thank Dr. Rodney Lax (EnzyPep B.V.) for useful discussions and providing corrections to this manuscript. Ed Zuidinga (UvA) and Dennis Suylen (Maastricht) are kindly acknowledged for exact mass analysis. Publisher Copyright: © 2019 American Chemical Society.

PY - 2019/4/5

Y1 - 2019/4/5

N2 - In Nature, multicyclic peptides constitute a versatile molecule class with various biological functions. For their pharmaceutical exploitation, chemical methodologies that enable selective consecutive macrocyclizations are required. We disclose a combination of enzymatic macrocyclization, CLIPS alkylation, and oxime ligation to prepare tetracyclic peptides. Five new small molecular scaffolds and differently sized model peptides featuring noncanonical amino acids were synthesized. Enzymatic macrocyclization, followed by one-pot scaffold-assisted cyclizations, yielded 21 tetracyclic peptides in a facile and robust manner.

AB - In Nature, multicyclic peptides constitute a versatile molecule class with various biological functions. For their pharmaceutical exploitation, chemical methodologies that enable selective consecutive macrocyclizations are required. We disclose a combination of enzymatic macrocyclization, CLIPS alkylation, and oxime ligation to prepare tetracyclic peptides. Five new small molecular scaffolds and differently sized model peptides featuring noncanonical amino acids were synthesized. Enzymatic macrocyclization, followed by one-pot scaffold-assisted cyclizations, yielded 21 tetracyclic peptides in a facile and robust manner.

KW - DISULFIDE-RICH PEPTIDES

KW - MACROCYCLIZATION

KW - CYCLIZATION

KW - SYSTEM

KW - SCAFFOLDS

KW - HYBRIDS

KW - SITE

U2 - 10.1021/acs.orglett.9b00378

DO - 10.1021/acs.orglett.9b00378

M3 - Article

C2 - 30912446

SN - 1523-7060

VL - 21

SP - 2095

EP - 2100

JO - Organic Letters

JF - Organic Letters

IS - 7

ER -