1,4-Thienodiazepine-2,5-diones via MCR (I): Synthesis, Virtual Space and p53-Mdm2 Activity

Yijun Huang; Siglinde Wolf; Michal Bista; Lidio Meireles; Carlos Camacho; Tad A. Holak; Alexander Doemling

doi:10.1111/j.1747-0285.2010.00989.x

1,4-Thienodiazepine-2,5-diones via MCR (I): Synthesis, Virtual Space and p53-Mdm2 Activity

Yijun Huang, Siglinde Wolf, Michal Bista, Lidio Meireles, Carlos Camacho, Tad A. Holak, Alexander Doemling^*

^*Corresponding author for this work

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

65 Citations (Scopus)

Abstract

1,4-Thienodiazepine-2,5-diones have been synthesized via the Ugi-Deprotection-Cyclization (UDC) approach starting from Gewald 2-aminothiophenes in a convergent and versatile manner. The resulting scaffold is unprecedented, cyclic, and peptidomimetic with four points of diversity introduced from readily available starting materials. In addition to eighteen synthesized and characterized compounds, a virtual compound library was generated and evaluated for chemical space distribution and drug-like properties. A small focused compound library of 1,4-thienodiazepine-2,5-diones has been screened for the activity against p53-Mdm2 interaction. Biological evaluations demonstrated that some compounds exhibited promising antagonistic activity.

Original language	English
Pages (from-to)	116-129
Number of pages	14
Journal	Chemical biology & drug design
Volume	76
Issue number	2
DOIs	https://doi.org/10.1111/j.1747-0285.2010.00989.x
Publication status	Published - Aug-2010
Externally published	Yes

Keywords

1,4-thienodiazepine-2,5-dione
multicomponent reaction
p53-Mdm2 interaction
virtual chemical space
PROTEIN-PROTEIN INTERACTION
SMALL-MOLECULE ANTAGONISTS
HDM2 ANTAGONISTS
MULTICOMPONENT REACTIONS
MDM2 INHIBITORS
CANCER-THERAPY
FORCE-FIELD
P53 PATHWAY
1,4-BENZODIAZEPINE-2,5-DIONES
CHEMISTRY

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title = "1,4-Thienodiazepine-2,5-diones via MCR (I): Synthesis, Virtual Space and p53-Mdm2 Activity",

abstract = "1,4-Thienodiazepine-2,5-diones have been synthesized via the Ugi-Deprotection-Cyclization (UDC) approach starting from Gewald 2-aminothiophenes in a convergent and versatile manner. The resulting scaffold is unprecedented, cyclic, and peptidomimetic with four points of diversity introduced from readily available starting materials. In addition to eighteen synthesized and characterized compounds, a virtual compound library was generated and evaluated for chemical space distribution and drug-like properties. A small focused compound library of 1,4-thienodiazepine-2,5-diones has been screened for the activity against p53-Mdm2 interaction. Biological evaluations demonstrated that some compounds exhibited promising antagonistic activity.",

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author = "Yijun Huang and Siglinde Wolf and Michal Bista and Lidio Meireles and Carlos Camacho and Holak, {Tad A.} and Alexander Doemling",

year = "2010",

month = aug,

doi = "10.1111/j.1747-0285.2010.00989.x",

language = "English",

volume = "76",

pages = "116--129",

journal = "Chemical biology & drug design",

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T1 - 1,4-Thienodiazepine-2,5-diones via MCR (I)

T2 - Synthesis, Virtual Space and p53-Mdm2 Activity

AU - Huang, Yijun

AU - Wolf, Siglinde

AU - Bista, Michal

AU - Meireles, Lidio

AU - Camacho, Carlos

AU - Holak, Tad A.

AU - Doemling, Alexander

PY - 2010/8

Y1 - 2010/8

N2 - 1,4-Thienodiazepine-2,5-diones have been synthesized via the Ugi-Deprotection-Cyclization (UDC) approach starting from Gewald 2-aminothiophenes in a convergent and versatile manner. The resulting scaffold is unprecedented, cyclic, and peptidomimetic with four points of diversity introduced from readily available starting materials. In addition to eighteen synthesized and characterized compounds, a virtual compound library was generated and evaluated for chemical space distribution and drug-like properties. A small focused compound library of 1,4-thienodiazepine-2,5-diones has been screened for the activity against p53-Mdm2 interaction. Biological evaluations demonstrated that some compounds exhibited promising antagonistic activity.

AB - 1,4-Thienodiazepine-2,5-diones have been synthesized via the Ugi-Deprotection-Cyclization (UDC) approach starting from Gewald 2-aminothiophenes in a convergent and versatile manner. The resulting scaffold is unprecedented, cyclic, and peptidomimetic with four points of diversity introduced from readily available starting materials. In addition to eighteen synthesized and characterized compounds, a virtual compound library was generated and evaluated for chemical space distribution and drug-like properties. A small focused compound library of 1,4-thienodiazepine-2,5-diones has been screened for the activity against p53-Mdm2 interaction. Biological evaluations demonstrated that some compounds exhibited promising antagonistic activity.

KW - 1,4-thienodiazepine-2,5-dione

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KW - p53-Mdm2 interaction

KW - virtual chemical space

KW - PROTEIN-PROTEIN INTERACTION

KW - SMALL-MOLECULE ANTAGONISTS

KW - HDM2 ANTAGONISTS

KW - MULTICOMPONENT REACTIONS

KW - MDM2 INHIBITORS

KW - CANCER-THERAPY

KW - FORCE-FIELD

KW - P53 PATHWAY

KW - 1,4-BENZODIAZEPINE-2,5-DIONES

KW - CHEMISTRY

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DO - 10.1111/j.1747-0285.2010.00989.x

M3 - Article

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EP - 129

JO - Chemical biology & drug design

JF - Chemical biology & drug design

IS - 2

ER -

1,4-Thienodiazepine-2,5-diones via MCR (I): Synthesis, Virtual Space and p53-Mdm2 Activity

Abstract

Keywords

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