Design, synthesis and evaluation of antiproliferative activity of fluorinated betulinic acid. Issue 13 (1st July 2019)

• Record Type: Journal Article
• 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
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 13(2019)
• Page Start: 2871
• Page End: 2882
• Publication Date: 2019-07-01
• Subjects: BA betulinic acid -- CPT camptothecin -- MDR multidrug-resistant -- SAR structure-activity relationship -- TNBC triple-negative breast cancer -- Topo topoisomerase; Betulinic acid -- Fluorine introduction -- Topoisomerase -- Antiproliferative activity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.05.016
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 (compound6 ) 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.