Synthesis, Anticancer, and Antibacterial Activity of Betulinic and Betulonic Acid C-28-Triphenylphosphonium Conjugates with Variable Alkyl Linker Length
| Autor: | O. V. Tsepaeva, Andrey V. Nemtarev, Vladimir F. Mironov, Leysan R Grigor Eva, Timur I. Abdullin, Taliya I. Salikhova, Svetlana A Khozyainova |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Antineoplastic Agents Apoptosis Conjugated system Gram-Positive Bacteria 01 natural sciences Antioxidants Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Cytosol Halogens Organophosphorus Compounds 0302 clinical medicine Superoxides Betulinic acid Alkanes Humans MTT assay Oleanolic Acid Betulinic Acid Cytotoxicity Alkyl Fluorescent Dyes Pharmacology chemistry.chemical_classification Molecular Structure 010405 organic chemistry Chemistry Esters Fluoresceins Combinatorial chemistry Triterpenes Anti-Bacterial Agents Mitochondria 0104 chemical sciences Drug Design 030220 oncology & carcinogenesis PC-3 Cells Molecular Medicine Pentacyclic Triterpenes Antibacterial activity Linker Conjugate |
| Zdroj: | Anti-Cancer Agents in Medicinal Chemistry. 20:286-300 |
| ISSN: | 1871-5206 |
| DOI: | 10.2174/1871520619666191014153554 |
| Popis: | 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 are discussed. Based on the results, 6a can be selected for further preclinical investigation as a potential anticancer compound. |
| Databáze: | OpenAIRE |
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