Precursor-directed generation of amidine containing ammosamide analogs: ammosamides E–P

Pan, Ende; Oswald, Nathaniel W.; Legako, Aaron G.; Life, Janie M.; Posner, Bruce A.; MacMillan, John B.

doi:10.1039/c2sc21442c

Cited by 73 publications

(56 citation statements)

References 32 publications

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“…In this work, we demonstrated the facile non-enzymatic incorporation of several substituted anthranilic acids to explore rubrolone chemical space. Similar non-enzymatic condensations between carbonyl and amine functional groups are well known in natural products biosynthesis and have afforded discoipyrroles 38 , ammosamides 39 , elansolids 40 and jadomycins 41 42 . Non-enzymatic Diels–Alder reactions have been widely observed en route to natural products such as paracaseolide A (ref.…”

Section: Discussionmentioning

confidence: 76%

Non-enzymatic pyridine ring formation in the biosynthesis of the rubrolone tropolone alkaloids

Yan

Yang

et al. 2016

Nat Commun

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The pyridine ring is a potent pharmacophore in alkaloid natural products. Nonetheless, its biosynthetic pathways are poorly understood. Rubrolones A and B are tropolone alkaloid natural products possessing a unique tetra-substituted pyridine moiety. Here, we report the gene cluster and propose a biosynthetic pathway for rubrolones, identifying a key intermediate that accumulates upon inactivation of sugar biosynthetic genes. Critically, this intermediate was converted to the aglycones of rubrolones by non-enzymatic condensation and cyclization with either ammonia or anthranilic acid to generate the respective pyridine rings. We propose that this non-enzymatic reaction occurs via hydrolysis of the key intermediate, which possesses a 1,5-dione moiety as an amine acceptor capable of cyclization. This study suggests that 1,5-dione moieties may represent a general strategy for pyridine ring biosynthesis, and more broadly highlights the utility of non-enzymatic diversification for exploring and expanding natural product chemical space.

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Section: Discussionmentioning

confidence: 76%

Non-enzymatic pyridine ring formation in the biosynthesis of the rubrolone tropolone alkaloids

Yan

Yang

et al. 2016

Nat Commun

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“…Previous work by MacMillan and co-workers showing that a wide range of amidine derivatives of the ammosamides can be generated from ammosamide C supports our observation. (Pan et al, 2013)…”

Section: Resultsmentioning

confidence: 99%

Biosynthetic Pathway Connects Cryptic Ribosomally Synthesized Posttranslationally Modified Peptide Genes with Pyrroloquinoline Alkaloids

Jordan

Moore

2016

Cell Chemical Biology

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Summary In an era where natural product biosynthetic gene clusters can be rapidly identified from sequenced genomes, it is unusual for the biosynthesis of an entire natural product class to remain unknown. Yet, the genetic determinates for pyrroloquinoline alkaloid biosynthesis have remained obscure despite their abundance and deceptive structural simplicity. In this work, we have identified the biosynthetic gene cluster for the ammosamides A-C, pyrroloquinoline alkaloids from Streptomyces sp. CNR-698. Through direct cloning, heterologous expression and gene deletions we have validated the ammosamide biosynthetic gene cluster and demonstrated that these seemingly simple molecules are derived from a surprisingly complex set of biosynthetic genes that are also found in the biosynthesis of lymphostin, a structurally related pyrroloquinoline alkaloid from Salinispora and Streptomyces. Our results implicate a conserved set of genes driving pyrroloquinoline biosynthesis, which consist of genes frequently associated with ribosomal peptide natural product biosynthesis, and whose exact biochemical role remains enigmatic.

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“…Examples include the jadomycins, [1] elansolids, [2] oxazinin A, [3] ammosamides [4] and discoipyrroles. [5] For many of these families of natural products listed above, it has been possible to harness the non-enzymatic chemistry by feeding alternative precursors into the fermentation media and carrying out structure-activity relationship studies.…”

mentioning

confidence: 99%

Discovery, Characterization, and Analogue Synthesis of Bohemamine Dimers Generated by Non‐enzymatic Biosynthesis

Legako

et al. 2016

Chemistry A European J

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Dibohemamines A–C (5–7), three novel dimeric bohemamine analogs dimerized through a methylene group, were isolated from a marine-derived Streptomyces spinoverrucosus. The structures determined by spectroscopic analysis were confirmed through the semi-synthetic derivatization of monomeric bohemamines and formaldehyde. These reactions, which could occur under mild conditions, together with the detection of formaldehyde in the culture, revealed that this dimerization is a non-enzymatic process. In addition to the unique dimerization of the dibohemamines, dibohemamines B and C were found to have nM cytotoxicity against the non-small cell lung cancer cell line A549. In view of the potent cytotoxicity of compounds 6 and 7, a small library of bohemamine analogs w as generated for biological evaluation by utilizing a series of aryl and alkyl aldehydes.

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Precursor-directed generation of amidine containing ammosamide analogs: ammosamides E–P

Cited by 73 publications

References 32 publications

Non-enzymatic pyridine ring formation in the biosynthesis of the rubrolone tropolone alkaloids

Non-enzymatic pyridine ring formation in the biosynthesis of the rubrolone tropolone alkaloids

Biosynthetic Pathway Connects Cryptic Ribosomally Synthesized Posttranslationally Modified Peptide Genes with Pyrroloquinoline Alkaloids

Discovery, Characterization, and Analogue Synthesis of Bohemamine Dimers Generated by Non‐enzymatic Biosynthesis

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