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 Citations (Scopus)

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

Fingerprint

Epoxide Hydrolases
Vascular Endothelial Growth Factor Receptor-2
Phosphotransferases
Human Umbilical Vein Endothelial Cells
Cell proliferation
Structure-Activity Relationship
Liver Neoplasms
Cytotoxicity
regorafenib
sorafenib
Liver
Cells
Cell Proliferation
Molecules

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

Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors. / Hwang, Sung Hee; Wecksler, Aaron T.; Zhang, Guodong; Morisseau, Christophe; Nguyen, Long V.; Fu, Samuel H.; Hammock, Bruce D.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 13, 01.07.2013, p. 3732-3737.

Research output: Contribution to journalArticle

Hwang, SH, Wecksler, AT, Zhang, G, Morisseau, C, Nguyen, LV, Fu, SH & Hammock, BD 2013, 'Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 13, pp. 3732-3737. https://doi.org/10.1016/j.bmcl.2013.05.011
Hwang, Sung Hee ; Wecksler, Aaron T. ; Zhang, Guodong ; Morisseau, Christophe ; Nguyen, Long V. ; Fu, Samuel H. ; Hammock, Bruce D. / Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 13. pp. 3732-3737.
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