Synthesis, Anticancer, and Antibacterial Activity of Betulinic and Betulonic Acid C-28-Triphenylphosphonium Conjugates with Variable Alkyl Linker Length

Author(s): Olga V. Tsepaeva, Andrey V. Nemtarev*, Taliya I. Salikhova, Timur I. Abdullin, Leysan R. Grigor`eva, Svetlana A. Khozyainova, Vladimir F. Mironov

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 3 , 2020


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Graphical Abstract:


Abstract:

Background: Conjugation of triterpenoids such as betulinic acid 1 with the Triphenylphosphonium (TPP) group is a powerful approach to generating medicinal compounds. Their development proposes structure optimization in respect of availability and activity towards target cells and organelles. Selection of 1 or its precursor betulonic acid 2 and the optimal linker is of particular importance for drug candidate identification among the TPP-triterpenoid conjugates.

Objective: In this study, new C-28-TPP conjugated derivatives of 1 and 2 with the alkyl/alkoxyalkyl linkers of variable length were synthesized and compared regarding their anticancer, antibacterial, and mitochondriatargeted effects.

Methods: The TPP conjugates of 1 and 2 [6a-f, 7a-f] were synthesized by the reaction of halogenalkyl esters [3a-f, 4a-f, 5] with triphenylphosphine in acetonitrile upon heating. Cytotoxicity (MTT assay), antibacterial activity (microdilution assay), and mitochondrial effects (flow cytofluorometry) were studied.

Results: Conjugation with the TPP group greatly increased the cytotoxicity of the triterpenoids up to 30 times. The conjugates were up to 10-17 times more active against MCF-7 (IC50 = 0.17μM, 72h, 6c) and PC-3 (IC50 = 0.14μM, 72h, 6a) cancer cells than for human skin fibroblasts. The enhanced antibacterial (bactericidal) activity of the TPP-triterpenoid conjugates with MIC for Gram-positive bacteria as low as 2μM (6a, 7a) was for the first time revealed. The conjugates were found to effectively inhibit fluorescence of 2′,7′-dichlorofluorescin probe in the cytosol upon oxidation, decrease transmembrane potential, and increase superoxide radical level in mitochondria.

Conclusion: Relationships between the effects and structure of the TPP-triterpenoid conjugates were evaluated and discussed. Based on the results, 6a can be selected for further preclinical investigation as a potential anticancer compound.

Keywords: Betulinic acid, betulonic acid, triphenylphosphonium derivatives, anticancer activity, antibacterial activity.

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VOLUME: 20
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Year: 2020
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DOI: 10.2174/1871520619666191014153554
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