Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors

Ju Hyeon Lee; Sang Chul Shin; Seon Hee Seo; Young Ho Seo; Nakcheol Jeong; Chan Wha Kim; Eunice Eun Kyeong Kim; Gyochang Keum

doi:10.1016/j.bmcl.2016.11.062

Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors

Ju Hyeon Lee, Sang Chul Shin, Seon Hee Seo, Young Ho Seo, Nakcheol Jeong, Chan Wha Kim, Eunice Eun Kyeong Kim, Gyochang Keum

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

17 Citations (Scopus)

Abstract

A novel series of heat shock protein 90 (Hsp90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent Hsp90 inhibition and broad-spectrum antiproliferative activity against NCI-60 cancer cell lines. The most potent compound, 6a, inhibited Hsp90 with an IC₅₀of 36 nM and showed a submicromolar mean GI₅₀value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of Hsp90 was confirmed by X-ray crystallography and Western blot analysis.

Original language	English
Pages (from-to)	237-241
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.bmcl.2016.11.062
Publication status	Published - 2017

Bibliographical note

Funding Information:
This research was supported by the Korea Institute of Science and Technology (KIST) Institutional Program (2E26650 and 2E26663). We express our sincere appreciation and gratitude for the National Cancer Institute (NCI, Bethesda, MD, USA) for performing the anticancer evaluation of the new compounds. This work was also supported by a grant from the Global Research Laboratory Program of the Ministry of Science, ICT, Future Planning of Korea (MISP: grant No. NRF 20110021713), and the R&D Convergence Program of National Research Council of Science & Technology of the Republic of Korea.

Publisher Copyright:
© 2016

Keywords

Antiproliferative
Cancer
Hsp90
Pyrrolo[2,3-d]pyrimidines
Structure-based design

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2016.11.062

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title = "Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors",

abstract = "A novel series of heat shock protein 90 (Hsp90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent Hsp90 inhibition and broad-spectrum antiproliferative activity against NCI-60 cancer cell lines. The most potent compound, 6a, inhibited Hsp90 with an IC50of 36 nM and showed a submicromolar mean GI50value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of Hsp90 was confirmed by X-ray crystallography and Western blot analysis.",

keywords = "Antiproliferative, Cancer, Hsp90, Pyrrolo[2,3-d]pyrimidines, Structure-based design",

author = "Lee, {Ju Hyeon} and Shin, {Sang Chul} and Seo, {Seon Hee} and Seo, {Young Ho} and Nakcheol Jeong and Kim, {Chan Wha} and Kim, {Eunice Eun Kyeong} and Gyochang Keum",

note = "Funding Information: This research was supported by the Korea Institute of Science and Technology (KIST) Institutional Program (2E26650 and 2E26663). We express our sincere appreciation and gratitude for the National Cancer Institute (NCI, Bethesda, MD, USA) for performing the anticancer evaluation of the new compounds. This work was also supported by a grant from the Global Research Laboratory Program of the Ministry of Science, ICT, Future Planning of Korea (MISP: grant No. NRF 20110021713), and the R&D Convergence Program of National Research Council of Science & Technology of the Republic of Korea. Publisher Copyright: {\textcopyright} 2016",

year = "2017",

doi = "10.1016/j.bmcl.2016.11.062",

language = "English",

volume = "27",

pages = "237--241",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

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T1 - Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors

AU - Lee, Ju Hyeon

AU - Shin, Sang Chul

AU - Seo, Seon Hee

AU - Seo, Young Ho

AU - Jeong, Nakcheol

AU - Kim, Chan Wha

AU - Kim, Eunice Eun Kyeong

AU - Keum, Gyochang

N1 - Funding Information: This research was supported by the Korea Institute of Science and Technology (KIST) Institutional Program (2E26650 and 2E26663). We express our sincere appreciation and gratitude for the National Cancer Institute (NCI, Bethesda, MD, USA) for performing the anticancer evaluation of the new compounds. This work was also supported by a grant from the Global Research Laboratory Program of the Ministry of Science, ICT, Future Planning of Korea (MISP: grant No. NRF 20110021713), and the R&D Convergence Program of National Research Council of Science & Technology of the Republic of Korea. Publisher Copyright: © 2016

PY - 2017

Y1 - 2017

N2 - A novel series of heat shock protein 90 (Hsp90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent Hsp90 inhibition and broad-spectrum antiproliferative activity against NCI-60 cancer cell lines. The most potent compound, 6a, inhibited Hsp90 with an IC50of 36 nM and showed a submicromolar mean GI50value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of Hsp90 was confirmed by X-ray crystallography and Western blot analysis.

AB - A novel series of heat shock protein 90 (Hsp90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent Hsp90 inhibition and broad-spectrum antiproliferative activity against NCI-60 cancer cell lines. The most potent compound, 6a, inhibited Hsp90 with an IC50of 36 nM and showed a submicromolar mean GI50value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of Hsp90 was confirmed by X-ray crystallography and Western blot analysis.

KW - Antiproliferative

KW - Cancer

KW - Hsp90

KW - Pyrrolo[2,3-d]pyrimidines

KW - Structure-based design

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Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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