Expedient total synthesis of pyrrothine natural products and analogs

Hjelmgaard, Thomas; Givskov, Michael; Nielsen, John

doi:10.1039/b616411k

Cited by 27 publications

(39 citation statements)

References 26 publications

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“…The proposed amine donor for TmlU-mediated amide coupling, holothin, could be readily accessed via total synthesis in five steps with 13% overall yield. [13] The 7-carbon fatty acyl monic acid, marinolic acid ( 8 ), was not readily available. The 8-carbon fatty acyl monic acid, pseudomonic acid A (PAA), which is commercially available (Sigma), was used instead.…”

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confidence: 99%

Enzymatic Basis of “Hybridity” in Thiomarinol Biosynthesis

et al. 2015

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Thiomarinol is a naturally occurring double-headed antibiotic that is highly potent against methicillin-resistant Staphylococcus aureus. Its structure comprises two antimicrobial sub-components, marinolic acid and holothin, linked by an amide bond. TmlU was thought to be the sole enzyme responsible for this amide bond formation. Contrary to this idea, we show that TmlU acts as a CoA ligase that activates marinolic acid as its thioester before it is processed by the acetyltransferase HolE to catalyze the amidation. TmlU prefers complex acyl acids as substrates, whereas HolE is relatively promiscuous, accepting a range of acyl-CoA and amine substrates. Our results provide detailed biochemical information on thiomarinol biosynthesis, and evolutionary insight regarding how the marinolic acid and holothin pathways converge to generate this potent hybrid antibiotic. This work also demonstrates the potential of TmlU/HolE enzymes as engineering tools to generate new “hybrid” molecules.

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confidence: 99%

Enzymatic Basis of “Hybridity” in Thiomarinol Biosynthesis

et al. 2015

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“…Nielsen and co-workers replaced the tert -butyl protecting groups used in the Ciba-Geigy synthesis with para -methoxybenzyl groups and, similarly, employed para -methoxybenzylamine in the pyrrolone formation reaction to yield substrates that could be fully deprotected in refluxing trifluoroacetic acid (Scheme 6b). 79 The latter deprotection has the benefits of installing the disulfide and trifluoro-acetylating the exo-cyclic amine, which protecting group can be further removed under milder conditions than standard acetate to allow variation of the acyl chain substituents…”

Section: Total Synthesis Of Naturally Occurring Dithiolopyrrolones mentioning

confidence: 99%

Dithiolopyrrolones: biosynthesis, synthesis, and activity of a unique class of disulfide-containing antibiotics

et al. 2014

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Dithiolopyrrolone (DTP) group antibiotics were first isolated in the early half of the 20th century, but only recently has research been reawakened by insights gained from the synthesis and biosynthesis of this structurally intriguing class of molecules. DTPs are characterized by an electronically unique bicyclic structure, which contains a compact disulfide bridge between two ene-thiols. Points of diversity within the compound class occur outside of the bicyclic core, at the two amide nitrogens. Such modifications distinguish three of the most well studied members of the class, holomycin, thiolutin, and aureothricin; the DTP core has also more recently been identified in the marine antibiotic thiomarinol, in which it is linked to a marinolic acid moiety, analog of the FDA-approved topical antibiotic Bactroban® (GlaxoSmithKline). Dithiolopyrrolones exhibit relatively broad-spectrum antibiotic activity against many Gram-positive and Gram-negative bacteria, as well as strains of Mycobacterium tuberculosis. Additionally, they have been shown to exhibit potent and selective anti-cancer activity. Despite this promising profile, there is still much unknown about the mechanisms of action for DTPs. Early reports suggested that they inhibit yeast growth at the level of transcription and that this effect is largely responsible for their distinctive microbial static properties; a similar mechanism is supported in bacteria. Elucidation of biosynthetic pathways for holomycin in Streptomyces clavuligerus and Yersinia ruckeri and thiomarinol in Alteromonas rava sp. nov. SANK 73390, have contributed evidence suggesting that multiple mechanisms may be operative in the activity of these compounds. This review will comprehensively cover the history and development of dithiolopyrrolones with particular emphasis on the biosynthesis, synthesis, biological activity and mechanism of action.

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“…By choosing appropriately the stoichiometric ratio between 1,3-dichloroacetone and the nucleophile, it is possible to obtain the substitution of both chlorine atoms. 9,10 Cl Cl …”

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confidence: 99%