Synthesis and anti-HIV activities of phorbol derivatives

  • Chin J Nat Med. 2024 Feb;22(2):146-160. doi: 10.1016/S1875-5364(24)60587-X.
Xiaolei Huang  1 ,  Chengrun Tang  2 ,  Xusheng Huang  3 ,  Yun Yang  1 ,  Qirun Li  1 ,  Mengdi Ma  2 ,  Lei Zhao  1 ,  Liumeng Yang  2 ,  Yadong Cui  1 ,  Zhenqing Zhang  4 ,  Yongtang Zheng  5 ,  Jian Zhang  6
Affiliations
  • 1. College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
  • 2. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
  • 3. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China.
  • 4. College of Pharmaceutical Science, Soochow University, Suzhou 215123, China. Electronic address: [email protected].
  • 5. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China. Electronic address: [email protected].
  • 6. College of Pharmaceutical Science, Soochow University, Suzhou 215123, China. Electronic address: [email protected].
PMID: 38342567 DOI: 10.1016/S1875-5364(24)60587-X
Abstract

In this study, 37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated, building upon our previous synthesis of 51 phorbol derivatives. 12-Para-electron-acceptor-trans-cinnamoyl-13-decanoyl phorbol derivatives stood out, demonstrating remarkable anti-HIV-1 activities and inhibitory effects on syncytia formation. These derivatives exhibited a higher safety index compared with the positive control drug. Among them, 12-(trans-4-fluorocinnamoyl)-13-decanoyl phorbol, designated as compound 3c, exhibited the most potent anti-HIV-1 activity (EC50 2.9 nmol·L-1, CC50/EC50 11 117.24) and significantly inhibited the formation of syncytium (EC50 7.0 nmol·L-1, CC50/EC50 4891.43). Moreover, compound 3c is hypothesized to act both as an HIV-1 entry inhibitor and as an HIV-1 Reverse Transcriptase Inhibitor. Isothermal titration calorimetry and molecular docking studies indicated that compound 3c may also function as a natural activator of protein kinase C (PKC). Therefore, compound 3c emerges as a potential candidate for developing new anti-HIV drugs.

Keywords
12-(Trans-4-fluorocinnamoyl)-13-decanoyl phorbol; Anti-HIV-1 activity; HIV-1 entry inhibitor; HIV-1 reverse transcriptase inhibitor; PKC activator; Phorbol esters; Safety index; Syncytia formation.
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