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

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

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

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Abstract:

Background: Conjugation of triterpenoids such as betulinic acid 1 with 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 mitochondria-targeted 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 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. 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 oxidation of 2′,7′-dichlorofluorescin probe in cytosol, 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 are 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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(E-pub Ahead of Print)
DOI: 10.2174/1871520619666191014153554
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