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 and Vladimir F. Mironov   Pages 286 - 300 ( 15 )

Abstract:

<P>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. </P><P> 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. </P><P> 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. </P><P> 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. </P><P> 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.</P>

Keywords:

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

Affiliation:

Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov Str., 420088 Kazan, Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov Str., 420088 Kazan, Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlevskaya Str., 420008 Kazan, Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlevskaya Str., 420008 Kazan, Alexander Butlerov Institute of Chemistry, Kazan (Volga Region) Federal University, 18 Kremlevskaya Str., 420008 Kazan, Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlevskaya Str., 420008 Kazan, Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov Str., 420088 Kazan

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