Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues
Aurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D thro...
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| Format: | Article |
| Language: | English |
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Beilstein-Institut
2013-07-01
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| Series: | Beilstein Journal of Organic Chemistry |
| Subjects: | |
| Online Access: | https://doi.org/10.3762/bjoc.9.176 |
| _version_ | 1818640088671715328 |
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| author | Xu-Wen Li Jennifer Herrmann Yi Zang Philippe Grellier Soizic Prado Rolf Müller Bastien Nay |
| author_facet | Xu-Wen Li Jennifer Herrmann Yi Zang Philippe Grellier Soizic Prado Rolf Müller Bastien Nay |
| author_sort | Xu-Wen Li |
| collection | DOAJ |
| description | Aurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad–Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure–activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization. |
| first_indexed | 2024-12-16T23:05:43Z |
| format | Article |
| id | doaj.art-11a323cd02fc4188892d42304d2b85a6 |
| institution | Directory Open Access Journal |
| issn | 1860-5397 |
| language | English |
| last_indexed | 2024-12-16T23:05:43Z |
| publishDate | 2013-07-01 |
| publisher | Beilstein-Institut |
| record_format | Article |
| series | Beilstein Journal of Organic Chemistry |
| spelling | doaj.art-11a323cd02fc4188892d42304d2b85a62022-12-21T22:12:34ZengBeilstein-InstitutBeilstein Journal of Organic Chemistry1860-53972013-07-01911551155810.3762/bjoc.9.1761860-5397-9-176Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analoguesXu-Wen Li0Jennifer Herrmann1Yi Zang2Philippe Grellier3Soizic Prado4Rolf Müller5Bastien Nay6Muséum National d’Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, FranceDepartment of Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Pharmaceutical Biotechnology, Saarland University, Campus C2 3, 66123 Saarbrücken, GermanyMuséum National d’Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, FranceMuséum National d’Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, FranceMuséum National d’Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, FranceDepartment of Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Pharmaceutical Biotechnology, Saarland University, Campus C2 3, 66123 Saarbrücken, GermanyMuséum National d’Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, FranceAurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad–Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure–activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization.https://doi.org/10.3762/bjoc.9.176antiplasmodial activitiesConrad–Limpach reactionmitochondrial membrane potentialnatural productsquinolonestotal synthesis |
| spellingShingle | Xu-Wen Li Jennifer Herrmann Yi Zang Philippe Grellier Soizic Prado Rolf Müller Bastien Nay Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues Beilstein Journal of Organic Chemistry antiplasmodial activities Conrad–Limpach reaction mitochondrial membrane potential natural products quinolones total synthesis |
| title | Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues |
| title_full | Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues |
| title_fullStr | Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues |
| title_full_unstemmed | Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues |
| title_short | Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues |
| title_sort | synthesis and biological activities of the respiratory chain inhibitor aurachin d and new ring versus chain analogues |
| topic | antiplasmodial activities Conrad–Limpach reaction mitochondrial membrane potential natural products quinolones total synthesis |
| url | https://doi.org/10.3762/bjoc.9.176 |
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