Design, synthesis and evaluation of antiproliferative activity of fluorinated betulinic acid

[Display omitted] Betulinic acid (BA), a pentacyclic triterpenoid, exhibits broad spectrum antiproliferative activity, but generally with only modest potency. To improve BA’s pharmacological properties, fluorine was introduced as a single atom at C-2, creating two diastereomers, or in a trifluoromet...

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Published in:Bioorganic & medicinal chemistry 2019-07, Vol.27 (13), p.2871-2882
Main Authors: Li, Jizhen, Chang, Ling-Chu, Hsieh, Kan-Yen, Hsu, Pei-Ling, Capuzzi, Stephen J., Zhang, Ying-Chao, Li, Kang-Po, Morris-Natschke, Susan L., Goto, Masuo, Lee, Kuo-Hsiung
Format: Article
Language:English
Subjects:
Antiproliferative activity
Betulinic acid
Fluorine introduction
Topoisomerase
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Summary:[Display omitted] Betulinic acid (BA), a pentacyclic triterpenoid, exhibits broad spectrum antiproliferative activity, but generally with only modest potency. To improve BA’s pharmacological properties, fluorine was introduced as a single atom at C-2, creating two diastereomers, or in a trifluoromethyl group at C-3. We evaluated the impact of these groups on antiproliferative activity against five human tumor cell lines. A racemic 2-F-BA (compound 6) showed significantly improved antiproliferative activity, while each diastereomer exhibited similar effects. We also demonstrated that 2-F-BA is a topoisomerase (Topo) I and IIα dual inhibitor in cell-based and cell-free assays. A hypothetical mode of binding to the Topo I-DNA suggested a difference between the hydrogen bonding of BA and 2-F-BA to DNA, which may account for the difference in bioactivity against Topo I.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2019.05.016