Bisintercalator natural products with potential therapeutic applications: isolation, structure determination, synthetic and biological studies

Dawson, Simon J.; Malkinson, John P.; Paumier, David; Searcey, Mark

doi:10.1039/b516347c

Cited by 90 publications

(77 citation statements)

References 130 publications

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“…Reflecting these distinct affinities, quinomycin antibiotics show different inhibitory activities against various enzymes, such as DNA polymerase, RNA polymerase, reverse transcriptase and topoisomerase. 5 Although thiocoraline has promising antitumor activity, most members of this family of compounds are toxic to mammalian cells. 5 To improve the profiles between antitumor activity and toxicity, we studied the biosynthetic pathway of 1 and synthesizing its derivatives by genetic engineering.…”

Section: Introductionmentioning

confidence: 99%

“…5 Although thiocoraline has promising antitumor activity, most members of this family of compounds are toxic to mammalian cells. 5 To improve the profiles between antitumor activity and toxicity, we studied the biosynthetic pathway of 1 and synthesizing its derivatives by genetic engineering. Recently, we have achieved de novo production of 1 using E. coli as a heterologous host.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics

et al. 2010

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Quinomycin antibiotics, represented by echinomycin, are an important class of antitumor antibiotics. We have recently succeeded in identification of biosynthetic gene clusters of echinomycin and SW-163D, and have achieved heterologous production of echinomycin in Escherichia coil. In addition, we have engineered echinomycin nonribosomal peptide synthetase (NRPS) to generate echinomycin derivatives. However, the biosynthetic pathways of intercalative chromophores quinoxaline-2-carboxylic acid (QXC) and 3-hydroxyquinaldic acid (HQA), which are important for biological activity, were not fully elucidated. Here, we report experiments involving incorporation of a putative advanced precursor, (2S, 3R)-[6'-2H]-3-hydroxy-L-kynurenine, and functional analysis of the enzymes Swb1 and Swb2 responsible for late-stage biosynthesis of HQA. Based on these experimental results, we propose biosynthetic pathways for both QXC and HQA via the common intermediate 3-hydroxy-L-kynurenine

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics

et al. 2010

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“…The first target was des-N-tetramethyl triostin A (2b) or TANDEM, which bis-intercalates into DNA and exhibits a distinct preference for AT sequences in contrast to echinomycin displaying a different DNA preference for GC-rich sequences. 4 In order to produce 2b in E. coli, we hypothesize the need to 1) inactivate the two methylation (M) domains of the 340-kDa bimodular NRPS Ecm7, responsible for the N-methylation of the cysteine and the valine residues in the core peptide backbone, and 2) omitting Ecm18, responsible for forming the thioacetal-bridge. 5 To this end, we had to redesign the echinomycin biosynthetic pathway into a TAN-DEM biosynthetic pathway.…”

Section: Synthesis Of Echinomycin Derivatives By Inactivation Of Specmentioning

confidence: 99%

“…4 This class of antibiotics are dimeric cyclic peptides with a pair of chromophores and have potent DNA binding affinities at a level between nM to M with different sequence selectivities. Reflecting these distinct affinities, bis-intercalator antibiotics such as 1-4 show fairly different inhibitory activities against various enzymes such as DNA polymerase, RNA polymerase, reverse transcriptase and topoisomerase.…”

Section: Enzymatic Synthesis Of Echinomycin and Its Derivativesmentioning

confidence: 99%

Enzymatic Synthesis of Molecular Skeletons of Complex Antitumor Antibiotics with Non-ribosomal Peptide Synthetases

