Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of Betulin
For several decades, natural products have been widely researched and their native scaffolds are the basis for the design and synthesis of new potential therapeutic agents. Betulin is an interesting biologically attractive natural parent molecule with a high safety profile and can easily undergo a v...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/16/5156 |
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| author | Mirosława Grymel Anna Lalik Alicja Kazek-Kęsik Marietta Szewczyk Patrycja Grabiec Karol Erfurt |
| author_facet | Mirosława Grymel Anna Lalik Alicja Kazek-Kęsik Marietta Szewczyk Patrycja Grabiec Karol Erfurt |
| author_sort | Mirosława Grymel |
| collection | DOAJ |
| description | For several decades, natural products have been widely researched and their native scaffolds are the basis for the design and synthesis of new potential therapeutic agents. Betulin is an interesting biologically attractive natural parent molecule with a high safety profile and can easily undergo a variety of structural modifications. Herein, we describe the synthesis of new molecular hybrids of betulin via covalent linkage with an alkyltriphenylphosphonium moiety. The proposed strategy enables the preparation of semi-synthetic derivatives (28-TPP<sup>⊕</sup> BN and 3,28-<i>bis</i>TPP<sup>⊕</sup> BN) from betulin through simple transformations in high yields. The obtained results showed that the presence of a lipophilic cation improved the solubility of the tested analogs compared to betulin, and increased their cytotoxicity. Among the triphenylphosphonium derivatives tested, analogs <b>7a</b> (IC<sub>50</sub> of 5.56 µM) and <b>7b</b> (IC<sub>50</sub> of 5.77 µM) demonstrated the highest cytotoxicity against the colorectal carcinoma cell line (HCT 116). TPP<sup>⊕</sup>-conjugates with betulin showed antimicrobial properties against Gram-positive reference <i>Staphylococcus aureus ATCC 25923</i> and <i>Staphylococcus epidermidis ATCC 12228</i> bacteria, at a 200 µM concentration in water. Hence, the conjugation of betulin’s parent backbone with a triphenylphosphonium moiety promotes transport through the hydrophobic barriers of the mitochondrial membrane, making it a promising strategy to improve the bioavailability of natural substances. |
| first_indexed | 2024-03-09T04:02:38Z |
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| id | doaj.art-879d5d9d1f134b02a785f3fa942c0c84 |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T04:02:38Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-879d5d9d1f134b02a785f3fa942c0c842023-12-03T14:11:14ZengMDPI AGMolecules1420-30492022-08-012716515610.3390/molecules27165156Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of BetulinMirosława Grymel0Anna Lalik1Alicja Kazek-Kęsik2Marietta Szewczyk3Patrycja Grabiec4Karol Erfurt5Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, PolandBiotechnology Center, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, PolandDepartment of Inorganic, Analytical Chemistry and Electrochemistry, Silesian University of Technology, B. Krzywoustego 6, 44-100 Gliwice, PolandDepartment of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, PolandDepartment of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, PolandDepartment of Chemical Organic Technology and Petrochemistry, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, PolandFor several decades, natural products have been widely researched and their native scaffolds are the basis for the design and synthesis of new potential therapeutic agents. Betulin is an interesting biologically attractive natural parent molecule with a high safety profile and can easily undergo a variety of structural modifications. Herein, we describe the synthesis of new molecular hybrids of betulin via covalent linkage with an alkyltriphenylphosphonium moiety. The proposed strategy enables the preparation of semi-synthetic derivatives (28-TPP<sup>⊕</sup> BN and 3,28-<i>bis</i>TPP<sup>⊕</sup> BN) from betulin through simple transformations in high yields. The obtained results showed that the presence of a lipophilic cation improved the solubility of the tested analogs compared to betulin, and increased their cytotoxicity. Among the triphenylphosphonium derivatives tested, analogs <b>7a</b> (IC<sub>50</sub> of 5.56 µM) and <b>7b</b> (IC<sub>50</sub> of 5.77 µM) demonstrated the highest cytotoxicity against the colorectal carcinoma cell line (HCT 116). TPP<sup>⊕</sup>-conjugates with betulin showed antimicrobial properties against Gram-positive reference <i>Staphylococcus aureus ATCC 25923</i> and <i>Staphylococcus epidermidis ATCC 12228</i> bacteria, at a 200 µM concentration in water. Hence, the conjugation of betulin’s parent backbone with a triphenylphosphonium moiety promotes transport through the hydrophobic barriers of the mitochondrial membrane, making it a promising strategy to improve the bioavailability of natural substances.https://www.mdpi.com/1420-3049/27/16/5156betulintriphenylphosphonium cationanticancerantibacterial activity |
| spellingShingle | Mirosława Grymel Anna Lalik Alicja Kazek-Kęsik Marietta Szewczyk Patrycja Grabiec Karol Erfurt Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of Betulin Molecules betulin triphenylphosphonium cation anticancer antibacterial activity |
| title | Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of Betulin |
| title_full | Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of Betulin |
| title_fullStr | Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of Betulin |
| title_full_unstemmed | Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of Betulin |
| title_short | Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of Betulin |
| title_sort | design synthesis and preliminary evaluation of the cytotoxicity and antibacterial activity of novel triphenylphosphonium derivatives of betulin |
| topic | betulin triphenylphosphonium cation anticancer antibacterial activity |
| url | https://www.mdpi.com/1420-3049/27/16/5156 |
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