Synthesis and biological evaluation of 2,4-diaminopyrimidines as selective Aurora A kinase inhibitors

Wen Wen Qin; Chun Yan Sang; Lin Lin Zhang; Wei Wei; Heng Zhi Tian; Huan Xiang Liu; Shi Wu Chen; Ling Hui

doi:10.1016/j.ejmech.2015.03.044

Synthesis and biological evaluation of 2,4-diaminopyrimidines as selective Aurora A kinase inhibitors

Wen Wen Qin, Chun Yan Sang, Lin Lin Zhang, Wei Wei, Heng Zhi Tian, Huan Xiang Liu, Shi Wu Chen, Ling Hui

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

27 Citations (Scopus)

Abstract

The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Here we synthesized 15 2,4-diaminopyrimidines and evaluated their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects. These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control, especially compound 11c, which showed the highest cytotoxicities, with IC₅₀ values of 0.5-4.0 1/4M. Compound 11c had more than 35-fold more selectivity for Aurora A over Aurora B, and molecular docking analysis indicated that compound 11c form better interaction with Aurora A both from the perspective of structure and energy. Furthermore, compound 11c induced G2/M cell cycle arrest in HeLa cells. This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity.

Original language	English
Pages (from-to)	174-184
Number of pages	11
Journal	European Journal of Medicinal Chemistry
Volume	95
DOIs	https://doi.org/10.1016/j.ejmech.2015.03.044
Publication status	Published - 5 May 2015
Externally published	Yes

Keywords

Aurora kinase
Cell cycle
Kinase inhibitors
Pyrimidine

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10.1016/j.ejmech.2015.03.044

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title = "Synthesis and biological evaluation of 2,4-diaminopyrimidines as selective Aurora A kinase inhibitors",

abstract = "The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Here we synthesized 15 2,4-diaminopyrimidines and evaluated their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects. These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control, especially compound 11c, which showed the highest cytotoxicities, with IC50 values of 0.5-4.0 1/4M. Compound 11c had more than 35-fold more selectivity for Aurora A over Aurora B, and molecular docking analysis indicated that compound 11c form better interaction with Aurora A both from the perspective of structure and energy. Furthermore, compound 11c induced G2/M cell cycle arrest in HeLa cells. This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity.",

keywords = "Aurora kinase, Cell cycle, Kinase inhibitors, Pyrimidine",

author = "Qin, {Wen Wen} and Sang, {Chun Yan} and Zhang, {Lin Lin} and Wei Wei and Tian, {Heng Zhi} and Liu, {Huan Xiang} and Chen, {Shi Wu} and Ling Hui",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Masson SAS.",

year = "2015",

month = may,

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doi = "10.1016/j.ejmech.2015.03.044",

language = "English",

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journal = "European Journal of Medicinal Chemistry",

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T1 - Synthesis and biological evaluation of 2,4-diaminopyrimidines as selective Aurora A kinase inhibitors

AU - Qin, Wen Wen

AU - Sang, Chun Yan

AU - Zhang, Lin Lin

AU - Wei, Wei

AU - Tian, Heng Zhi

AU - Liu, Huan Xiang

AU - Chen, Shi Wu

AU - Hui, Ling

PY - 2015/5/5

Y1 - 2015/5/5

N2 - The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Here we synthesized 15 2,4-diaminopyrimidines and evaluated their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects. These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control, especially compound 11c, which showed the highest cytotoxicities, with IC50 values of 0.5-4.0 1/4M. Compound 11c had more than 35-fold more selectivity for Aurora A over Aurora B, and molecular docking analysis indicated that compound 11c form better interaction with Aurora A both from the perspective of structure and energy. Furthermore, compound 11c induced G2/M cell cycle arrest in HeLa cells. This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity.

AB - The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Here we synthesized 15 2,4-diaminopyrimidines and evaluated their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects. These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control, especially compound 11c, which showed the highest cytotoxicities, with IC50 values of 0.5-4.0 1/4M. Compound 11c had more than 35-fold more selectivity for Aurora A over Aurora B, and molecular docking analysis indicated that compound 11c form better interaction with Aurora A both from the perspective of structure and energy. Furthermore, compound 11c induced G2/M cell cycle arrest in HeLa cells. This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity.

KW - Aurora kinase

KW - Cell cycle

KW - Kinase inhibitors

KW - Pyrimidine

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DO - 10.1016/j.ejmech.2015.03.044

M3 - Article

C2 - 25812967

AN - SCOPUS:84925452900

SN - 0223-5234

VL - 95

SP - 174

EP - 184

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

Synthesis and biological evaluation of 2,4-diaminopyrimidines as selective Aurora A kinase inhibitors

Abstract

Keywords

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