Watanabe

Oguri

Oikawa

2009

J. Synth. Org. Chem. Jpn.

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Nonribosomal peptide synthetase (NRPS) is a programmable modular machinery which produces a number of biologically active small-molecule peptides. Recent progress on understanding the catalytic mechanism of NRPS enabled us to engineer this complex catalytic system. We demonstrated both in vivo and in vitro enzymatic synthesis of complex natural antitumor peptides echinomycin and saframycin. An Escherichia coli-based expression system served as a flexible yet robust platform for producing complex natural products and their analogs by deletion, mutation and swapping of a specific subunit. The excised thioesterase domain of echinomycin exhibited remarkable substrate tolerance and created a cyclic peptide library. On the other hand, saframycin NRPS catalyzed highly unusual seven-step transformations to construct a pentacyclic tetrahydro-isoquinoline skeleton. According to the generally accepted mechanism (colinearity rule), 3 NRPS produces polypeptides different in size and amino acid-sequence with various modifications. An important strategy that this enzyme adopts is that condensation substrates are always bound to the enzyme (T) and that the chain-elongated intermediates are never released from NRPS until the final cleavage. Therefore, this system guarantees reliable and safe delivery of the substrates. This allows rather broad substrate specificity of the C-domain. Each module is a self-consistent portable component. This suggests that replacing A-domain or a specific module may create new peptides in a programmable manner. Hence, the rational design of NRPS makes it possible to synthesize novel peptides just in the same way as organic synthesis. In this account, we describe an enzymatic synthesis of two important families of antitumor peptide antibiotics, echinomycin and saframycin. Enzymatic Synthesis of Echinomycin and its DerivativesEchinomycin (1) belongs to quinomycin bis-intercalator antibiotics (Figure 2). 4 This class of antibiotics are dimeric cyclic peptides with a pair of chromophores and have potent DNA binding affinities at a level between nM to M with different sequence selectivities. Reflecting these distinct affinities, bis-intercalator antibiotics such as 1-4 show fairly different inhibitory activities against various enzymes such as DNA polymerase, RNA polymerase, reverse transcriptase and topoisomerase. Based on structure-activity relationships among this class of antibiotics, one can expect that minute structural difference may drastically change profiles between antitumor activity and toxicity. To examine this possibility, we became interested in synthesizing echinomycin derivatives.To identify and isolate the echinomycin biosynthetic gene cluster, a cosmid library was constructed using S. lasaliensis total DNA. Screening with the PCR product from degenerate primers for NRPS afforded plasmids encoding the 36-kb echinomycin biosynthetic gene clusters. 5 Homology of these genes enabled us to speculate their functions in the biosynthesis of quinoxaline-2-carboxylic acid (5, QXC) and ...

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“…[27] Several studies of synthetic variants have shown that the composition of the depsipeptide linker has a profound effect on the sequence selectivity of the bisintercalators. [34] A family of nine cysteine (Cys)-containing quinoline tripeptides (Fig. 4b) was oxidized to form a library of 45 unique disulfide dimers.…”

Section: Reaction Conditions and Analysismentioning

confidence: 99%

Targeting Nucleic Acids using Dynamic Combinatorial Chemistry

Durai

Harding

2011

Aust. J. Chem.

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Dynamic combinatorial chemistry (DCC) is a powerful method for the identification of novel ligands for the molecular recognition of receptor molecules. The method relies on self-assembly processes to generate libraries of compounds under reversible conditions, allowing a receptor molecule to select the optimal binding ligand from the mixture. However, while DCC is now an established field of chemistry, there are limited examples of the application of DCC to nucleic acids. The requirement to conduct experiments under physiologically relevant conditions, and avoid reaction with, or denaturation of, the target nucleic acid secondary structure, limits the choice of the reversible chemistry, and presents restrictions on the building block design. This review will summarize recent examples of applications of DCC to the recognition of nucleic acids. Studies with duplex DNA, quadruplex DNA, and RNA have utilized mainly thiol disulfide libraries, although applications of imine libraries, in combination with metal coordination, have been reported. The use of thiol disulfide libraries produces lead compounds with limited biostability, and hence design of stable analogues or mimics is required for many applications.

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Bisintercalator natural products with potential therapeutic applications: isolation, structure determination, synthetic and biological studies

Cited by 90 publications

References 130 publications

Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics

Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics

Enzymatic Synthesis of Molecular Skeletons of Complex Antitumor Antibiotics with Non-ribosomal Peptide Synthetases

Targeting Nucleic Acids using Dynamic Combinatorial Chemistry

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