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Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues.
Li, Xu-Wen Herrmann, Jennifer Zang, Yi Grellier, Philippe Prado, Soizic Müller, Rolf Nay, Bastien
Li, Xu-Wen
Herrmann, Jennifer
Zang, Yi
Grellier, Philippe
Prado, Soizic
Müller, Rolf
Nay, Bastien
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Abstract
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.
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Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues. 2013, 9:1551-8 Beilstein J Org Chem
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en
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1860-5397
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Archived with thanks to Beilstein journal of organic chemistry