4.7 Article

Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression

Journal

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 85, Issue -, Pages 517-525

Publisher

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.08.022

Keywords

Parthenolide; Melampomagnolide B; Heck reaction; Oocyte maturation; Anti-cancer activity

Funding

  1. NCI/NIH [R01 CA158275]
  2. Arkansas Research Alliance (ARA)
  3. National Institutes of Health [RO1 HD35688]
  4. Sturgis Diabetes Research Pilot Award
  5. Arkansas Breast Cancer Research Program Award
  6. UAMS College of Medicine Research Council
  7. NIGMS IDeA Program Award [P30 GM110702]
  8. UAMS Translational Research Institute - NIH National Center for Research Resources [UL1 TR0000039, KL2TR000063]
  9. NSF [CHE-0541848]

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(E)-13-(Aryl/heteroaryl)parthenolides (5a-i and 6a-i) were synthesized and evaluated for their ability to modify cell cycle progression during progesterone-stimulated Xenopus oocyte maturation and screened for their anticancer activity against a panel of 60 human cancer cell lines. (E)-13-(4-aminophenyl) parthenolide (5b) caused a significant inhibition of progesterone-stimulated oocyte maturation, and was determined to function downstream of MAP kinase signaling, but upstream of the activation of the universal G(2)/M regulator, M-phase promoting factor (MPF), cyclin B/Cyclin-dependent kinase (CDK). The compound (E)-13-(2-bromo-phenyl)parthenolide (5c) activates oocyte maturation independently of progesterone stimulation. Compounds 5b and 5c displayed modest growth inhibition on select cancer cell lines at 10 mu M dose when tested on the panel of 60 cancer cell lines. By contrast, compounds (5f and 7) did not modulate oocyte maturation but did exhibit micromolar level growth inhibition against most of the human cancer cell lines over a range of doses. Together, our findings indicate that screening of compounds in the oocyte maturation assay may identify additional effective cell cycle regulatory compounds that do not necessarily exert overt cytotoxicity as assessed in traditional drug screening assays. (C) 2014 Elsevier Masson SAS. All rights reserved.

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