Functionalization of Betulinic Acid with Polyphenolic Fragments for the Development of New Amphiphilic Antioxidants
The present work aimed at the valorization of biomass derived compounds by their transformation into new added-value compounds with enhanced antioxidant properties. In this context, betulinic acid (BA) was decorated with polyphenolic fragments, and polyhydroxylated (<i>E</i>)-2-benzylide...
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| Format: | Article |
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MDPI AG
2021-01-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/2/148 |
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| author | Joana L. C. Sousa Cristiana Gonçalves Ricardo M. Ferreira Susana M. Cardoso Carmen S. R. Freire Armando J. D. Silvestre Artur M. S. Silva |
| author_facet | Joana L. C. Sousa Cristiana Gonçalves Ricardo M. Ferreira Susana M. Cardoso Carmen S. R. Freire Armando J. D. Silvestre Artur M. S. Silva |
| author_sort | Joana L. C. Sousa |
| collection | DOAJ |
| description | The present work aimed at the valorization of biomass derived compounds by their transformation into new added-value compounds with enhanced antioxidant properties. In this context, betulinic acid (BA) was decorated with polyphenolic fragments, and polyhydroxylated (<i>E</i>)-2-benzylidene-19,28-epoxyoleanane-3,28-diones <b>4a</b>–<b>d</b> were obtained. For that, the synthetic strategy relied on base-promoted aldol condensation reactions of methyl betulonate, which was previously prepared from natural BA, with appropriate benzaldehydes, followed by cleavage of the methyl protecting groups with BBr<sub>3</sub>. It is noteworthy that the HBr release during the work-up of the cleavage reactions led to the rearrangement of the lupane-type skeleton of the expected betulonic acid derivatives into oleanane-type compounds <b>4a</b>–<b>d</b>. The synthesized compounds <b>4a</b>–<b>d</b> were designed to have specific substitution patterns at C-2 of the triterpene scaffold, allowing the establishment of a structure-activity relationship. The radical scavenging ability of <b>4a</b>–<b>d</b> was evaluated using the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH<sup>•</sup>) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical cation (ABTS<sup>•+</sup>) scavenging assays. In particular, derivative <b>4c</b>, bearing a catechol unit, revealed to be the most efficient scavenger against both free radicals DPPH<sup>•</sup> and ABTS<sup>•+</sup>. Subsequently, we designed two analogues of the hit derivative <b>4c</b> in order to achieve more potent antioxidant agents: (i) the first analogue carries an additional unsaturation in its lateral chain at C-2 (analogue <b>5</b>) and (ii) in the second analogue, E-ring was kept in its open form (analogue <b>6</b>). It was observed that the presence of an extended π-conjugated system at C-2 contributed to an increased scavenging effect, since analogue <b>5</b> was more active than <b>6</b>, α-tocopherol, and <b>4c</b> in the ABTS<sup>•+</sup> assay. |
| first_indexed | 2024-03-09T04:10:23Z |
| format | Article |
| id | doaj.art-1fec0189b3134914aade130d6f0331cb |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T04:10:23Z |
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| series | Antioxidants |
| spelling | doaj.art-1fec0189b3134914aade130d6f0331cb2023-12-03T14:00:06ZengMDPI AGAntioxidants2076-39212021-01-0110214810.3390/antiox10020148Functionalization of Betulinic Acid with Polyphenolic Fragments for the Development of New Amphiphilic AntioxidantsJoana L. C. Sousa0Cristiana Gonçalves1Ricardo M. Ferreira2Susana M. Cardoso3Carmen S. R. Freire4Armando J. D. Silvestre5Artur M. S. Silva6LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, PortugalLAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, PortugalLAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, PortugalLAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, PortugalDepartment of Chemistry, CICECO–Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, PortugalDepartment of Chemistry, CICECO–Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, PortugalLAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, PortugalThe present work aimed at the valorization of biomass derived compounds by their transformation into new added-value compounds with enhanced antioxidant properties. In this context, betulinic acid (BA) was decorated with polyphenolic fragments, and polyhydroxylated (<i>E</i>)-2-benzylidene-19,28-epoxyoleanane-3,28-diones <b>4a</b>–<b>d</b> were obtained. For that, the synthetic strategy relied on base-promoted aldol condensation reactions of methyl betulonate, which was previously prepared from natural BA, with appropriate benzaldehydes, followed by cleavage of the methyl protecting groups with BBr<sub>3</sub>. It is noteworthy that the HBr release during the work-up of the cleavage reactions led to the rearrangement of the lupane-type skeleton of the expected betulonic acid derivatives into oleanane-type compounds <b>4a</b>–<b>d</b>. The synthesized compounds <b>4a</b>–<b>d</b> were designed to have specific substitution patterns at C-2 of the triterpene scaffold, allowing the establishment of a structure-activity relationship. The radical scavenging ability of <b>4a</b>–<b>d</b> was evaluated using the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH<sup>•</sup>) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical cation (ABTS<sup>•+</sup>) scavenging assays. In particular, derivative <b>4c</b>, bearing a catechol unit, revealed to be the most efficient scavenger against both free radicals DPPH<sup>•</sup> and ABTS<sup>•+</sup>. Subsequently, we designed two analogues of the hit derivative <b>4c</b> in order to achieve more potent antioxidant agents: (i) the first analogue carries an additional unsaturation in its lateral chain at C-2 (analogue <b>5</b>) and (ii) in the second analogue, E-ring was kept in its open form (analogue <b>6</b>). It was observed that the presence of an extended π-conjugated system at C-2 contributed to an increased scavenging effect, since analogue <b>5</b> was more active than <b>6</b>, α-tocopherol, and <b>4c</b> in the ABTS<sup>•+</sup> assay.https://www.mdpi.com/2076-3921/10/2/148betulinic acidoleanane-type compoundspolyhydroxylated compoundsamphiphilic antioxidantsradical scavenging activityantioxidant activity |
| spellingShingle | Joana L. C. Sousa Cristiana Gonçalves Ricardo M. Ferreira Susana M. Cardoso Carmen S. R. Freire Armando J. D. Silvestre Artur M. S. Silva Functionalization of Betulinic Acid with Polyphenolic Fragments for the Development of New Amphiphilic Antioxidants Antioxidants betulinic acid oleanane-type compounds polyhydroxylated compounds amphiphilic antioxidants radical scavenging activity antioxidant activity |
| title | Functionalization of Betulinic Acid with Polyphenolic Fragments for the Development of New Amphiphilic Antioxidants |
| title_full | Functionalization of Betulinic Acid with Polyphenolic Fragments for the Development of New Amphiphilic Antioxidants |
| title_fullStr | Functionalization of Betulinic Acid with Polyphenolic Fragments for the Development of New Amphiphilic Antioxidants |
| title_full_unstemmed | Functionalization of Betulinic Acid with Polyphenolic Fragments for the Development of New Amphiphilic Antioxidants |
| title_short | Functionalization of Betulinic Acid with Polyphenolic Fragments for the Development of New Amphiphilic Antioxidants |
| title_sort | functionalization of betulinic acid with polyphenolic fragments for the development of new amphiphilic antioxidants |
| topic | betulinic acid oleanane-type compounds polyhydroxylated compounds amphiphilic antioxidants radical scavenging activity antioxidant activity |
| url | https://www.mdpi.com/2076-3921/10/2/148 |
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