Enzymatic Synthesis of New Acetoacetate–Ursodeoxycholic Acid Hybrids as Potential Therapeutic Agents and Useful Synthetic Scaffolds as Well
Ursodeoxycholic acid (UDCA) and acetoacetate are natural compounds present in the human intestine and blood, respectively. A number of studies highlighted that besides their well-known primary biological roles, both compounds possess the ability to influence a variety of cellular processes involved...
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MDPI AG
2024-03-01
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| Online Access: | https://www.mdpi.com/1420-3049/29/6/1305 |
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| author | Valentina Venturi Elena Marchesi Daniela Perrone Valentina Costa Martina Catani Simona Aprile Lindomar Alberto Lerin Federico Zappaterra Pier Paolo Giovannini Lorenzo Preti |
| author_facet | Valentina Venturi Elena Marchesi Daniela Perrone Valentina Costa Martina Catani Simona Aprile Lindomar Alberto Lerin Federico Zappaterra Pier Paolo Giovannini Lorenzo Preti |
| author_sort | Valentina Venturi |
| collection | DOAJ |
| description | Ursodeoxycholic acid (UDCA) and acetoacetate are natural compounds present in the human intestine and blood, respectively. A number of studies highlighted that besides their well-known primary biological roles, both compounds possess the ability to influence a variety of cellular processes involved in the etiology of various diseases. These reasons suggested the potential of acetoacetate–UDCA hybrids as possible therapeutic agents and prompted us to develop a synthetic strategy to selectively derivatize the hydroxyl groups of the bile acid with acetoacetyl moieties. 3α-acetoacetoxy UDCA was obtained (60% isolated yield) via the regioselective transesterification of methyl acetoacetate with UDCA promoted by the <i>Candida antarctica</i> lipase B (CAL-B). 3α,7β-bis-acetoacetoxy UDCA was obtained instead by thermal condensation of methyl acetoacetate and UDCA (80% isolated yield). This bis-adduct was finally converted to the 7β-acetoacetoxy UDCA (82% isolated yield) via CAL-B catalyzed regioselective alcoholysis of the ester group on the 3α position. In order to demonstrate the value of the above new hybrids as UDCA-based scaffolds, 3α-acetoacetoxy UDCA was subjected to multicomponent Biginelli reaction with benzaldehyde and urea to obtain the corresponding 4-phenyl-3,4-dihydropyrimidin-2-(<i>1H</i>)-one derivative in 65% isolated yield. |
| first_indexed | 2024-04-24T17:58:50Z |
| format | Article |
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| language | English |
| last_indexed | 2024-04-24T17:58:50Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-eca37f5df30646c3b896a276b4314dc92024-03-27T13:57:00ZengMDPI AGMolecules1420-30492024-03-01296130510.3390/molecules29061305Enzymatic Synthesis of New Acetoacetate–Ursodeoxycholic Acid Hybrids as Potential Therapeutic Agents and Useful Synthetic Scaffolds as WellValentina Venturi0Elena Marchesi1Daniela Perrone2Valentina Costa3Martina Catani4Simona Aprile5Lindomar Alberto Lerin6Federico Zappaterra7Pier Paolo Giovannini8Lorenzo Preti9Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Chemical Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Chemical Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Chemical Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Chemical Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Chemical Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Chemical Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, ItalyUrsodeoxycholic acid (UDCA) and acetoacetate are natural compounds present in the human intestine and blood, respectively. A number of studies highlighted that besides their well-known primary biological roles, both compounds possess the ability to influence a variety of cellular processes involved in the etiology of various diseases. These reasons suggested the potential of acetoacetate–UDCA hybrids as possible therapeutic agents and prompted us to develop a synthetic strategy to selectively derivatize the hydroxyl groups of the bile acid with acetoacetyl moieties. 3α-acetoacetoxy UDCA was obtained (60% isolated yield) via the regioselective transesterification of methyl acetoacetate with UDCA promoted by the <i>Candida antarctica</i> lipase B (CAL-B). 3α,7β-bis-acetoacetoxy UDCA was obtained instead by thermal condensation of methyl acetoacetate and UDCA (80% isolated yield). This bis-adduct was finally converted to the 7β-acetoacetoxy UDCA (82% isolated yield) via CAL-B catalyzed regioselective alcoholysis of the ester group on the 3α position. In order to demonstrate the value of the above new hybrids as UDCA-based scaffolds, 3α-acetoacetoxy UDCA was subjected to multicomponent Biginelli reaction with benzaldehyde and urea to obtain the corresponding 4-phenyl-3,4-dihydropyrimidin-2-(<i>1H</i>)-one derivative in 65% isolated yield.https://www.mdpi.com/1420-3049/29/6/1305biocatalysisursodeoxycholic acidketone bodiesacetoacetatelipasehybrid compounds |
| spellingShingle | Valentina Venturi Elena Marchesi Daniela Perrone Valentina Costa Martina Catani Simona Aprile Lindomar Alberto Lerin Federico Zappaterra Pier Paolo Giovannini Lorenzo Preti Enzymatic Synthesis of New Acetoacetate–Ursodeoxycholic Acid Hybrids as Potential Therapeutic Agents and Useful Synthetic Scaffolds as Well Molecules biocatalysis ursodeoxycholic acid ketone bodies acetoacetate lipase hybrid compounds |
| title | Enzymatic Synthesis of New Acetoacetate–Ursodeoxycholic Acid Hybrids as Potential Therapeutic Agents and Useful Synthetic Scaffolds as Well |
| title_full | Enzymatic Synthesis of New Acetoacetate–Ursodeoxycholic Acid Hybrids as Potential Therapeutic Agents and Useful Synthetic Scaffolds as Well |
| title_fullStr | Enzymatic Synthesis of New Acetoacetate–Ursodeoxycholic Acid Hybrids as Potential Therapeutic Agents and Useful Synthetic Scaffolds as Well |
| title_full_unstemmed | Enzymatic Synthesis of New Acetoacetate–Ursodeoxycholic Acid Hybrids as Potential Therapeutic Agents and Useful Synthetic Scaffolds as Well |
| title_short | Enzymatic Synthesis of New Acetoacetate–Ursodeoxycholic Acid Hybrids as Potential Therapeutic Agents and Useful Synthetic Scaffolds as Well |
| title_sort | enzymatic synthesis of new acetoacetate ursodeoxycholic acid hybrids as potential therapeutic agents and useful synthetic scaffolds as well |
| topic | biocatalysis ursodeoxycholic acid ketone bodies acetoacetate lipase hybrid compounds |
| url | https://www.mdpi.com/1420-3049/29/6/1305 |
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