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Names | |
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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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Identifiers | |
3D model (
JSmol)
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ChEMBL | |
ChemSpider | |
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]
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.
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]
![]() | |
Names | |
---|---|
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
| |
Identifiers | |
3D model (
JSmol)
|
|
ChEMBL | |
ChemSpider | |
PubChem
CID
|
|
CompTox Dashboard (
EPA)
|
|
| |
| |
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).
|
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]
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.
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]