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

Reon Takeuchi; Kasumi Ogihara; Junko Fujimoto; Kohei Sato; Nobuyuki Mase; Kazuhisa Yoshimura; Shigeyoshi Harada; Tetsuo Narumi

doi:10.1016/j.bmcl.2022.128768

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. Epub 2022 May 2.

Authors

Reon Takeuchi¹, Kasumi Ogihara², Junko Fujimoto³, Kohei Sato⁴, Nobuyuki Mase⁵, Kazuhisa Yoshimura⁶, Shigeyoshi Harada⁷, Tetsuo Narumi⁸

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: shigeh@nih.go.jp.
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: narumi.tetsuo@shizuoka.ac.jp.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents*
HIV Fusion Inhibitors* / pharmacology
HIV-1*
Oleanolic Acid* / pharmacology
Triterpenes* / chemistry

Substances

Anti-HIV Agents
HIV Fusion Inhibitors
Triterpenes
Oleanolic Acid