Design, synthesis, and bio-evaluation of novel triterpenoid derivatives as anti-HIV-1 compounds

  • Bioorg Med Chem Lett. 2022 Aug 1;69:128768. doi: 10.1016/j.bmcl.2022.128768.
Reon Takeuchi  1 ,  Kasumi Ogihara  2 ,  Junko Fujimoto  3 ,  Kohei Sato  4 ,  Nobuyuki Mase  5 ,  Kazuhisa Yoshimura  6 ,  Shigeyoshi Harada  7 ,  Tetsuo Narumi  8
Affiliations
  • 1. Graduate School of Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan.
  • 2. Course of Applied Chemistry and Biochemical Engineering, Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan.
  • 3. Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, Shizuoka, Japan.
  • 4. Graduate School of Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan; Course of Applied Chemistry and Biochemical Engineering, Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan; Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, Shizuoka, Japan.
  • 5. Graduate School of Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan; Course of Applied Chemistry and Biochemical Engineering, Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan; Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, Shizuoka, Japan; Research Institute of Green Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan.
  • 6. Institute of Public Health, Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government, 3-24-1 Hyakunin-cho, Shinjuku-ku, Tokyo, Japan; AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, Japan.
  • 7. AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, Japan. Electronic address: [email protected].
  • 8. Graduate School of Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan; Course of Applied Chemistry and Biochemical Engineering, Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan; Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, Shizuoka, Japan; Research Institute of Green Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan. Electronic address: [email protected].
PMID: 35513221 DOI: 10.1016/j.bmcl.2022.128768
Abstract

Two betulinic acid derivatives, RPR103611 (2) and IC9564 (3) were previously reported to be potent HIV-1 entry inhibitors. In this current study, a SAR study of the triterpenoid moiety of 2 and 3 has been performed and an oleanolic acid derivative (4) was identified as a novel HIV-1 entry inhibitor. In addition, the combination of 4 with several-type of HIV-1 neutralizing antibodies provided significant synergistic effects. The synthetic utility of the CC double bond in the C-ring of 4 was also demonstrated to develop the 12-keto-type oleanolic acid derivative (5) as a potent anti-HIV compound. This simple transformation led to a significantly increased anti-HIV activity and a reduced cytotoxicity of the compound.

Keywords
Anti-HIV-1 activity; HIV-1 entry inhibitor; Neutralizing antibodies; SAR study; Triterpenoid.
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