Regioselective and Stereoselective Synthesis of Parthenolide Analogs by Acyl Nitroso-Ene Reaction and Their Biological Evaluation against <i>Mycobacterium tuberculosis</i>
Historically, natural products have played a major role in the development of antibiotics. Their complex chemical structures and high polarity give them advantages in the drug discovery process. In the broad range of natural products, sesquiterpene lactones are interesting compounds because of their...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/24/17395 |
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| author | Bruna Gioia Francesca Ruggieri Alexandre Biela Valérie Landry Pascal Roussel Catherine Piveteau Florence Leroux Ruben C. Hartkoorn Nicolas Willand |
| author_facet | Bruna Gioia Francesca Ruggieri Alexandre Biela Valérie Landry Pascal Roussel Catherine Piveteau Florence Leroux Ruben C. Hartkoorn Nicolas Willand |
| author_sort | Bruna Gioia |
| collection | DOAJ |
| description | Historically, natural products have played a major role in the development of antibiotics. Their complex chemical structures and high polarity give them advantages in the drug discovery process. In the broad range of natural products, sesquiterpene lactones are interesting compounds because of their diverse biological activities, their high-polarity, and sp<sup>3</sup>-carbon-rich chemical structures. Parthenolide (PTL) is a natural compound isolated from <i>Tanacetum parthenium</i>, of the family of germacranolide-type sesquiterpene lactones. In recent years, parthenolide has been studied for its anti-inflammatory, antimigraine, and anticancer properties. Recently, PTL has shown antibacterial activities, especially against Gram-positive bacteria. However, few studies are available on the potential antitubercular activities of parthenolide and its analogs. It has been demonstrated that parthenolide’s biological effects are linked to the reactivity of <i>α</i>-exo-methylene-<i>γ</i>-butyrolactone, which reacts with cysteine in targeted proteins via a Michael addition. In this work, we describe the ene reaction of acylnitroso intermediates with parthenolide leading to the regioselective and stereoselective synthesis of new derivatives and their biological evaluation. The addition of hydroxycarbamates and hydroxyureas led to original analogs with higher polarity and solubility than parthenolide. Through this synthetic route, the Michael acceptor motif was preserved and is thus believed to be involved in the selective activity against <i>Mycobacterium tuberculosis</i>. |
| first_indexed | 2024-03-08T20:41:47Z |
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| id | doaj.art-5a89e68bc6d74619afa0300946749f17 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T20:41:47Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5a89e68bc6d74619afa0300946749f172023-12-22T14:14:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0124241739510.3390/ijms242417395Regioselective and Stereoselective Synthesis of Parthenolide Analogs by Acyl Nitroso-Ene Reaction and Their Biological Evaluation against <i>Mycobacterium tuberculosis</i>Bruna Gioia0Francesca Ruggieri1Alexandre Biela2Valérie Landry3Pascal Roussel4Catherine Piveteau5Florence Leroux6Ruben C. Hartkoorn7Nicolas Willand8Univ. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, F-59000 Lille, FranceUniv. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, F-59000 Lille, FranceUniv. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, F-59000 Lille, FranceUniv. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, F-59000 Lille, FranceUniv. Lille, CNRS, ENSCL, Centrale Lille, Univ. Artois, UMR 8181—UCCS—Unité de Catalyse et de Chimie du Solide, F-59000 Lille, FranceUniv. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, F-59000 Lille, FranceUniv. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, F-59000 Lille, FranceUniv. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019—UMR 8204—CIIL—Center for Infection and Immunity of Lille, F-59000 Lille, FranceUniv. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, F-59000 Lille, FranceHistorically, natural products have played a major role in the development of antibiotics. Their complex chemical structures and high polarity give them advantages in the drug discovery process. In the broad range of natural products, sesquiterpene lactones are interesting compounds because of their diverse biological activities, their high-polarity, and sp<sup>3</sup>-carbon-rich chemical structures. Parthenolide (PTL) is a natural compound isolated from <i>Tanacetum parthenium</i>, of the family of germacranolide-type sesquiterpene lactones. In recent years, parthenolide has been studied for its anti-inflammatory, antimigraine, and anticancer properties. Recently, PTL has shown antibacterial activities, especially against Gram-positive bacteria. However, few studies are available on the potential antitubercular activities of parthenolide and its analogs. It has been demonstrated that parthenolide’s biological effects are linked to the reactivity of <i>α</i>-exo-methylene-<i>γ</i>-butyrolactone, which reacts with cysteine in targeted proteins via a Michael addition. In this work, we describe the ene reaction of acylnitroso intermediates with parthenolide leading to the regioselective and stereoselective synthesis of new derivatives and their biological evaluation. The addition of hydroxycarbamates and hydroxyureas led to original analogs with higher polarity and solubility than parthenolide. Through this synthetic route, the Michael acceptor motif was preserved and is thus believed to be involved in the selective activity against <i>Mycobacterium tuberculosis</i>.https://www.mdpi.com/1422-0067/24/24/17395natural productssemisynthesis<i>Mycobacterium tuberculosis</i> |
| spellingShingle | Bruna Gioia Francesca Ruggieri Alexandre Biela Valérie Landry Pascal Roussel Catherine Piveteau Florence Leroux Ruben C. Hartkoorn Nicolas Willand Regioselective and Stereoselective Synthesis of Parthenolide Analogs by Acyl Nitroso-Ene Reaction and Their Biological Evaluation against <i>Mycobacterium tuberculosis</i> International Journal of Molecular Sciences natural products semisynthesis <i>Mycobacterium tuberculosis</i> |
| title | Regioselective and Stereoselective Synthesis of Parthenolide Analogs by Acyl Nitroso-Ene Reaction and Their Biological Evaluation against <i>Mycobacterium tuberculosis</i> |
| title_full | Regioselective and Stereoselective Synthesis of Parthenolide Analogs by Acyl Nitroso-Ene Reaction and Their Biological Evaluation against <i>Mycobacterium tuberculosis</i> |
| title_fullStr | Regioselective and Stereoselective Synthesis of Parthenolide Analogs by Acyl Nitroso-Ene Reaction and Their Biological Evaluation against <i>Mycobacterium tuberculosis</i> |
| title_full_unstemmed | Regioselective and Stereoselective Synthesis of Parthenolide Analogs by Acyl Nitroso-Ene Reaction and Their Biological Evaluation against <i>Mycobacterium tuberculosis</i> |
| title_short | Regioselective and Stereoselective Synthesis of Parthenolide Analogs by Acyl Nitroso-Ene Reaction and Their Biological Evaluation against <i>Mycobacterium tuberculosis</i> |
| title_sort | regioselective and stereoselective synthesis of parthenolide analogs by acyl nitroso ene reaction and their biological evaluation against i mycobacterium tuberculosis i |
| topic | natural products semisynthesis <i>Mycobacterium tuberculosis</i> |
| url | https://www.mdpi.com/1422-0067/24/24/17395 |
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