Chlorotonil A
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| IUPAC name
(1S,2R,3Z,5E,7S,10S,14R,15R,16S,20S)-12,12-dichloro-2,7,10,16,18-pentamethyl-8-oxatricyclo[12.8.0.015,20]docosa-3,5,17,21-tetraene-9,11,13-trione
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3D model (JSmol)
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| ChEMBL | |
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PubChem CID
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CompTox Dashboard (EPA)
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| Properties | |
| C26H32Cl2O4 | |
| Molar mass | 479.436 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Chlorotonil A is a polyketide natural product produced by the myxobacterium Sorangium cellulosum So ce1525.[2] It displays antimalarial activity in an animal model,[3] and has in vitro antibacterial and antifungal activity.[citation needed] The activity of chlorotonil A has been attributed to the gem-dichloro-1,3-dione moiety, which is a unique functionality in polyketides. In addition to its unique halogenation, the structure of chlorotonil A has also garnered interest due to its similarity to anthracimycin, a polyketide natural product with antibiotic activity against Gram-positive bacteria. Recently, structure-optimization resulted in semi-synthetic derivatives ChB1-Epo2 and Dehalogenil, molecules with significantly improved physicochemical properties.[4][5]
Biosynthesis
[edit]Chlorotonil A is synthesized from a type I modular polyketide synthase (PKS). This gene cluster does not have any acyltransferase (AT) domains, indicating that it is a trans-AT PKS; in these systems, there is a tandem-AT domain that loads the extender subunits onto the acyl carrier protein (ACP) and checks the intermediates, rather than individual AT domains in each module. The gene cluster of chlorotonil A is organized so that the initiator, acetyl-CoA, is loaded onto the tandem-AT domain, then is iteratively elongated with malonyl-CoA units to construct the macrolactone backbone. At modules 3 and 7, a double bond shift occurs in the elongation module to allow for the β,γ-unsaturation and α-methylation. There is a spontaneous, non-enzymatic intramolecular Diels-Alder-like [4+2] cycloaddition at module 8 to furnish the decalin motif.
PKS architecture of chlorotonil A. Squares represent the enzymatic domains: KS, ketosynthase; DH, dehydratase; ACP, acyl carrier protein; KR, keto reductase; MT, methyl transferase; ER, enoyl reductase; TE, thioesterase. Inactive domains are shaded in grey.
Following macrolactonization by the thioesterase domain of module 10, the premature chlorotonil A core is chlorinated twice by CtoA, a flavin-dependent halogenase. The halogenated core is then methylated by the standalone SAM-dependent methyltransferase CtoF to yield chlorotonil A.[6]
Halogenation and methylation of the post-PKS macrolactonized core of chlorotonil A
References
[edit]- ^ "Chlorotonil A | Chemical Substance Information | J-GLOBAL". jglobal.jst.go.jp.
- ^ Gerth, Klaus; Steinmetz, Heinrich; Höfle, Gerhard; Jansen, Rolf (2008). "Chlorotonil A, a Macrolide with a Unique gem-Dichloro-1,3-dione Functionality from Sorangium cellulosum, So ce1525". Angewandte Chemie International Edition. 47 (3): 600–602. doi:10.1002/anie.200703993. hdl:10033/23152. PMID 18058875.
- ^ Held, Jana; Gebru, Tamirat; Kalesse, Markus; Jansen, Rolf; Gerth, Klaus; Müller, Rolf; Mordmüller, Benjamin (2014). "Antimalarial Activity of the Myxobacterial Macrolide Chlorotonil A". Antimicrobial Agents and Chemotherapy. 58 (11): 6378–6384. doi:10.1128/AAC.03326-14. PMC 4249382. PMID 25114138.
- ^ Hofer, Walter; Oueis, Emilia; Fayad, Antoine Abou; Deschner, Felix; Andreas, Anastasia; de Carvalho, Laìs Pessanha; Hüttel, Stephan; Bernecker, Steffen; Pätzold, Linda; Morgenstern, Bernd; Zaburannyi, Nestor; Bischoff, Markus; Stadler, Marc; Held, Jana; Herrmann, Jennifer; Müller, Rolf (25 July 2022). "Regio‐ and Stereoselective Epoxidation and Acidic Epoxide Opening of Antibacterial and Antiplasmodial Chlorotonils Yield Highly Potent Derivatives". Angewandte Chemie International Edition. 61 (30). doi:10.1002/ANIE.202202816. PMC 9400904.
- ^ Hofer, Walter; Deschner, Felix; Jézéquel, Gwenaëlle; Pessanha de Carvalho, Laìs; Abdel‐Wadood, Noran; Pätzold, Linda; Bernecker, Steffen; Morgenstern, Bernd; Kany, Andreas M.; Große, Miriam; Stadler, Marc; Bischoff, Markus; Hirsch, Anna K. H.; Held, Jana; Herrmann, Jennifer; Müller, Rolf (6 May 2024). "Functionalization of Chlorotonils: Dehalogenil as Promising Lead Compound for In Vivo Application". Angewandte Chemie International Edition. 63 (19). doi:10.1002/ANIE.202319765.
- ^ Jungmann, Katrin; Jansen, Rolf; Gerth, Klaus; Huch, Volker; Krug, Daniel; Fenical, William; Müller, Rolf (2015). "Two of a Kind— The Biosynthetic Pathways of Chlorotonil and Anthracimycin". ACS Chemical Biology. 10 (11): 2480–2490. doi:10.1021/acschembio.5b00523. PMID 26348978.