2. Academic Validation
  3. Synthesis and anti-HIV activities of phorbol derivatives

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

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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