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Novel Betulinic Acid-Nucleoside Hybrids with Potent Anti-HIV Activity.

ABSTRACT: Novel betulinic/betulonic acid-nucleoside hybrids were synthesized as possible new anti-HIV agents. Among the synthesized hybrids, two compounds were highly effective against HIV. Compared with AZT and DSB, compounds 10a (IC₅₀ = 0.0078 μM, CC₅₀ = 9.6 μM) and 10b (IC₅₀ = 0.020 μM, CC₅₀ = 23.8 μM) showed more potent or equipotent, respectively, anti-HIV activity but displayed lower cytotoxicity.

SUBMITTER: Wang Q

PROVIDER: S-EPMC7667853 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Novel Betulinic Acid-Nucleoside Hybrids with Potent Anti-HIV Activity.

Wang Qiang Q Li Yujiang Y Zheng Liyun L Huang Xiaowan X Wang Yanli Y Chen Chin-Ho CH Cheng Yung-Yi YY Morris-Natschke Susan L SL Lee Kuo-Hsiung KH

ACS medicinal chemistry letters 20200909 11

Novel betulinic/betulonic acid-nucleoside hybrids were synthesized as possible new anti-HIV agents. Among the synthesized hybrids, two compounds were highly effective against HIV. Compared with AZT and DSB, compounds 10a (IC50 = 0.0078 μM, CC50 = 9.6 μM) and 10b (IC50 = 0.020 μM, CC50 = 23.8 μM) showed more potent or equipotent, respectively, anti-HIV activity but displayed lower cytotoxicity. ...[more]

PMID: 33214842

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Project description:BackgroundPrevention and treatment of chronic inflammatory diseases require effective and low-toxic medicines. Molecular hybridization is an effective strategy to enhance the biological activity of new compounds. Triterpenoid scaffolds are in the focus of attention owing to their anti-inflammatory, antiviral, antiproliferative, and immunomodulatory activities. Heteroprostanoids have different pleiotropic effects in acute and chronic inflammatory processes.ObjectiveThe study aimed to develop structurally new and low toxic anti-inflammatory agents via hybridization of betulinic acid with azaprostanoic acids.MethodsA series of betulinic acid-azaprostanoid hybrids was synthesized. The synthetic pathway included the transformation of betulin via Jones' oxidation into betulonic acid, reductive amination of the latter and coupling obtained by 3β-amino-3-deoxybetulinic acid with the 7- or 13-azaprostanoic acids and their homo analogues. The hybrids 1-9 were investigated in vivo on histamine-, formalin- and concanavalin A-induced mouse paw edema models and two models of pain - the acetic acid-induced abdominal writhing and the hotplate test. The hybrids were in vitro evaluated for cytotoxic activity on cancer (MCF7, U- 87 MG) and non-cancer humane cell lines.ResultsIn the immunogenic inflammation model, the substances showed a pronounced anti-inflammatory effect, which was comparable to that of indomethacin. In the models of the exudative inflammation, none of the compounds displayed a statistically significant effect. The hybrids produced weak or moderate analgesic effects. All the agents revealed low cytotoxicity on human immortalized fibroblasts and cancer cell lines compared with 3β- amino-3-deoxybetulinic acid and doxorubicin.ConclusionThe results indicate that the principal anti-inflammatory effect of hybrids is substantially provided with the triterpenoid scaffold and in some cases with the azaprostanoid scaffold, but the latter makes a significant contribution to reducing the toxicity of hybrids. Hybrid 1 is of interest as a potent low toxic agent against immune-mediated inflammation.

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Novel Betulinic Acid-Nucleoside Hybrids with Potent Anti-HIV Activity.

Publications

Novel Betulinic Acid-Nucleoside Hybrids with Potent Anti-HIV Activity.

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