Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors

Sung Hee Hwang, Aaron T. Wecksler, Guodong Zhang, Christophe Morisseau, Long V. Nguyen, Samuel H. Fu, Bruce D. Hammock

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

To reduce the pro-angiogenic effects of sEH inhibition, a structure-activity relationship (SAR) study was performed by incorporating structural features of the anti-angiogenic multi-kinase inhibitor sorafenib into soluble epoxide hydrolase (sEH) inhibitors. The structural modifications of this series of molecules enabled the altering of selectivity towards the pro-angiogenic kinases C-RAF and vascular endothelial growth factor receptor-2 (VEGFR-2), while retaining their sEH inhibition. As a result, sEH inhibitors with greater potency against C-RAF and VEGFR-2 were obtained. Compound 4 (t-CUPM) possesses inhibition potency higher than sorafenib towards sEH but similar against C-RAF and VEGFR-2. Compound 7 (t-CUCB) selectively inhibits sEH, while inhibiting HUVEC cell proliferation, a potential anti-angiogenic property, without liver cancer cell cytotoxicity. The data presented suggest a potential rational approach to control the angiogenic responses stemming from sEH inhibition.

Original languageEnglish (US)
Pages (from-to)3732-3737
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number13
DOIs
StatePublished - Jul 1 2013

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Keywords

  • Angiogenesis
  • C-RAF kinase
  • Regorafenib
  • Soluble epoxide hydrolase (sEH)
  • Sorafenib
  • VEGFR-2

ASJC Scopus subject areas

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

Cite this

Hwang, S. H., Wecksler, A. T., Zhang, G., Morisseau, C., Nguyen, L. V., Fu, S. H., & Hammock, B. D. (2013). Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors. Bioorganic and Medicinal Chemistry Letters, 23(13), 3732-3737. https://doi.org/10.1016/j.bmcl.2013.05.011