Novel 5,6-disubstituted pyrrolo[2,3-d]pyrimidine derivatives as broad spectrum antiproliferative agents: Synthesis, cell based assays, kinase profile and molecular docking study

Ju Hyeon Lee, Ashraf K. El-Damasy, Seon Hee Seo, Changdev G. Gadhe, Ae Nim Pae, Nakcheol Jeong, Soon Sun Hong, Gyochang Keum

Research output: Contribution to journalArticle

Abstract

Two new series of 5-subtituted and 5,6-disubstituted pyrrolo[2,3-d]pyrimidine octamides (4a–o and 6a–g) and their corresponding free amines 5a–m and 7a–g have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides 6d–g as well as the amine derivative 7b have shown the best anticancer activity with single digit micromolar GI50 values over the tested cancer cells, and low cytotoxic effects (GI50 > 10.0 µM) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-d]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member 6f was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI50 and TGI values over multiple cancer cells. Kinase profile of compound 6f over 53 oncogenic kinases at 10 µM concentration showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of 6f against TrkA (IC50 = 2.25 µM), FGFR4 (IC50 = 6.71 µM) and Tie2 (IC50 = 6.84 µM) was explained by molecular docking study, which also proposed that 6f may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound 6f may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents.

Original languageEnglish
JournalBioorganic and Medicinal Chemistry
DOIs
Publication statusAccepted/In press - 2018 Jan 1

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Assays
Phosphotransferases
Derivatives
Cells
Inhibitory Concentration 50
Amines
Neoplasms
Piperazines
Allosteric Site
Lead compounds
Cell Line
Hinges
Structure-Activity Relationship
Antineoplastic Agents
Pyrrolo(2,3-d)pyrimidine

Keywords

  • Antiproliferative activity
  • FGFR4 kinase
  • Mannich reaction
  • Molecular docking
  • Pyrrolo[2,3-d]pyrimidine octamides
  • Tie2
  • TrKA

ASJC Scopus subject areas

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

Cite this

Novel 5,6-disubstituted pyrrolo[2,3-d]pyrimidine derivatives as broad spectrum antiproliferative agents : Synthesis, cell based assays, kinase profile and molecular docking study. / Lee, Ju Hyeon; El-Damasy, Ashraf K.; Seo, Seon Hee; Gadhe, Changdev G.; Pae, Ae Nim; Jeong, Nakcheol; Hong, Soon Sun; Keum, Gyochang.

In: Bioorganic and Medicinal Chemistry, 01.01.2018.

Research output: Contribution to journalArticle

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abstract = "Two new series of 5-subtituted and 5,6-disubstituted pyrrolo[2,3-d]pyrimidine octamides (4a–o and 6a–g) and their corresponding free amines 5a–m and 7a–g have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides 6d–g as well as the amine derivative 7b have shown the best anticancer activity with single digit micromolar GI50 values over the tested cancer cells, and low cytotoxic effects (GI50 > 10.0 µM) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-d]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member 6f was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI50 and TGI values over multiple cancer cells. Kinase profile of compound 6f over 53 oncogenic kinases at 10 µM concentration showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of 6f against TrkA (IC50 = 2.25 µM), FGFR4 (IC50 = 6.71 µM) and Tie2 (IC50 = 6.84 µM) was explained by molecular docking study, which also proposed that 6f may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound 6f may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents.",
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AU - Lee, Ju Hyeon

AU - El-Damasy, Ashraf K.

AU - Seo, Seon Hee

AU - Gadhe, Changdev G.

AU - Pae, Ae Nim

AU - Jeong, Nakcheol

AU - Hong, Soon Sun

AU - Keum, Gyochang

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