2. Academic Validation
  3. Discovery and synthesis of novel beesioside I derivatives with potent anti-HIV activity

Discovery and synthesis of novel beesioside I derivatives with potent anti-HIV activity

  • Eur J Med Chem. 2019 Mar 15:166:159-166. doi: 10.1016/j.ejmech.2019.01.020.
Haifeng Wu 1,  Guoxu Ma 1,  Qinwen Yang 1,  Yindi Zhu 2,  Li Huang 3,  Yu Tian 1,  Xiaoming Yang 4,  Menghan Zhang 4,  Chin-Ho Chen 3,  Susan L Morris-Natschke 4,  Meihua Yang 1,  Xudong Xu 5,  Kuo-Hsiung Lee 6
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription, Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, PR China.
  • 2 School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, PR China.
  • 3 Surgical Oncology Research Facility, Duke University Medical Center, Durham, NC, 27710, USA.
  • 4 Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 5 Beijing Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription, Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, PR China. Electronic address: xdxu@implad.ac.cn.
  • 6 Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung 404, Taiwan. Electronic address: khlee@unc.edu.
PMID: 30703659 DOI: 10.1016/j.ejmech.2019.01.020
Abstract

In this study, 12 known cycloartane triterpenoids (1-12) with four different skeletons isolated from the roots of Souliea vaginata were screened for the first time for in vitro anti-HIV activity using AZT as a standard. Among the compounds, beesioside I (1) showed the highest potency against HIV-1NL4-3 with an EC50 value of 2.32 μM (CC50 > 40 μM). Preliminary structure-activity relationship (SAR) studies on 1 indicated that simple modification of its aglycone (13) could significantly influence the Antiviral activity. Particularly, the introduction of an acyl group at the C-3 position of 13 led to significant improvement in both anti-HIV potency and selectivity index. Among all synthetically modified derivatives, compound 13g was the most potent compound with an EC50 value of 0.025 μM and TI value greater than 800, comparable to those of 3-O-(3',3'-dimethylsuccinyl)-betulinic acid (DSB, bevirimat). Other analogues exhibited strong to weak inhibition of HIV-1 replication in MT-4 cells. The length, carboxylic terminus, and C-3' dimethyl substitution of the C-3 side chain substantially affected the anti-HIV activity. Finally, compound 13g was an effective agent against HIV with high potential for further investigation.

Keywords

Anti-HIV; Cycloartane triterpenoids; Structure and activity relationship; Structure modification.

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