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 journalArticlepeer-review

14 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 languageEnglish
Pages (from-to)237-241
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number2
DOIs
Publication statusPublished - 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

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