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. 2018 Aug 5:156:618-627.
doi: 10.1016/j.ejmech.2018.07.020. Epub 2018 Jul 19.

Identification, structural modification, and dichotomous effects on human immunodeficiency virus type 1 (HIV-1) replication of ingenane esters from Euphorbia kansui

Qingbo Liu  1 , Wei Li  2 , Li Huang  3 , Yoshihisa Asada  4 , Susan L Morris-Natschke  5 , Chin-Ho Chen  6 , Kuo-Hsiung Lee  7 , Kazuo Koike  8
Affiliations

Identification, structural modification, and dichotomous effects on human immunodeficiency virus type 1 (HIV-1) replication of ingenane esters from Euphorbia kansui

Qingbo Liu et al. Eur J Med Chem. .

Abstract

Euphorbia kansui showed potent anti-HIV-1 activity during screening of a library composed of plant extracts from Euphorbiaceae and Thymelaeaceae families. Bioassay-guided isolation led to identification of ingenane esters as the active compounds. Further chemical modification resulted in 3-(2-naphthoyl)ingenol (23), which exhibited the most potent anti-HIV-1 activity. Compound 23 also acted as an HIV-1-latency-reversing agent on activation of HIV-1 replication in a latently infected U1 cell model and a T cell latent HIV-1 model JLat-A2.

Keywords: 3-(2-Naphthoyl)ingenol; Anti-HIV; Euphorbia kansui; Ingenane; Latency-reversing agent.

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Figures

Figure 1.
Figure 1.
Compounds obtained from E. kansui by bioactivity-guided isolation.
Figure 2.
Figure 2.
LC-MS monitoring of preparation of starting materials from E3-fraction of E. kansui extract. (a) TIC spectrum of E3-fraction in positive mode; (b) TIC spectrum of E3-fraction after deacylation in positive mode;(c) SIM chromatogram (m/z 297) of E3-fraction in positive mode; (d) SIM chromatograms (m/z 297) of E3-fraction after deacylation in positive mode; (e) SIM chromatogram (m/z 313) of E3-fraction in positive mode; (f) SIM chromatogram (m/z 313) of E3-fraction after deacylation in positive mode; (g) SIM chromatogram (m/z 329) of E3-fraction in positive mode; (h) SIM chromatogram (m/z 329) of E3-fraction after deacylation in positive mode.
Figure 3.
Figure 3.
Fluorescence-activated cell sorting (FACS) analysis of GFP-expressing J-Lat cells in the presence of the compounds 22 and 23.
Scheme 1.
Scheme 1.
Preparation of starting materials.
Scheme 2.
Scheme 2.
Synthesis of 20-deoxyingenol ester derivatives.a a Reagents and conditions: (i) respective acid, DMAP, EDCI, DMF/DCM, 0 °C→rt, 4-48 h; (ii) respective anhydride, DMAP, pyridine, rt or 40 °C, 24 h.
Scheme 3.
Scheme 3.
Synthesis of ingenol ester derivatives.a a Reagents and conditions: (i) p-TsOH.H2O, acetone, rt, 2 h; (ii) angelic anhydride, CS2CO3, MeCN, rt, 4 h; (iii) 2-naphthoic acid, DMAP, EDCI, DMF/DCM, 0 °C→rt, 4 h; (iv) 2M HCl, MeOH, rt, 4 h
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