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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.