title: Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression.
abstract: (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 G2/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 μM 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Narsimha R
authors.initials: NR
authors.lastname: Penthala
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Shobanbabu
authors.initials: S
authors.lastname: Bommagani
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Venumadhav
authors.initials: V
authors.lastname: Janganati
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Kenzie B
authors.initials: KB
authors.lastname: MacNicol
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Cragle
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Nikhil R
authors.initials: NR
authors.lastname: Madadi
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Linda L
authors.initials: LL
authors.lastname: Hardy
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: Angus@uams.edu.
authors.forename: Angus M
authors.initials: AM
authors.lastname: MacNicol
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: pacrooks@uams.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D009865:Oocytes / Q000166:cytology / Q000187:drug effects; D012717:Sesquiterpenes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D000970:Antineoplastic Agents; D012717:Sesquiterpenes; C558241:melampomagnolide B; C002669:parthenolide
keywords: Anti-cancer activity; Heck reaction; Melampomagnolide B; Oocyte maturation; Parthenolide