2. Academic Validation
  3. Design, synthesis and evaluation of antiproliferative activity of fluorinated betulinic acid

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

  • Bioorg Med Chem. 2019 Jul 1;27(13):2871-2882. doi: 10.1016/j.bmc.2019.05.016.
Jizhen Li 1,  Ling-Chu Chang 2,  Kan-Yen Hsieh 3,  Pei-Ling Hsu 3,  Stephen J Capuzzi 2,  Ying-Chao Zhang 4,  Kang-Po Li 3,  Susan L Morris-Natschke 3,  Masuo Goto 5,  Kuo-Hsiung Lee 6
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, College of Chemistry, Jilin University, 2519 Jiefang Road, Changchun 130023, China; Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States. Electronic address: ljz@jlu.edu.cn.
  • 2 Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
  • 3 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
  • 4 Department of Organic Chemistry, College of Chemistry, Jilin University, 2519 Jiefang Road, Changchun 130023, China.
  • 5 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States. Electronic address: goto@med.unc.edu.
  • 6 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: khlee@unc.edu.
PMID: 31126820 DOI: 10.1016/j.bmc.2019.05.016
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 (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.

Keywords

Antiproliferative activity; Betulinic acid; Fluorine introduction; Topoisomerase.

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