The tandem chain extension aldol reaction used for synthesis of ketomethylene tripeptidomimetics targeting hPEPT1

Karina Thorn; Carsten Uhd Nielsen; Palle Jakobsen; Bente Steffansen; Charles K Zercher; Mikael Begtrup

doi:10.1016/j.bmcl.2011.05.108

The tandem chain extension aldol reaction used for synthesis of ketomethylene tripeptidomimetics targeting hPEPT1

Karina Thorn, Carsten Uhd Nielsen, Palle Jakobsen, Bente Steffansen, Charles K Zercher, Mikael Begtrup

Research output: Contribution to journal › Journal article › Research › peer-review

2 Citations (Scopus)

Abstract

The rationale for targeting the human di-/tripeptide transporter hPEPT1 for oral drug delivery has been well established by several drug and prodrug cases. The aim of this study was to synthesize novel ketomethylene modified tripeptidomimetics and to investigate their binding affinity for hPEPT1. Three related tripeptidomimetics of the structure H-Phe-¿[COCH(2)]-Ser(Bz)-X(aa)-OH were synthesized applying the tandem chain extension aldol reaction, where amino acid derived ß-keto imides were stereoselectively converted to a-substituted ¿-keto imides. In addition, three corresponding tripeptides, composed of amide bonds, were synthesized for comparison of binding affinities. The six investigated compounds were all defined as high affinity ligands (K(i)-values

Original language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	21
Issue number	15
Pages (from-to)	4597-4601
ISSN	0960-894X
DOIs	https://doi.org/10.1016/j.bmcl.2011.05.108
Publication status	Published - Aug 2011

Keywords

Former Faculty of Pharmaceutical Sciences

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@article{3a2f0e8f7bd743f6b907e2dc82ad9778,

title = "The tandem chain extension aldol reaction used for synthesis of ketomethylene tripeptidomimetics targeting hPEPT1",

abstract = "The rationale for targeting the human di-/tripeptide transporter hPEPT1 for oral drug delivery has been well established by several drug and prodrug cases. The aim of this study was to synthesize novel ketomethylene modified tripeptidomimetics and to investigate their binding affinity for hPEPT1. Three related tripeptidomimetics of the structure H-Phe-¿[COCH(2)]-Ser(Bz)-X(aa)-OH were synthesized applying the tandem chain extension aldol reaction, where amino acid derived {\ss}-keto imides were stereoselectively converted to a-substituted ¿-keto imides. In addition, three corresponding tripeptides, composed of amide bonds, were synthesized for comparison of binding affinities. The six investigated compounds were all defined as high affinity ligands (K(i)-values ",

keywords = "Former Faculty of Pharmaceutical Sciences",

author = "Karina Thorn and Nielsen, {Carsten Uhd} and Palle Jakobsen and Bente Steffansen and Zercher, {Charles K} and Mikael Begtrup",

note = "Keywords: hPEPT1, ketomethylene, peptides, peptidomimetics, TCEA reaction",

year = "2011",

month = aug,

doi = "10.1016/j.bmcl.2011.05.108",

language = "English",

volume = "21",

pages = "4597--4601",

journal = "Bioorganic & Medicinal Chemistry Letters",

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T1 - The tandem chain extension aldol reaction used for synthesis of ketomethylene tripeptidomimetics targeting hPEPT1

AU - Thorn, Karina

AU - Nielsen, Carsten Uhd

AU - Jakobsen, Palle

AU - Steffansen, Bente

AU - Zercher, Charles K

AU - Begtrup, Mikael

N1 - Keywords: hPEPT1, ketomethylene, peptides, peptidomimetics, TCEA reaction

PY - 2011/8

Y1 - 2011/8

N2 - The rationale for targeting the human di-/tripeptide transporter hPEPT1 for oral drug delivery has been well established by several drug and prodrug cases. The aim of this study was to synthesize novel ketomethylene modified tripeptidomimetics and to investigate their binding affinity for hPEPT1. Three related tripeptidomimetics of the structure H-Phe-¿[COCH(2)]-Ser(Bz)-X(aa)-OH were synthesized applying the tandem chain extension aldol reaction, where amino acid derived ß-keto imides were stereoselectively converted to a-substituted ¿-keto imides. In addition, three corresponding tripeptides, composed of amide bonds, were synthesized for comparison of binding affinities. The six investigated compounds were all defined as high affinity ligands (K(i)-values

AB - The rationale for targeting the human di-/tripeptide transporter hPEPT1 for oral drug delivery has been well established by several drug and prodrug cases. The aim of this study was to synthesize novel ketomethylene modified tripeptidomimetics and to investigate their binding affinity for hPEPT1. Three related tripeptidomimetics of the structure H-Phe-¿[COCH(2)]-Ser(Bz)-X(aa)-OH were synthesized applying the tandem chain extension aldol reaction, where amino acid derived ß-keto imides were stereoselectively converted to a-substituted ¿-keto imides. In addition, three corresponding tripeptides, composed of amide bonds, were synthesized for comparison of binding affinities. The six investigated compounds were all defined as high affinity ligands (K(i)-values

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1016/j.bmcl.2011.05.108

DO - 10.1016/j.bmcl.2011.05.108

M3 - Journal article

C2 - 21703856

SN - 0960-894X

VL - 21

SP - 4597

EP - 4601

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 15

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