Novel fluorinated curcuminoids and their pyrazole and isoxazole derivatives

Synthesis, structural studies, Computational/Docking and in-vitro bioassay

Kenneth K. Laali, William J. Greves, Sebastian J. Correa-Smits, Angela T. Zwarycz, Scott D. Bunge, Gabriela L. Borosky, Alak Manna, Aneel Paulus, Asher A Chanan Khan

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

In a continuing search for “curcuminoid (CUR) inspired” compounds with potential antitumor activity, a series of 21 new CUR-BF2 adducts and CURs bearing fluorine, trifluoromethylthio, trifluoromethoxy, and trifluoromethyl substitutents were synthesized in an effort to improve physicochemical properties such as lipophilicity and metabolic stability. Bulky activating groups namely methoxy, acetoxy, and benzyloxy groups were introduced as a way to tune steric/electronic effects. Multinuclear NMR, X-ray analysis and DFT optimizations confirmed that despite significant differences in their substitution patterns these curcuminoids all exist as enolic tautomers, and their CUR-BF2 adducts are symmetrical with equal B-O bond distances. To gauge the potential role of the enolic moiety in interaction with proteins, a library consisting of 22 aryl-pyrazole and isoxazole derivatives were synthesized. 19F NMR provided a rapid and convenient assay to monitor these transformations. Computational/docking studies were performed to compare binding efficiency to target proteins involved in specific cancers versus known inhibitor drugs. Several CUR pyrazoles and isoxazoles presented very favorable binding affinities, particularly those bearing CF3 groups. Highly favorable docking affinities were observed for the benzyloxy-substituted CURs. Selected compounds were tested by in-vitro bioassay against a panel of 60 cancer cell lines, and more specifically against leukemia cell lines by cell viability assay.

Original languageEnglish (US)
Pages (from-to)82-98
Number of pages17
JournalJournal of Fluorine Chemistry
Volume206
DOIs
StatePublished - Feb 1 2018

Fingerprint

Isoxazoles
bioassay
Bioassay
Bearings (structural)
Biological Assay
nuclear magnetic resonance
cancer
Cells
Pyrazoles
assay
Biomolecular Nuclear Magnetic Resonance
Derivatives
cultured cells
Cell Line
adducts
protein
Fluorine
affinity
Assays
fluorine

Keywords

  • Computational docking
  • Curcuminoid-BF adducts
  • Fluorinated CUR-pyrazoles and isoxazoles
  • Fluorocurcuminoids
  • in-vitro bioassay
  • X-ray analysis

ASJC Scopus subject areas

  • Biochemistry
  • Environmental Chemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Novel fluorinated curcuminoids and their pyrazole and isoxazole derivatives : Synthesis, structural studies, Computational/Docking and in-vitro bioassay. / Laali, Kenneth K.; Greves, William J.; Correa-Smits, Sebastian J.; Zwarycz, Angela T.; Bunge, Scott D.; Borosky, Gabriela L.; Manna, Alak; Paulus, Aneel; Chanan Khan, Asher A.

In: Journal of Fluorine Chemistry, Vol. 206, 01.02.2018, p. 82-98.

Research output: Contribution to journalArticle

Laali, Kenneth K. ; Greves, William J. ; Correa-Smits, Sebastian J. ; Zwarycz, Angela T. ; Bunge, Scott D. ; Borosky, Gabriela L. ; Manna, Alak ; Paulus, Aneel ; Chanan Khan, Asher A. / Novel fluorinated curcuminoids and their pyrazole and isoxazole derivatives : Synthesis, structural studies, Computational/Docking and in-vitro bioassay. In: Journal of Fluorine Chemistry. 2018 ; Vol. 206. pp. 82-98.
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abstract = "In a continuing search for “curcuminoid (CUR) inspired” compounds with potential antitumor activity, a series of 21 new CUR-BF2 adducts and CURs bearing fluorine, trifluoromethylthio, trifluoromethoxy, and trifluoromethyl substitutents were synthesized in an effort to improve physicochemical properties such as lipophilicity and metabolic stability. Bulky activating groups namely methoxy, acetoxy, and benzyloxy groups were introduced as a way to tune steric/electronic effects. Multinuclear NMR, X-ray analysis and DFT optimizations confirmed that despite significant differences in their substitution patterns these curcuminoids all exist as enolic tautomers, and their CUR-BF2 adducts are symmetrical with equal B-O bond distances. To gauge the potential role of the enolic moiety in interaction with proteins, a library consisting of 22 aryl-pyrazole and isoxazole derivatives were synthesized. 19F NMR provided a rapid and convenient assay to monitor these transformations. Computational/docking studies were performed to compare binding efficiency to target proteins involved in specific cancers versus known inhibitor drugs. Several CUR pyrazoles and isoxazoles presented very favorable binding affinities, particularly those bearing CF3 groups. Highly favorable docking affinities were observed for the benzyloxy-substituted CURs. Selected compounds were tested by in-vitro bioassay against a panel of 60 cancer cell lines, and more specifically against leukemia cell lines by cell viability assay.",
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AU - Correa-Smits, Sebastian J.

AU - Zwarycz, Angela T.

AU - Bunge, Scott D.

AU - Borosky, Gabriela L.

AU - Manna, Alak

AU - Paulus, Aneel

AU - Chanan Khan, Asher A

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AB - In a continuing search for “curcuminoid (CUR) inspired” compounds with potential antitumor activity, a series of 21 new CUR-BF2 adducts and CURs bearing fluorine, trifluoromethylthio, trifluoromethoxy, and trifluoromethyl substitutents were synthesized in an effort to improve physicochemical properties such as lipophilicity and metabolic stability. Bulky activating groups namely methoxy, acetoxy, and benzyloxy groups were introduced as a way to tune steric/electronic effects. Multinuclear NMR, X-ray analysis and DFT optimizations confirmed that despite significant differences in their substitution patterns these curcuminoids all exist as enolic tautomers, and their CUR-BF2 adducts are symmetrical with equal B-O bond distances. To gauge the potential role of the enolic moiety in interaction with proteins, a library consisting of 22 aryl-pyrazole and isoxazole derivatives were synthesized. 19F NMR provided a rapid and convenient assay to monitor these transformations. Computational/docking studies were performed to compare binding efficiency to target proteins involved in specific cancers versus known inhibitor drugs. Several CUR pyrazoles and isoxazoles presented very favorable binding affinities, particularly those bearing CF3 groups. Highly favorable docking affinities were observed for the benzyloxy-substituted CURs. Selected compounds were tested by in-vitro bioassay against a panel of 60 cancer cell lines, and more specifically against leukemia cell lines by cell viability assay.

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